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Global burden of brain disorders surpasses cardiovascular disease and cancer
– at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.
“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.
“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”
Other factors related to brain disorders, she noted, include education level, obesity, and smoking.
“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.
The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
An ‘ambitious exercise’
Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”
A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.
They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
Increase in dementia, mental health conditions
The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”
The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.
Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.
Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.
Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.
To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).
This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.
The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.
This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.
The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.
“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
Worrying increase in stroke
Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.
“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”
Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”
“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.
The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
– at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.
“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.
“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”
Other factors related to brain disorders, she noted, include education level, obesity, and smoking.
“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.
The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
An ‘ambitious exercise’
Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”
A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.
They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
Increase in dementia, mental health conditions
The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”
The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.
Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.
Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.
Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.
To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).
This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.
The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.
This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.
The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.
“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
Worrying increase in stroke
Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.
“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”
Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”
“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.
The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
– at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.
“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.
“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”
Other factors related to brain disorders, she noted, include education level, obesity, and smoking.
“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.
The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
An ‘ambitious exercise’
Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”
A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.
They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
Increase in dementia, mental health conditions
The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”
The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.
Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.
Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.
Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.
To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).
This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.
The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.
This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.
The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.
“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
Worrying increase in stroke
Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.
“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”
Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”
“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.
The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New consensus on biomarkers for diagnosis of neurocognitive disorders
A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.
Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.
The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
Which biomarker?
Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.
A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”
“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.
“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”
He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.
“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.
“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”
Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”
For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
Harmonizing clinical practice
In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.
They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.
A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.
The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.
When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.
When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.
Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”
Dr. Frisoni noted that the consensus document has a number of limitations.
“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”
He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.
The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.
“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.
“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”
In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.
This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
Pros and cons
Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.
On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.
He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.
On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”
From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”
He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.
Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.
The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”
Achieving uniformity will require a pan-regional collaboration, he noted.
The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.
Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.
The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
Which biomarker?
Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.
A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”
“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.
“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”
He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.
“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.
“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”
Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”
For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
Harmonizing clinical practice
In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.
They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.
A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.
The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.
When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.
When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.
Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”
Dr. Frisoni noted that the consensus document has a number of limitations.
“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”
He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.
The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.
“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.
“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”
In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.
This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
Pros and cons
Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.
On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.
He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.
On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”
From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”
He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.
Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.
The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”
Achieving uniformity will require a pan-regional collaboration, he noted.
The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.
Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.
The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
Which biomarker?
Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.
A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”
“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.
“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”
He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.
“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.
“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”
Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”
For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
Harmonizing clinical practice
In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.
They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.
A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.
The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.
When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.
When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.
Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”
Dr. Frisoni noted that the consensus document has a number of limitations.
“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”
He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.
The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.
“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.
“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”
In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.
This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
Pros and cons
Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.
On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.
He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.
On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”
From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”
He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.
Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.
The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”
Achieving uniformity will require a pan-regional collaboration, he noted.
The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Huge underuse of germline testing for cancer patients
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Gilteritinib maintenance reduces relapse in MRD+ AML
The research was presented at the European Hematology Association Hybrid Congress 2023.
For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.
The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.
However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.
While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”
“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”
Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.
He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”
Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.
“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”
He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”
Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.
He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.
As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.
He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”
This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”
Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”
He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”
“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.
Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”
He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”
“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”
Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.
The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”
They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.
Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.
Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.
He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.
MRD positivity, assessed at a cell count of ≥ 10-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.
The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.
He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”
The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.
Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).
However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”
He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10-6. “In our study, 98% of participants had samples pre- and post-[transplant].”
Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).
When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.
Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).
Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.
He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.
“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.
Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”
In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.
The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
The research was presented at the European Hematology Association Hybrid Congress 2023.
For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.
The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.
However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.
While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”
“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”
Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.
He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”
Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.
“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”
He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”
Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.
He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.
As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.
He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”
This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”
Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”
He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”
“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.
Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”
He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”
“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”
Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.
The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”
They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.
Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.
Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.
He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.
MRD positivity, assessed at a cell count of ≥ 10-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.
The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.
He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”
The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.
Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).
However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”
He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10-6. “In our study, 98% of participants had samples pre- and post-[transplant].”
Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).
When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.
Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).
Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.
He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.
“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.
Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”
In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.
The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
The research was presented at the European Hematology Association Hybrid Congress 2023.
For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.
The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.
However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.
While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”
“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”
Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.
He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”
Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.
“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”
He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”
Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.
He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.
As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.
He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”
This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”
Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”
He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”
“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.
Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”
He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”
“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”
Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.
The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”
They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.
Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.
Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.
He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.
MRD positivity, assessed at a cell count of ≥ 10-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.
The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.
He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”
The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.
Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).
However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”
He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10-6. “In our study, 98% of participants had samples pre- and post-[transplant].”
Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).
When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.
Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).
Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.
He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.
“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.
Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”
In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.
The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
AT EHA 2023
CLL: Venetoclax-obinutuzumab combo effective long term
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
FROM EHA 2023
‘Professional grief’ is a daily reality for oncologists
– but when it is also accompanied by a sense of emotional isolation, it can lead to reduced well-being and burnout.
The issue was discussed at a special session at the annual meeting of the American Society of Clinical Oncology, and several speakers offered solutions.
Laurie Jean Lyckholm, MD, professor, Hematology/Oncology, West Virginia University School of Medicine, Morgantown, polled the audience to ask how they deal with patient-related loss and grief.
The responses showed that 44.4% said they talk with their colleagues, 16.7% said they talk about it with family and friends, but 22.2% said that they simply move on to the next patient.
Dr. Lyckholm noted that there are positive and negative ways of dealing with grief.
One example of a positive way comes from an oncologist who attended one of her talks and shared with her how his practice deals with the issue.
“At the end of every fourth Friday, he closes his community practice office early and all the oncologists, everyone, stays for a while, and they have a list of the people who have died,” Dr. Lyckholm explained. As a group, they go through the list and reminisce about the patients who died, recalling funny incidents or things that person had said.
“I love this idea,” she said. “The most important thing is to commemorate that person.”
Amplified during pandemic
Like many other issues, the problem of how to deal with “professional grief” was amplified during the COVID-19 pandemic. Many people were unable to see their dying relatives because of the restricted access to sealed-off, dedicated COVID-19 units. One oncologist who had developed a friendly relationship with a patient while treating them for cancer over several years was unable to visit the patient once they were ill with the disease and was left to communicate via an iPad. “It was the only way I could say ‘goodbye’ before she died. ... It still haunts me today, 2 years later,” the clinician recalled.
This anecdote illustrates “disenfranchised grief,” which occurs when an individual experiences a “significant loss and the resultant grief is not openly acknowledged, socially validated, or publicly mourned,” Dr. Lyckholm explained.
If this goes unrecognized, it can lead to shame, guilt, and organizational mistrust, resulting in reduced well-being and clinician burnout, she warned.
The pandemic also had an impact on clinicians directly. Dr. Lyckholm quoted one nurse practitioner who talked about coming back to a new “lonely normal” when returning to a Veterans Affairs hospital.
“I am still getting used to calling colleagues, and paging colleagues, and realizing that they just aren’t there,” the nurse practitioner said. “They aren’t there because they either left or died. I just didn’t expect that.”
Dr. Lyckholm said, “I don’t think we can ever stop acknowledging COVID, because it just had such a terrible impact on all of us.”
Teamwork intervention
The next speaker also polled the audience. Christopher Ryan Friese, PhD, RN, AOCN, Elizabeth Tone Hosmer Professor of Nursing, University of Michigan, Ann Arbor, asked the audience what strategy they would prioritize to reduce burnout, from the perspective of the entire cancer care team.
The response indicated that many (43.6%) would like to see team-based grief and bereavement sessions, while 31.1% thought it best to tackle low-value administrative work.
Dr. Friese drew on a teamwork intervention that researchers at the Dana-Farber Cancer Institute, Boston, with support from the National Cancer Institute, implemented to help identify opportunities to improve cancer care delivery services.
It began with a focus group of nurses who were invited to identify practice pain points, then six 2-hour sessions with all members of the clinical team to identify and develop service expectations and commitments across the various roles.
After these sessions, the researchers saw a decrease in missing orders from 30% to 2%, while patient satisfaction increased from 93% to 97% as a result. Interestingly, there was also a reported rise in efficiency, practice quality and safety, and respectful professional behaviors.
The pilot was then rolled out across the whole institution, and Dr. Friese and colleagues also implemented a version of the program at their community medical oncology practice.
They had a huge response from patients and clinicians alike (with participation rates of 90% and 78%, respectively), and the survey results led to changes in workflow and the standardization of communications.
Importantly for Dr. Friese, the clinicians who took part wanted to repeat the survey to evaluate any practice changes, which was not part of the study protocol and had not been envisaged by the researchers.
So they developed a survey for clinicians, using as an inspiration the Choosing Wisely campaign by the American Board of Internal Medicine Foundation to identify the best treatments to improve patient outcomes and those to deprioritize.
They used the survey on 373 clinicians at the University of Michigan Health System and found that “the number one thing was getting rid of the administrative work” – that it doesn’t have to be done specifically by physicians or other providers and that other people can do it.
The second was time-consuming electronic health record tasks.
Both of these have since been the focus of an elimination and reduction process to give clinicians more time to do what matters most to them and their patients.
“We have the opportunity to do this in a different way,” Dr. Friese said, “and I think it’s a really powerful opportunity.”
“We can retrofit the solution, which is the pizza parties, and the yoga apps, and the T-shirts ... [or] we could actually redesign the work that we’re asking clinicians to do on a daily basis,” he commented.
“We could make the work easier to do so that you have more time with patients and less time with administrative work and have more time to process grief or to celebrate successes,” he concluded.
Tackling burnout
The final speaker, Vicki A. Jackson, MD, MPH, chief of palliative care, Massachusetts General Hospital, emphasized that the recognition of grief by a cancer care provider is “imperative” for physician well-being and pointed out that that interventions to help “do exist,” including ASCO’s SafeHaven collection of physician well-being resources.
Oncology inherently carries with it “threats” to well-being, including uncertainty and doubt, isolation, fears over one’s usefulness, exhaustion, the witnessing of suffering, and moral distress, she noted.
Things that are necessary for well-being, in contrast, include a sense of connection and community, having boundaries between work and personal life, self-awareness, compassion, and empowerment, among others.
Dr. Jackson believes that in the current era community building within oncology must be “intentional” and not just based around “water cooler moments,” as the sense of isolation experienced by clinicians is “not fluff; this is critical.”
Initiatives such as virtual happy hours and game nights may be helpful, she suggested.
A colleague of hers likes to send out the dad joke of the day, “which made everybody groan, but let me tell you, it changed the affective tone before they started seeing all these really hard, sad patients.”
Setting boundaries, which was the topic of another session at ASCO 2023, is also an important way to address the “emotionally powerful” work of oncology, Dr. Jackson commented.
She underlined the need to channel or be “fully present when you are in the room” but emphasized the need to detach at the end of the day, commenting that “when you leave, you leave.”
No funding was declared. Dr. Friese reported relationships with Merck, NCCN/Pfizer, National Cancer Institute, Patient-Centered Outcomes Research Institute, and the Simms/Mann Foundation. No other speakers reported relevant financial relationships.
A version of this article first appeared on Medscape.com.
– but when it is also accompanied by a sense of emotional isolation, it can lead to reduced well-being and burnout.
The issue was discussed at a special session at the annual meeting of the American Society of Clinical Oncology, and several speakers offered solutions.
Laurie Jean Lyckholm, MD, professor, Hematology/Oncology, West Virginia University School of Medicine, Morgantown, polled the audience to ask how they deal with patient-related loss and grief.
The responses showed that 44.4% said they talk with their colleagues, 16.7% said they talk about it with family and friends, but 22.2% said that they simply move on to the next patient.
Dr. Lyckholm noted that there are positive and negative ways of dealing with grief.
One example of a positive way comes from an oncologist who attended one of her talks and shared with her how his practice deals with the issue.
“At the end of every fourth Friday, he closes his community practice office early and all the oncologists, everyone, stays for a while, and they have a list of the people who have died,” Dr. Lyckholm explained. As a group, they go through the list and reminisce about the patients who died, recalling funny incidents or things that person had said.
“I love this idea,” she said. “The most important thing is to commemorate that person.”
Amplified during pandemic
Like many other issues, the problem of how to deal with “professional grief” was amplified during the COVID-19 pandemic. Many people were unable to see their dying relatives because of the restricted access to sealed-off, dedicated COVID-19 units. One oncologist who had developed a friendly relationship with a patient while treating them for cancer over several years was unable to visit the patient once they were ill with the disease and was left to communicate via an iPad. “It was the only way I could say ‘goodbye’ before she died. ... It still haunts me today, 2 years later,” the clinician recalled.
This anecdote illustrates “disenfranchised grief,” which occurs when an individual experiences a “significant loss and the resultant grief is not openly acknowledged, socially validated, or publicly mourned,” Dr. Lyckholm explained.
If this goes unrecognized, it can lead to shame, guilt, and organizational mistrust, resulting in reduced well-being and clinician burnout, she warned.
The pandemic also had an impact on clinicians directly. Dr. Lyckholm quoted one nurse practitioner who talked about coming back to a new “lonely normal” when returning to a Veterans Affairs hospital.
“I am still getting used to calling colleagues, and paging colleagues, and realizing that they just aren’t there,” the nurse practitioner said. “They aren’t there because they either left or died. I just didn’t expect that.”
Dr. Lyckholm said, “I don’t think we can ever stop acknowledging COVID, because it just had such a terrible impact on all of us.”
Teamwork intervention
The next speaker also polled the audience. Christopher Ryan Friese, PhD, RN, AOCN, Elizabeth Tone Hosmer Professor of Nursing, University of Michigan, Ann Arbor, asked the audience what strategy they would prioritize to reduce burnout, from the perspective of the entire cancer care team.
The response indicated that many (43.6%) would like to see team-based grief and bereavement sessions, while 31.1% thought it best to tackle low-value administrative work.
Dr. Friese drew on a teamwork intervention that researchers at the Dana-Farber Cancer Institute, Boston, with support from the National Cancer Institute, implemented to help identify opportunities to improve cancer care delivery services.
It began with a focus group of nurses who were invited to identify practice pain points, then six 2-hour sessions with all members of the clinical team to identify and develop service expectations and commitments across the various roles.
After these sessions, the researchers saw a decrease in missing orders from 30% to 2%, while patient satisfaction increased from 93% to 97% as a result. Interestingly, there was also a reported rise in efficiency, practice quality and safety, and respectful professional behaviors.
The pilot was then rolled out across the whole institution, and Dr. Friese and colleagues also implemented a version of the program at their community medical oncology practice.
They had a huge response from patients and clinicians alike (with participation rates of 90% and 78%, respectively), and the survey results led to changes in workflow and the standardization of communications.
Importantly for Dr. Friese, the clinicians who took part wanted to repeat the survey to evaluate any practice changes, which was not part of the study protocol and had not been envisaged by the researchers.
So they developed a survey for clinicians, using as an inspiration the Choosing Wisely campaign by the American Board of Internal Medicine Foundation to identify the best treatments to improve patient outcomes and those to deprioritize.
They used the survey on 373 clinicians at the University of Michigan Health System and found that “the number one thing was getting rid of the administrative work” – that it doesn’t have to be done specifically by physicians or other providers and that other people can do it.
The second was time-consuming electronic health record tasks.
Both of these have since been the focus of an elimination and reduction process to give clinicians more time to do what matters most to them and their patients.
“We have the opportunity to do this in a different way,” Dr. Friese said, “and I think it’s a really powerful opportunity.”
“We can retrofit the solution, which is the pizza parties, and the yoga apps, and the T-shirts ... [or] we could actually redesign the work that we’re asking clinicians to do on a daily basis,” he commented.
“We could make the work easier to do so that you have more time with patients and less time with administrative work and have more time to process grief or to celebrate successes,” he concluded.
Tackling burnout
The final speaker, Vicki A. Jackson, MD, MPH, chief of palliative care, Massachusetts General Hospital, emphasized that the recognition of grief by a cancer care provider is “imperative” for physician well-being and pointed out that that interventions to help “do exist,” including ASCO’s SafeHaven collection of physician well-being resources.
Oncology inherently carries with it “threats” to well-being, including uncertainty and doubt, isolation, fears over one’s usefulness, exhaustion, the witnessing of suffering, and moral distress, she noted.
Things that are necessary for well-being, in contrast, include a sense of connection and community, having boundaries between work and personal life, self-awareness, compassion, and empowerment, among others.
Dr. Jackson believes that in the current era community building within oncology must be “intentional” and not just based around “water cooler moments,” as the sense of isolation experienced by clinicians is “not fluff; this is critical.”
Initiatives such as virtual happy hours and game nights may be helpful, she suggested.
A colleague of hers likes to send out the dad joke of the day, “which made everybody groan, but let me tell you, it changed the affective tone before they started seeing all these really hard, sad patients.”
Setting boundaries, which was the topic of another session at ASCO 2023, is also an important way to address the “emotionally powerful” work of oncology, Dr. Jackson commented.
She underlined the need to channel or be “fully present when you are in the room” but emphasized the need to detach at the end of the day, commenting that “when you leave, you leave.”
No funding was declared. Dr. Friese reported relationships with Merck, NCCN/Pfizer, National Cancer Institute, Patient-Centered Outcomes Research Institute, and the Simms/Mann Foundation. No other speakers reported relevant financial relationships.
A version of this article first appeared on Medscape.com.
– but when it is also accompanied by a sense of emotional isolation, it can lead to reduced well-being and burnout.
The issue was discussed at a special session at the annual meeting of the American Society of Clinical Oncology, and several speakers offered solutions.
Laurie Jean Lyckholm, MD, professor, Hematology/Oncology, West Virginia University School of Medicine, Morgantown, polled the audience to ask how they deal with patient-related loss and grief.
The responses showed that 44.4% said they talk with their colleagues, 16.7% said they talk about it with family and friends, but 22.2% said that they simply move on to the next patient.
Dr. Lyckholm noted that there are positive and negative ways of dealing with grief.
One example of a positive way comes from an oncologist who attended one of her talks and shared with her how his practice deals with the issue.
“At the end of every fourth Friday, he closes his community practice office early and all the oncologists, everyone, stays for a while, and they have a list of the people who have died,” Dr. Lyckholm explained. As a group, they go through the list and reminisce about the patients who died, recalling funny incidents or things that person had said.
“I love this idea,” she said. “The most important thing is to commemorate that person.”
Amplified during pandemic
Like many other issues, the problem of how to deal with “professional grief” was amplified during the COVID-19 pandemic. Many people were unable to see their dying relatives because of the restricted access to sealed-off, dedicated COVID-19 units. One oncologist who had developed a friendly relationship with a patient while treating them for cancer over several years was unable to visit the patient once they were ill with the disease and was left to communicate via an iPad. “It was the only way I could say ‘goodbye’ before she died. ... It still haunts me today, 2 years later,” the clinician recalled.
This anecdote illustrates “disenfranchised grief,” which occurs when an individual experiences a “significant loss and the resultant grief is not openly acknowledged, socially validated, or publicly mourned,” Dr. Lyckholm explained.
If this goes unrecognized, it can lead to shame, guilt, and organizational mistrust, resulting in reduced well-being and clinician burnout, she warned.
The pandemic also had an impact on clinicians directly. Dr. Lyckholm quoted one nurse practitioner who talked about coming back to a new “lonely normal” when returning to a Veterans Affairs hospital.
“I am still getting used to calling colleagues, and paging colleagues, and realizing that they just aren’t there,” the nurse practitioner said. “They aren’t there because they either left or died. I just didn’t expect that.”
Dr. Lyckholm said, “I don’t think we can ever stop acknowledging COVID, because it just had such a terrible impact on all of us.”
Teamwork intervention
The next speaker also polled the audience. Christopher Ryan Friese, PhD, RN, AOCN, Elizabeth Tone Hosmer Professor of Nursing, University of Michigan, Ann Arbor, asked the audience what strategy they would prioritize to reduce burnout, from the perspective of the entire cancer care team.
The response indicated that many (43.6%) would like to see team-based grief and bereavement sessions, while 31.1% thought it best to tackle low-value administrative work.
Dr. Friese drew on a teamwork intervention that researchers at the Dana-Farber Cancer Institute, Boston, with support from the National Cancer Institute, implemented to help identify opportunities to improve cancer care delivery services.
It began with a focus group of nurses who were invited to identify practice pain points, then six 2-hour sessions with all members of the clinical team to identify and develop service expectations and commitments across the various roles.
After these sessions, the researchers saw a decrease in missing orders from 30% to 2%, while patient satisfaction increased from 93% to 97% as a result. Interestingly, there was also a reported rise in efficiency, practice quality and safety, and respectful professional behaviors.
The pilot was then rolled out across the whole institution, and Dr. Friese and colleagues also implemented a version of the program at their community medical oncology practice.
They had a huge response from patients and clinicians alike (with participation rates of 90% and 78%, respectively), and the survey results led to changes in workflow and the standardization of communications.
Importantly for Dr. Friese, the clinicians who took part wanted to repeat the survey to evaluate any practice changes, which was not part of the study protocol and had not been envisaged by the researchers.
So they developed a survey for clinicians, using as an inspiration the Choosing Wisely campaign by the American Board of Internal Medicine Foundation to identify the best treatments to improve patient outcomes and those to deprioritize.
They used the survey on 373 clinicians at the University of Michigan Health System and found that “the number one thing was getting rid of the administrative work” – that it doesn’t have to be done specifically by physicians or other providers and that other people can do it.
The second was time-consuming electronic health record tasks.
Both of these have since been the focus of an elimination and reduction process to give clinicians more time to do what matters most to them and their patients.
“We have the opportunity to do this in a different way,” Dr. Friese said, “and I think it’s a really powerful opportunity.”
“We can retrofit the solution, which is the pizza parties, and the yoga apps, and the T-shirts ... [or] we could actually redesign the work that we’re asking clinicians to do on a daily basis,” he commented.
“We could make the work easier to do so that you have more time with patients and less time with administrative work and have more time to process grief or to celebrate successes,” he concluded.
Tackling burnout
The final speaker, Vicki A. Jackson, MD, MPH, chief of palliative care, Massachusetts General Hospital, emphasized that the recognition of grief by a cancer care provider is “imperative” for physician well-being and pointed out that that interventions to help “do exist,” including ASCO’s SafeHaven collection of physician well-being resources.
Oncology inherently carries with it “threats” to well-being, including uncertainty and doubt, isolation, fears over one’s usefulness, exhaustion, the witnessing of suffering, and moral distress, she noted.
Things that are necessary for well-being, in contrast, include a sense of connection and community, having boundaries between work and personal life, self-awareness, compassion, and empowerment, among others.
Dr. Jackson believes that in the current era community building within oncology must be “intentional” and not just based around “water cooler moments,” as the sense of isolation experienced by clinicians is “not fluff; this is critical.”
Initiatives such as virtual happy hours and game nights may be helpful, she suggested.
A colleague of hers likes to send out the dad joke of the day, “which made everybody groan, but let me tell you, it changed the affective tone before they started seeing all these really hard, sad patients.”
Setting boundaries, which was the topic of another session at ASCO 2023, is also an important way to address the “emotionally powerful” work of oncology, Dr. Jackson commented.
She underlined the need to channel or be “fully present when you are in the room” but emphasized the need to detach at the end of the day, commenting that “when you leave, you leave.”
No funding was declared. Dr. Friese reported relationships with Merck, NCCN/Pfizer, National Cancer Institute, Patient-Centered Outcomes Research Institute, and the Simms/Mann Foundation. No other speakers reported relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
It’s okay to say ‘no’: Setting boundaries in oncology
CHICAGO – in order to protect their well-being and reduce their risk of burnout.
This was the message from speakers at a special session on “Setting Boundaries” during the annual meeting of the American Society of Clinical Oncology (ASCO).
Monica Sheila Chatwal, MD, a medical oncologist at Moffitt Cancer Center and Research Institute, Tampa, Fla., suggested that, like a painting in a museum, physicians should have “some level of guardrail” to protect their knowledge and expertise, and also their ability to be able to continue to care for patients.
Having set boundaries “provides more emotional and cognitive flexibility, and less uncertainty, in the relationships that we have with our colleagues, with our patients, with everyone around us,” she argued.
“More importantly, boundaries acknowledge that, as humans, we are multifaceted, multidimensional people,” and that “we have lives outside of medicine, much as we may or may not want to admit that.
“It’s great to be devoted to what we do, but there are so many other aspects of ourselves that make us who we are, and that is wonderful,” she said.
A calling, not a job
However, the idea of demarcating one’s professional and personal life can go against the still-persistent idea that being a doctor is a calling rather than a job.
“I don’t think it matters whether you call it a job or a calling,” commented another speaker at the session, Jonathan M. Marron, MD, MPH, Dana-Farber/Boston Children’s Cancer.
But even if it is a calling, which implies that “you are supposed to devote all of yourself to the work and not to anything else,” there is still a need for setting boundaries, he argued. Saying “no” and allowing “yourself to be yourself” are important measures, Dr. Marron emphasized, as taking time out can make you a better clinician.
Crucial to that is being able to communicate with colleagues and share a degree of “vulnerability,” added Dr. Chatwal. “Showing that you’re vulnerable not only to your trainees, but also to your staff and to your patients really normalizes everything.”
“I have nurses who are feeling like they have to work 24/7 and manage their inbox to answer all of their messages, because they feel like they have to keep up.
“But it’s nice for me to be able to model that and say: ‘Listen, I want you to know it’s not urgent, please take 24 hours and we’ll come back to it.’ ”
Communicating with patients
Dr. Chatwal noted that, while there are clear boundaries related to sexual or physical relationships between doctors and patients and around not treating family members or friends, the boundaries pertaining to communication, and “how frequently [patients] have access to us ... are not so clearly defined.”
The advent of telemedicine has added to that, she believes, as it offers a “patient portal that can allow access 24/7.”
“Does that mean we as physicians or providers also give that level of access? Are we supposed to check messages at all periods of time?”
“More and more people are becoming more cognizant of this,” she commented, noting that the issue has taken on greater import with the rise of social media and the “ability for our patients to request us as friends.”
She pointed out that former president of the American College of Physicians Wayne J. Riley, MD, MPH, MBA, suggested doctors should maintain an air of detachment with their patients, as “it allows us to protect ourselves and continue to provide that great level of care.”
On the other hand, she noted that there has been a sea change in how patients see doctors. Whereas in the past, medicine “was very paternalistic” with doctors seen as the “be all and end all,” now patients tend to be more knowledgeable and Dr. Google “makes them much more engaged in their care.”
But this can also cause problems when patients become “demanding for certain treatments,” she said.
Limits to ethical care?
Dr. Marron posed the question: “Is there a limit to my ethical obligations to ethical care?”
He described a hypothetical scenario where a patient has found their doctor’s email address online and they now sends “frequent emails, despite very clear instructions to use the on-call paging system for something that’s urgent, and the electronic health record messaging system otherwise.”
This patient’s behavior is “causing a huge amount of stress” for the doctor, and this is affecting their care of other patients, as well as their academic work and home life.
Dr. Marron asked the audience: Would it be ethically acceptable to stop seeing such a patient?
Taking a quick straw poll of the audience, Dr. Marron noted that there were “not a lot of hands” raised in favor.
He suggested this is because the notion of nonabandonment comes into play, in which there is an obligation to not let patients go without providing adequate time for them to find an alternative clinician.
In this scenario, for example, the doctor could find “several local oncologists who are willing to accept the patient,” as well as talk the situation through with a trusted colleagues, and only then “compassionately but resolutely” tell the patient that they will be transferred.
Dr. Marron acknowledged that this may seem at odds with the theme of this year’s ASCO annual meeting, which emphasizes “partnering with patients.” But he argued that “it doesn’t have to be.”
When thoughtfully done, setting boundaries “can ethically allow us to give more to, and partner more with, our patients, while supporting our well-being, sense of purpose, and job satisfaction,” he argued.
Goldilocks situation
Speaking more broadly, Dr. Marron said that boundaries might be considered on a spectrum.
Too few boundaries can lead to conflicts of interest, loss of balance in the patient-physician relationship, and overengagement, while too many boundaries may result in insufficient connection with patients, thus reducing the “human element” and increasing a sense of disengagement.
Either way, “we run the risk of having decreased satisfaction what with what we’re doing, and decreasing the quality of patient care.”
“It’s a little bit of a Goldilocks situation: You want to find just the right balance, somewhere in the middle,” he said.
In the past, issues around having too few boundaries related to conflicts of interest. This reduced trust in the medical profession, he commented, which may have affected patient outcomes, and certainly increased the risk of reduced well-being and burnout.
“Today, we probably still lie on the end of the spectrum with too few boundaries,” Dr. Marron said, “but in a very different way, as we worry about limited work-life balance, and always being connected.”
“I don’t think there’s anybody in the room who doesn’t have some kind of electronic device, either in their hand or not too far from their hand,” he continued.
Moreover, “the patients that we’re taking care of have a greater amount of complexity than they’ve ever had before ... [with] greater numbers of needs than ever before,” and as a result, they require “a greater amount of our time as clinicians.”
Just as with the lack of boundaries in the past, this “runs the risk of us having decreased well-being and an increased risk of burnout,” he suggested.
Wearing several hats
The third speaker, Arif Kamal, MD, MBA, MHS, associate professor of medicine and population health, Duke University, Durham, N.C., and chief patient officer at the American Cancer Society, said that every oncologist wears several “hats” in addition to being a clinician.
These may include, in his case, being “a father, a husband, and a brother, and a soccer coach, and a lot of different things.”
Dr. Kamal underlined that recognizing these various roles is “really important,” especially when it comes to the “moment of comparison with others,” as there is a temptation to see one’s own complexity but not that of a colleague.
“The question is: What are all the other competing priorities that a person faces?”
For example, a person’s tally of publications is “just one of many metrics” when it comes to measuring the “success of a career, and, frankly, I’m not sure that’s one of the good ones,” Dr. Kamal said.
He recalled how a mentor of his when he was at the Mayo Clinic had a “remarkable dip” in the number of publications at a certain point in his career, and he explained to Dr. Kamal that this was the time “when my kids needed me the most.”
“That was really important,” Dr. Kamal said, “because it taught me a lesson about having mentors in your life that are not only focused on your career and academic success, but also those who are very interested in the other hats that you wear.”
Fear of saying no
One way of setting boundaries is saying no to certain requests, Dr. Kamal commented.
He gave an example from his own life – when he was at a soccer game and received a call on his cell from a patient who has seen test results before he has had a chance to review them.
Dr. Kamal also painted a hypothetical scenario, where a doctor on junior faculty, staffing a GI oncology clinic 4 days a week, is also volunteering to collect and organize new cases for the tumor board, and is writing several letters of intent for pharmaceutical trials. They are saying “yes” to 90% of the requests for their time, he said, and the result is they go home “most days feeling like their tank is on empty.”
“Then this person gets asked by the division chief to serve on the hospital’s pain committee,” he said, “regardless of the fact that this is not necessarily in their clinical or research interests.”
“So this is really a bit of an [out of] left field request, and how does this person address this?”
Dr. Kamal said that a useful concept to consider is something commonly ascribed to teenagers, that of the fear of missing out, or FOMO.
The problem is that, “due to this concept of FOMO, when opportunities come your way, saying ‘no’ to them gives rise to the question: What if the opportunity never comes back?”
But Dr. Kamal also reminded the audience that “without being able to say no to things ... your capacity will go down.”
“That’s really important to recognize, because for a long time, healing professions have been thought of as [having] people that can continue to expand and expand and expand, without calling out this concept of inflation.”
This is really about “being true to yourself,” and acknowledging that “no one is going to set boundaries for you.”
“That was a tough lesson I learned in my career,” Dr. Kamal commented, and when he looked for guidance, he found that “everyone is struggling with this.”
Setting boundaries, he emphasized, requires “a certain amount of looking inward ... and it requires some bravery.”
“You just have to ask yourself: Is the only reason you’re going to do something because of FOMO?” Dr. Kamal commented. “Maybe that’s okay, but you have to acknowledge that’s the case.”
Dr. Chatwal reported a relationship with Merck. Dr. Marron reported relationships with Genzyme, Partner Therapeutics, ROM Technologies, Arnett, Draper, & Hagood, and Trentalange & Kelley. Dr. Kamal reported relationships with Acclivity Health, Prepped Health, Private Diagnostic Clinic, AstraZeneca, Care4ward, Compassus, HERON, Janssen Oncology, Medtronic, New Century Health, UnitedHealth Group, and Janssen Oncology.
A version of this article first appeared on Medscape.com.
CHICAGO – in order to protect their well-being and reduce their risk of burnout.
This was the message from speakers at a special session on “Setting Boundaries” during the annual meeting of the American Society of Clinical Oncology (ASCO).
Monica Sheila Chatwal, MD, a medical oncologist at Moffitt Cancer Center and Research Institute, Tampa, Fla., suggested that, like a painting in a museum, physicians should have “some level of guardrail” to protect their knowledge and expertise, and also their ability to be able to continue to care for patients.
Having set boundaries “provides more emotional and cognitive flexibility, and less uncertainty, in the relationships that we have with our colleagues, with our patients, with everyone around us,” she argued.
“More importantly, boundaries acknowledge that, as humans, we are multifaceted, multidimensional people,” and that “we have lives outside of medicine, much as we may or may not want to admit that.
“It’s great to be devoted to what we do, but there are so many other aspects of ourselves that make us who we are, and that is wonderful,” she said.
A calling, not a job
However, the idea of demarcating one’s professional and personal life can go against the still-persistent idea that being a doctor is a calling rather than a job.
“I don’t think it matters whether you call it a job or a calling,” commented another speaker at the session, Jonathan M. Marron, MD, MPH, Dana-Farber/Boston Children’s Cancer.
But even if it is a calling, which implies that “you are supposed to devote all of yourself to the work and not to anything else,” there is still a need for setting boundaries, he argued. Saying “no” and allowing “yourself to be yourself” are important measures, Dr. Marron emphasized, as taking time out can make you a better clinician.
Crucial to that is being able to communicate with colleagues and share a degree of “vulnerability,” added Dr. Chatwal. “Showing that you’re vulnerable not only to your trainees, but also to your staff and to your patients really normalizes everything.”
“I have nurses who are feeling like they have to work 24/7 and manage their inbox to answer all of their messages, because they feel like they have to keep up.
“But it’s nice for me to be able to model that and say: ‘Listen, I want you to know it’s not urgent, please take 24 hours and we’ll come back to it.’ ”
Communicating with patients
Dr. Chatwal noted that, while there are clear boundaries related to sexual or physical relationships between doctors and patients and around not treating family members or friends, the boundaries pertaining to communication, and “how frequently [patients] have access to us ... are not so clearly defined.”
The advent of telemedicine has added to that, she believes, as it offers a “patient portal that can allow access 24/7.”
“Does that mean we as physicians or providers also give that level of access? Are we supposed to check messages at all periods of time?”
“More and more people are becoming more cognizant of this,” she commented, noting that the issue has taken on greater import with the rise of social media and the “ability for our patients to request us as friends.”
She pointed out that former president of the American College of Physicians Wayne J. Riley, MD, MPH, MBA, suggested doctors should maintain an air of detachment with their patients, as “it allows us to protect ourselves and continue to provide that great level of care.”
On the other hand, she noted that there has been a sea change in how patients see doctors. Whereas in the past, medicine “was very paternalistic” with doctors seen as the “be all and end all,” now patients tend to be more knowledgeable and Dr. Google “makes them much more engaged in their care.”
But this can also cause problems when patients become “demanding for certain treatments,” she said.
Limits to ethical care?
Dr. Marron posed the question: “Is there a limit to my ethical obligations to ethical care?”
He described a hypothetical scenario where a patient has found their doctor’s email address online and they now sends “frequent emails, despite very clear instructions to use the on-call paging system for something that’s urgent, and the electronic health record messaging system otherwise.”
This patient’s behavior is “causing a huge amount of stress” for the doctor, and this is affecting their care of other patients, as well as their academic work and home life.
Dr. Marron asked the audience: Would it be ethically acceptable to stop seeing such a patient?
Taking a quick straw poll of the audience, Dr. Marron noted that there were “not a lot of hands” raised in favor.
He suggested this is because the notion of nonabandonment comes into play, in which there is an obligation to not let patients go without providing adequate time for them to find an alternative clinician.
In this scenario, for example, the doctor could find “several local oncologists who are willing to accept the patient,” as well as talk the situation through with a trusted colleagues, and only then “compassionately but resolutely” tell the patient that they will be transferred.
Dr. Marron acknowledged that this may seem at odds with the theme of this year’s ASCO annual meeting, which emphasizes “partnering with patients.” But he argued that “it doesn’t have to be.”
When thoughtfully done, setting boundaries “can ethically allow us to give more to, and partner more with, our patients, while supporting our well-being, sense of purpose, and job satisfaction,” he argued.
Goldilocks situation
Speaking more broadly, Dr. Marron said that boundaries might be considered on a spectrum.
Too few boundaries can lead to conflicts of interest, loss of balance in the patient-physician relationship, and overengagement, while too many boundaries may result in insufficient connection with patients, thus reducing the “human element” and increasing a sense of disengagement.
Either way, “we run the risk of having decreased satisfaction what with what we’re doing, and decreasing the quality of patient care.”
“It’s a little bit of a Goldilocks situation: You want to find just the right balance, somewhere in the middle,” he said.
In the past, issues around having too few boundaries related to conflicts of interest. This reduced trust in the medical profession, he commented, which may have affected patient outcomes, and certainly increased the risk of reduced well-being and burnout.
“Today, we probably still lie on the end of the spectrum with too few boundaries,” Dr. Marron said, “but in a very different way, as we worry about limited work-life balance, and always being connected.”
“I don’t think there’s anybody in the room who doesn’t have some kind of electronic device, either in their hand or not too far from their hand,” he continued.
Moreover, “the patients that we’re taking care of have a greater amount of complexity than they’ve ever had before ... [with] greater numbers of needs than ever before,” and as a result, they require “a greater amount of our time as clinicians.”
Just as with the lack of boundaries in the past, this “runs the risk of us having decreased well-being and an increased risk of burnout,” he suggested.
Wearing several hats
The third speaker, Arif Kamal, MD, MBA, MHS, associate professor of medicine and population health, Duke University, Durham, N.C., and chief patient officer at the American Cancer Society, said that every oncologist wears several “hats” in addition to being a clinician.
These may include, in his case, being “a father, a husband, and a brother, and a soccer coach, and a lot of different things.”
Dr. Kamal underlined that recognizing these various roles is “really important,” especially when it comes to the “moment of comparison with others,” as there is a temptation to see one’s own complexity but not that of a colleague.
“The question is: What are all the other competing priorities that a person faces?”
For example, a person’s tally of publications is “just one of many metrics” when it comes to measuring the “success of a career, and, frankly, I’m not sure that’s one of the good ones,” Dr. Kamal said.
He recalled how a mentor of his when he was at the Mayo Clinic had a “remarkable dip” in the number of publications at a certain point in his career, and he explained to Dr. Kamal that this was the time “when my kids needed me the most.”
“That was really important,” Dr. Kamal said, “because it taught me a lesson about having mentors in your life that are not only focused on your career and academic success, but also those who are very interested in the other hats that you wear.”
Fear of saying no
One way of setting boundaries is saying no to certain requests, Dr. Kamal commented.
He gave an example from his own life – when he was at a soccer game and received a call on his cell from a patient who has seen test results before he has had a chance to review them.
Dr. Kamal also painted a hypothetical scenario, where a doctor on junior faculty, staffing a GI oncology clinic 4 days a week, is also volunteering to collect and organize new cases for the tumor board, and is writing several letters of intent for pharmaceutical trials. They are saying “yes” to 90% of the requests for their time, he said, and the result is they go home “most days feeling like their tank is on empty.”
“Then this person gets asked by the division chief to serve on the hospital’s pain committee,” he said, “regardless of the fact that this is not necessarily in their clinical or research interests.”
“So this is really a bit of an [out of] left field request, and how does this person address this?”
Dr. Kamal said that a useful concept to consider is something commonly ascribed to teenagers, that of the fear of missing out, or FOMO.
The problem is that, “due to this concept of FOMO, when opportunities come your way, saying ‘no’ to them gives rise to the question: What if the opportunity never comes back?”
But Dr. Kamal also reminded the audience that “without being able to say no to things ... your capacity will go down.”
“That’s really important to recognize, because for a long time, healing professions have been thought of as [having] people that can continue to expand and expand and expand, without calling out this concept of inflation.”
This is really about “being true to yourself,” and acknowledging that “no one is going to set boundaries for you.”
“That was a tough lesson I learned in my career,” Dr. Kamal commented, and when he looked for guidance, he found that “everyone is struggling with this.”
Setting boundaries, he emphasized, requires “a certain amount of looking inward ... and it requires some bravery.”
“You just have to ask yourself: Is the only reason you’re going to do something because of FOMO?” Dr. Kamal commented. “Maybe that’s okay, but you have to acknowledge that’s the case.”
Dr. Chatwal reported a relationship with Merck. Dr. Marron reported relationships with Genzyme, Partner Therapeutics, ROM Technologies, Arnett, Draper, & Hagood, and Trentalange & Kelley. Dr. Kamal reported relationships with Acclivity Health, Prepped Health, Private Diagnostic Clinic, AstraZeneca, Care4ward, Compassus, HERON, Janssen Oncology, Medtronic, New Century Health, UnitedHealth Group, and Janssen Oncology.
A version of this article first appeared on Medscape.com.
CHICAGO – in order to protect their well-being and reduce their risk of burnout.
This was the message from speakers at a special session on “Setting Boundaries” during the annual meeting of the American Society of Clinical Oncology (ASCO).
Monica Sheila Chatwal, MD, a medical oncologist at Moffitt Cancer Center and Research Institute, Tampa, Fla., suggested that, like a painting in a museum, physicians should have “some level of guardrail” to protect their knowledge and expertise, and also their ability to be able to continue to care for patients.
Having set boundaries “provides more emotional and cognitive flexibility, and less uncertainty, in the relationships that we have with our colleagues, with our patients, with everyone around us,” she argued.
“More importantly, boundaries acknowledge that, as humans, we are multifaceted, multidimensional people,” and that “we have lives outside of medicine, much as we may or may not want to admit that.
“It’s great to be devoted to what we do, but there are so many other aspects of ourselves that make us who we are, and that is wonderful,” she said.
A calling, not a job
However, the idea of demarcating one’s professional and personal life can go against the still-persistent idea that being a doctor is a calling rather than a job.
“I don’t think it matters whether you call it a job or a calling,” commented another speaker at the session, Jonathan M. Marron, MD, MPH, Dana-Farber/Boston Children’s Cancer.
But even if it is a calling, which implies that “you are supposed to devote all of yourself to the work and not to anything else,” there is still a need for setting boundaries, he argued. Saying “no” and allowing “yourself to be yourself” are important measures, Dr. Marron emphasized, as taking time out can make you a better clinician.
Crucial to that is being able to communicate with colleagues and share a degree of “vulnerability,” added Dr. Chatwal. “Showing that you’re vulnerable not only to your trainees, but also to your staff and to your patients really normalizes everything.”
“I have nurses who are feeling like they have to work 24/7 and manage their inbox to answer all of their messages, because they feel like they have to keep up.
“But it’s nice for me to be able to model that and say: ‘Listen, I want you to know it’s not urgent, please take 24 hours and we’ll come back to it.’ ”
Communicating with patients
Dr. Chatwal noted that, while there are clear boundaries related to sexual or physical relationships between doctors and patients and around not treating family members or friends, the boundaries pertaining to communication, and “how frequently [patients] have access to us ... are not so clearly defined.”
The advent of telemedicine has added to that, she believes, as it offers a “patient portal that can allow access 24/7.”
“Does that mean we as physicians or providers also give that level of access? Are we supposed to check messages at all periods of time?”
“More and more people are becoming more cognizant of this,” she commented, noting that the issue has taken on greater import with the rise of social media and the “ability for our patients to request us as friends.”
She pointed out that former president of the American College of Physicians Wayne J. Riley, MD, MPH, MBA, suggested doctors should maintain an air of detachment with their patients, as “it allows us to protect ourselves and continue to provide that great level of care.”
On the other hand, she noted that there has been a sea change in how patients see doctors. Whereas in the past, medicine “was very paternalistic” with doctors seen as the “be all and end all,” now patients tend to be more knowledgeable and Dr. Google “makes them much more engaged in their care.”
But this can also cause problems when patients become “demanding for certain treatments,” she said.
Limits to ethical care?
Dr. Marron posed the question: “Is there a limit to my ethical obligations to ethical care?”
He described a hypothetical scenario where a patient has found their doctor’s email address online and they now sends “frequent emails, despite very clear instructions to use the on-call paging system for something that’s urgent, and the electronic health record messaging system otherwise.”
This patient’s behavior is “causing a huge amount of stress” for the doctor, and this is affecting their care of other patients, as well as their academic work and home life.
Dr. Marron asked the audience: Would it be ethically acceptable to stop seeing such a patient?
Taking a quick straw poll of the audience, Dr. Marron noted that there were “not a lot of hands” raised in favor.
He suggested this is because the notion of nonabandonment comes into play, in which there is an obligation to not let patients go without providing adequate time for them to find an alternative clinician.
In this scenario, for example, the doctor could find “several local oncologists who are willing to accept the patient,” as well as talk the situation through with a trusted colleagues, and only then “compassionately but resolutely” tell the patient that they will be transferred.
Dr. Marron acknowledged that this may seem at odds with the theme of this year’s ASCO annual meeting, which emphasizes “partnering with patients.” But he argued that “it doesn’t have to be.”
When thoughtfully done, setting boundaries “can ethically allow us to give more to, and partner more with, our patients, while supporting our well-being, sense of purpose, and job satisfaction,” he argued.
Goldilocks situation
Speaking more broadly, Dr. Marron said that boundaries might be considered on a spectrum.
Too few boundaries can lead to conflicts of interest, loss of balance in the patient-physician relationship, and overengagement, while too many boundaries may result in insufficient connection with patients, thus reducing the “human element” and increasing a sense of disengagement.
Either way, “we run the risk of having decreased satisfaction what with what we’re doing, and decreasing the quality of patient care.”
“It’s a little bit of a Goldilocks situation: You want to find just the right balance, somewhere in the middle,” he said.
In the past, issues around having too few boundaries related to conflicts of interest. This reduced trust in the medical profession, he commented, which may have affected patient outcomes, and certainly increased the risk of reduced well-being and burnout.
“Today, we probably still lie on the end of the spectrum with too few boundaries,” Dr. Marron said, “but in a very different way, as we worry about limited work-life balance, and always being connected.”
“I don’t think there’s anybody in the room who doesn’t have some kind of electronic device, either in their hand or not too far from their hand,” he continued.
Moreover, “the patients that we’re taking care of have a greater amount of complexity than they’ve ever had before ... [with] greater numbers of needs than ever before,” and as a result, they require “a greater amount of our time as clinicians.”
Just as with the lack of boundaries in the past, this “runs the risk of us having decreased well-being and an increased risk of burnout,” he suggested.
Wearing several hats
The third speaker, Arif Kamal, MD, MBA, MHS, associate professor of medicine and population health, Duke University, Durham, N.C., and chief patient officer at the American Cancer Society, said that every oncologist wears several “hats” in addition to being a clinician.
These may include, in his case, being “a father, a husband, and a brother, and a soccer coach, and a lot of different things.”
Dr. Kamal underlined that recognizing these various roles is “really important,” especially when it comes to the “moment of comparison with others,” as there is a temptation to see one’s own complexity but not that of a colleague.
“The question is: What are all the other competing priorities that a person faces?”
For example, a person’s tally of publications is “just one of many metrics” when it comes to measuring the “success of a career, and, frankly, I’m not sure that’s one of the good ones,” Dr. Kamal said.
He recalled how a mentor of his when he was at the Mayo Clinic had a “remarkable dip” in the number of publications at a certain point in his career, and he explained to Dr. Kamal that this was the time “when my kids needed me the most.”
“That was really important,” Dr. Kamal said, “because it taught me a lesson about having mentors in your life that are not only focused on your career and academic success, but also those who are very interested in the other hats that you wear.”
Fear of saying no
One way of setting boundaries is saying no to certain requests, Dr. Kamal commented.
He gave an example from his own life – when he was at a soccer game and received a call on his cell from a patient who has seen test results before he has had a chance to review them.
Dr. Kamal also painted a hypothetical scenario, where a doctor on junior faculty, staffing a GI oncology clinic 4 days a week, is also volunteering to collect and organize new cases for the tumor board, and is writing several letters of intent for pharmaceutical trials. They are saying “yes” to 90% of the requests for their time, he said, and the result is they go home “most days feeling like their tank is on empty.”
“Then this person gets asked by the division chief to serve on the hospital’s pain committee,” he said, “regardless of the fact that this is not necessarily in their clinical or research interests.”
“So this is really a bit of an [out of] left field request, and how does this person address this?”
Dr. Kamal said that a useful concept to consider is something commonly ascribed to teenagers, that of the fear of missing out, or FOMO.
The problem is that, “due to this concept of FOMO, when opportunities come your way, saying ‘no’ to them gives rise to the question: What if the opportunity never comes back?”
But Dr. Kamal also reminded the audience that “without being able to say no to things ... your capacity will go down.”
“That’s really important to recognize, because for a long time, healing professions have been thought of as [having] people that can continue to expand and expand and expand, without calling out this concept of inflation.”
This is really about “being true to yourself,” and acknowledging that “no one is going to set boundaries for you.”
“That was a tough lesson I learned in my career,” Dr. Kamal commented, and when he looked for guidance, he found that “everyone is struggling with this.”
Setting boundaries, he emphasized, requires “a certain amount of looking inward ... and it requires some bravery.”
“You just have to ask yourself: Is the only reason you’re going to do something because of FOMO?” Dr. Kamal commented. “Maybe that’s okay, but you have to acknowledge that’s the case.”
Dr. Chatwal reported a relationship with Merck. Dr. Marron reported relationships with Genzyme, Partner Therapeutics, ROM Technologies, Arnett, Draper, & Hagood, and Trentalange & Kelley. Dr. Kamal reported relationships with Acclivity Health, Prepped Health, Private Diagnostic Clinic, AstraZeneca, Care4ward, Compassus, HERON, Janssen Oncology, Medtronic, New Century Health, UnitedHealth Group, and Janssen Oncology.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Ticagrelor may reduce brain lesions after carotid stenting
MUNICH – secondary endpoint results of the PRECISE-MRI trial suggest.
More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.
Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.
There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.
The research was presented at the annual European Stroke Organisation Conference .
Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”
Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.
Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”
Dr. Bonati cautioned, however, that the findings are preliminary.
‘Promising’ results
Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”
She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.
Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”
“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
Major complication
Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.
Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.
Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.
To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.
They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.
The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.
The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.
Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.
The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.
The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.
Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).
However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).
Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).
Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.
Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).
There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.
The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
MUNICH – secondary endpoint results of the PRECISE-MRI trial suggest.
More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.
Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.
There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.
The research was presented at the annual European Stroke Organisation Conference .
Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”
Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.
Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”
Dr. Bonati cautioned, however, that the findings are preliminary.
‘Promising’ results
Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”
She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.
Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”
“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
Major complication
Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.
Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.
Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.
To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.
They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.
The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.
The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.
Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.
The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.
The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.
Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).
However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).
Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).
Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.
Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).
There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.
The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
MUNICH – secondary endpoint results of the PRECISE-MRI trial suggest.
More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.
Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.
There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.
The research was presented at the annual European Stroke Organisation Conference .
Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”
Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.
Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”
Dr. Bonati cautioned, however, that the findings are preliminary.
‘Promising’ results
Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”
She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.
Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”
“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
Major complication
Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.
Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.
Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.
To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.
They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.
The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.
The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.
Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.
The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.
The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.
Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).
However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).
Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).
Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.
Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).
There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.
The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
FROM ESOC 2023
Immediate statin after acute stroke reduces disability
MUNICH, GERMANY – without compromising safety, results of the INSPIRES trial show.
The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.
The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.
Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.
Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.
Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.
There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.
Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”
He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
Recurrence and progression
Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.
Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.
In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.
Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.
To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.
The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.
Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.
TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.
Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.
Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:
- Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
- Intensive antiplatelet therapy plus delayed high-intensity statin therapy
- Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
- Standard antiplatelet therapy plus delayed high-intensity statin therapy
In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.
The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.
The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).
Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).
The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).
Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).
There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).
Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.
Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).
Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).
The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.
A version of this article originally appeared on Medscape.com.
MUNICH, GERMANY – without compromising safety, results of the INSPIRES trial show.
The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.
The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.
Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.
Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.
Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.
There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.
Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”
He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
Recurrence and progression
Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.
Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.
In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.
Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.
To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.
The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.
Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.
TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.
Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.
Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:
- Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
- Intensive antiplatelet therapy plus delayed high-intensity statin therapy
- Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
- Standard antiplatelet therapy plus delayed high-intensity statin therapy
In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.
The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.
The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).
Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).
The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).
Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).
There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).
Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.
Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).
Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).
The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.
A version of this article originally appeared on Medscape.com.
MUNICH, GERMANY – without compromising safety, results of the INSPIRES trial show.
The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.
The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.
Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.
Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.
Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.
There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.
Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”
He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
Recurrence and progression
Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.
Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.
In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.
Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.
To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.
The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.
Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.
TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.
Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.
Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:
- Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
- Intensive antiplatelet therapy plus delayed high-intensity statin therapy
- Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
- Standard antiplatelet therapy plus delayed high-intensity statin therapy
In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.
The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.
The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).
Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).
The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).
Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).
There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).
Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.
Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).
Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).
The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.
A version of this article originally appeared on Medscape.com.
AT ESOC 2023
High Lp(a) tied to higher coronary plaque volume, progression
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
AT EAS 2023