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T3 in hypothyroidism gets extra recommendation: British medical groups
New recommendations from the Joint British Thyroid Association/Society add to the increasingly general consensus that liothyronine (LT3) may be useful in combination with standard levothyroxine (LT4) in the treatment of hypothyroidism in some patients whose symptoms persist after standard treatment, despite a lack of evidence of benefit in clinical trials.
“Most patients with primary hypothyroidism respond well to levothyroxine replacement therapy,” recommends the joint association in the consensus statement, by Rupa Ahluwalia, MBBS, MD, of Norfolk and Norwich University Hospitals NHS Trust, United Kingdom, and colleagues, recently published in Clinical Endocrinology.
they wrote.
The ongoing debate over the use of LT3/LT4 combination therapy has persisted for more than 2 decades, with at least 16 randomized controlled trials and four meta-analyses failing to show any significant benefit of the combined regimen in key quality of life and cognitive function outcomes compared with LT4 monotherapy. However, many patients continue to report benefits with combination therapy, so the issue has not been laid to rest.
Wilmar M. Wiersinga, MD, PhD, emeritus professor of endocrinology at the University of Amsterdam, said in an interview: “The scientific community is divided as to whether or not the LT4/LT3 combination therapy has any value whatsoever, whereas the pressure from individual patients and patient associations on physicians – both general practitioners and specialists/endocrinologists – can be very high [in terms of] demanding prescriptions for the combination therapy.
“I welcome this joint statement very much because it provides guidance, especially for clinicians, on a hotly debated issue,” he said.
Persistent symptoms drive pursuit of alternatives
T4 refers to the hormone thyroxine made in the body, and LT4 to the pharmaceutical replacement product for that hormone, levothyroxine. Similarly, T3 refers to the hormone triiodothyronine, made in the body and a precursor to thyroxine, and LT3 refers to its pharmaceutical replacement, liothyronine.
Driving the continued demand from some patients with hypothyroidism and interest among clinicians is the relatively high proportion of patients who continue to experience symptoms even after the normalization of biochemical levels after treatment with LT4, which resolves symptoms in most patients within weeks of therapy.
Those who don’t improve report common ongoing symptoms: fatigue, sleepiness, memory problems, cognitive difficulties (brain fog), and weight gain.
However, with 60% of people commonly having one or more of the same symptoms even when their thyroid levels are normal, pinpointing the actual causes is a challenge, the societies report.
In the absence of other diagnoses, clinicians often turn to alternative treatment strategies, which, as well as addition of LT3 to LT4, also include the use of desiccated thyroid extract (DTE).
DTE was the medication first used to treat hypothyroidism years ago, originally made from pig glands. There are now several prescription medications made from the desiccated (dried) thyroid glands of animals, including brands such as Armour Thyroid, NP Thyroid, and WP Thyroid.
The practice of prescribing combination therapy has already been deemed acceptable by both the European Thyroid Association (ETA) and American Thyroid Association (ATA). The latter recommended in its 2014 guidelines that the combination of LT3/LT4 therapy may be trialed in exceptional circumstances or among patients who fail to improve with LT4 alone.
In following suit, the new Joint British Thyroid Association/Society consensus statement cautions that, first and foremost, “most patients with hypothyroidism should be treated with levothyroxine alone.”
However, combination LT3/LT4 therapy may be considered an option under key important conditions, including:
- When a diagnosis of overt hypothyroidism (documented TSH ≥ 10 mU/L and/or low FT4 pretreatment with thyroid replacement hormones) is established. If overt hypothyroidism cannot be confirmed, patients are recommended to first have a trial without LT4 and a repeat serum TSH after 6 weeks.
- For patients with overt hypothyroidism, prior to consideration of LT3, the dose of LT4 should be optimized to a TSH in the target range of 0.3-2.0 mU/L for 3 to 6 months. In some patients, it may be acceptable to have serum TSH below reference range (e.g., 0.1-0.3 mU/L), but not fully suppressed in the long term, instead of starting LT3.
- A trial of combination therapy may be warranted with confirmed overt hypothyroidism and persistent symptoms despite LT4 treatment and the exclusion of other comorbidities.
- Clinicians should not feel obliged to start LT3 or continue LT3 medication provided by other health care practitioners or accessed without medical advice if they judge this not to be in the patient’s best interest.
- When opting for LT3, a minimum of 3 to 6 months on the combination therapy should be considered before determining response to the trial, and for assessment, monitoring with serum TSH only is recommended.
- Patients should be counseled regarding the risk of arrhythmias, accelerated bone loss, and stroke associated with iatrogenic hyperthyroidism and the need for long-term monitoring.
- Given the short half-life of LT3, splitting doses across 24 hours is recommended for many people.
The joint association does not recommend the use of desiccated thyroid extract (which appears to be surprisingly on the rise, as recently reported).
Reasons for persistent symptoms are murky; don’t forget menopause
The key reason for the emphasis on making sure patients have overt hypothyroidism before trying LT3 is that patients are often treated with LT4 despite not even having hypothyroidism to begin with.
“In reality, many patients with subclinical hypothyroidism [TSH 5-10 mU/L] are now treated with levothyroxine, fueling a rise in its use, such that it is now the third most frequently prescribed medication in the United Kingdom,” the authors explained.
“In contrast, few patients are advised to seek lifestyle and exercise changes, despite the fact that there is positive evidence to support their benefits,” they continued.
In a recent podcast, Anthony Bianco, MD, a past president of the ATA, underscored another important factor complicating the ability to make conclusive hypothyroidism diagnoses in women: menopause.
“In my experience, the most confusing factor [in treatment decisions] is menopausal syndrome,” he said.
“The symptoms are very similar. Most patients with hypothyroidism are women. Are we getting close to menopause? Are we dealing with this? Is estrogen replacement therapy an option for this woman? Should we consult a colleague?” Dr. Bianco explained.
And there are other possibilities, including anemia, iron deficiency, other autoimmune diseases, and diabetes, he added.
“Exclude everything that you know,” Dr. Bianco said. “Use your common sense.”
Although the new statement echoes other guidelines, the recommendations are helpful amid the ever-present debate, said Dr. Wiersinga, the endocrinologist from the Netherlands.
Because of the pressure to try combination therapy, from patients and patient associations, the statement’s position that doctors must stand by their clinical judgment is important, he noted.
“I think many doctors would welcome the recommendation that doctors are not obliged to prescribe any medication that they believe is not in the patient’s best interest, and, in particular, that ‘doctors have no obligation to continue to provide prescriptions for LT3 or desiccated thyroid extract that have been started by other health care practitioners or accessed without medical advice if they judge this not to be in the patient’s best interest,’” he asserted.
“Also, the recommendation that an endocrinologist should be involved when a trial of T3 is considered is very valuable,” he added, noting the potential scenario of patients going to a general practitioner if turned down by a specialist for LT3.
An international consensus statement published by members of the ATA, ETA, and British Thyroid Association in 2021 further set forth recommendations for the development of future trials of LT3/LT4 combination therapy to establish more conclusive guidance.
Senior author Simon H. Pearce has reported receiving speaker fees from IBSA, Merck, Quidel, Berlin-Chemie, and consulting for Apitope/Worg and Immunovant/Roivant on issues unrelated to T3. The other authors of the consensus statement have reported no relevant financial relationships. Dr. Wiersinga has reporting consulting for Prolevi Bio.
A version of this article first appeared on Medscape.com.
New recommendations from the Joint British Thyroid Association/Society add to the increasingly general consensus that liothyronine (LT3) may be useful in combination with standard levothyroxine (LT4) in the treatment of hypothyroidism in some patients whose symptoms persist after standard treatment, despite a lack of evidence of benefit in clinical trials.
“Most patients with primary hypothyroidism respond well to levothyroxine replacement therapy,” recommends the joint association in the consensus statement, by Rupa Ahluwalia, MBBS, MD, of Norfolk and Norwich University Hospitals NHS Trust, United Kingdom, and colleagues, recently published in Clinical Endocrinology.
they wrote.
The ongoing debate over the use of LT3/LT4 combination therapy has persisted for more than 2 decades, with at least 16 randomized controlled trials and four meta-analyses failing to show any significant benefit of the combined regimen in key quality of life and cognitive function outcomes compared with LT4 monotherapy. However, many patients continue to report benefits with combination therapy, so the issue has not been laid to rest.
Wilmar M. Wiersinga, MD, PhD, emeritus professor of endocrinology at the University of Amsterdam, said in an interview: “The scientific community is divided as to whether or not the LT4/LT3 combination therapy has any value whatsoever, whereas the pressure from individual patients and patient associations on physicians – both general practitioners and specialists/endocrinologists – can be very high [in terms of] demanding prescriptions for the combination therapy.
“I welcome this joint statement very much because it provides guidance, especially for clinicians, on a hotly debated issue,” he said.
Persistent symptoms drive pursuit of alternatives
T4 refers to the hormone thyroxine made in the body, and LT4 to the pharmaceutical replacement product for that hormone, levothyroxine. Similarly, T3 refers to the hormone triiodothyronine, made in the body and a precursor to thyroxine, and LT3 refers to its pharmaceutical replacement, liothyronine.
Driving the continued demand from some patients with hypothyroidism and interest among clinicians is the relatively high proportion of patients who continue to experience symptoms even after the normalization of biochemical levels after treatment with LT4, which resolves symptoms in most patients within weeks of therapy.
Those who don’t improve report common ongoing symptoms: fatigue, sleepiness, memory problems, cognitive difficulties (brain fog), and weight gain.
However, with 60% of people commonly having one or more of the same symptoms even when their thyroid levels are normal, pinpointing the actual causes is a challenge, the societies report.
In the absence of other diagnoses, clinicians often turn to alternative treatment strategies, which, as well as addition of LT3 to LT4, also include the use of desiccated thyroid extract (DTE).
DTE was the medication first used to treat hypothyroidism years ago, originally made from pig glands. There are now several prescription medications made from the desiccated (dried) thyroid glands of animals, including brands such as Armour Thyroid, NP Thyroid, and WP Thyroid.
The practice of prescribing combination therapy has already been deemed acceptable by both the European Thyroid Association (ETA) and American Thyroid Association (ATA). The latter recommended in its 2014 guidelines that the combination of LT3/LT4 therapy may be trialed in exceptional circumstances or among patients who fail to improve with LT4 alone.
In following suit, the new Joint British Thyroid Association/Society consensus statement cautions that, first and foremost, “most patients with hypothyroidism should be treated with levothyroxine alone.”
However, combination LT3/LT4 therapy may be considered an option under key important conditions, including:
- When a diagnosis of overt hypothyroidism (documented TSH ≥ 10 mU/L and/or low FT4 pretreatment with thyroid replacement hormones) is established. If overt hypothyroidism cannot be confirmed, patients are recommended to first have a trial without LT4 and a repeat serum TSH after 6 weeks.
- For patients with overt hypothyroidism, prior to consideration of LT3, the dose of LT4 should be optimized to a TSH in the target range of 0.3-2.0 mU/L for 3 to 6 months. In some patients, it may be acceptable to have serum TSH below reference range (e.g., 0.1-0.3 mU/L), but not fully suppressed in the long term, instead of starting LT3.
- A trial of combination therapy may be warranted with confirmed overt hypothyroidism and persistent symptoms despite LT4 treatment and the exclusion of other comorbidities.
- Clinicians should not feel obliged to start LT3 or continue LT3 medication provided by other health care practitioners or accessed without medical advice if they judge this not to be in the patient’s best interest.
- When opting for LT3, a minimum of 3 to 6 months on the combination therapy should be considered before determining response to the trial, and for assessment, monitoring with serum TSH only is recommended.
- Patients should be counseled regarding the risk of arrhythmias, accelerated bone loss, and stroke associated with iatrogenic hyperthyroidism and the need for long-term monitoring.
- Given the short half-life of LT3, splitting doses across 24 hours is recommended for many people.
The joint association does not recommend the use of desiccated thyroid extract (which appears to be surprisingly on the rise, as recently reported).
Reasons for persistent symptoms are murky; don’t forget menopause
The key reason for the emphasis on making sure patients have overt hypothyroidism before trying LT3 is that patients are often treated with LT4 despite not even having hypothyroidism to begin with.
“In reality, many patients with subclinical hypothyroidism [TSH 5-10 mU/L] are now treated with levothyroxine, fueling a rise in its use, such that it is now the third most frequently prescribed medication in the United Kingdom,” the authors explained.
“In contrast, few patients are advised to seek lifestyle and exercise changes, despite the fact that there is positive evidence to support their benefits,” they continued.
In a recent podcast, Anthony Bianco, MD, a past president of the ATA, underscored another important factor complicating the ability to make conclusive hypothyroidism diagnoses in women: menopause.
“In my experience, the most confusing factor [in treatment decisions] is menopausal syndrome,” he said.
“The symptoms are very similar. Most patients with hypothyroidism are women. Are we getting close to menopause? Are we dealing with this? Is estrogen replacement therapy an option for this woman? Should we consult a colleague?” Dr. Bianco explained.
And there are other possibilities, including anemia, iron deficiency, other autoimmune diseases, and diabetes, he added.
“Exclude everything that you know,” Dr. Bianco said. “Use your common sense.”
Although the new statement echoes other guidelines, the recommendations are helpful amid the ever-present debate, said Dr. Wiersinga, the endocrinologist from the Netherlands.
Because of the pressure to try combination therapy, from patients and patient associations, the statement’s position that doctors must stand by their clinical judgment is important, he noted.
“I think many doctors would welcome the recommendation that doctors are not obliged to prescribe any medication that they believe is not in the patient’s best interest, and, in particular, that ‘doctors have no obligation to continue to provide prescriptions for LT3 or desiccated thyroid extract that have been started by other health care practitioners or accessed without medical advice if they judge this not to be in the patient’s best interest,’” he asserted.
“Also, the recommendation that an endocrinologist should be involved when a trial of T3 is considered is very valuable,” he added, noting the potential scenario of patients going to a general practitioner if turned down by a specialist for LT3.
An international consensus statement published by members of the ATA, ETA, and British Thyroid Association in 2021 further set forth recommendations for the development of future trials of LT3/LT4 combination therapy to establish more conclusive guidance.
Senior author Simon H. Pearce has reported receiving speaker fees from IBSA, Merck, Quidel, Berlin-Chemie, and consulting for Apitope/Worg and Immunovant/Roivant on issues unrelated to T3. The other authors of the consensus statement have reported no relevant financial relationships. Dr. Wiersinga has reporting consulting for Prolevi Bio.
A version of this article first appeared on Medscape.com.
New recommendations from the Joint British Thyroid Association/Society add to the increasingly general consensus that liothyronine (LT3) may be useful in combination with standard levothyroxine (LT4) in the treatment of hypothyroidism in some patients whose symptoms persist after standard treatment, despite a lack of evidence of benefit in clinical trials.
“Most patients with primary hypothyroidism respond well to levothyroxine replacement therapy,” recommends the joint association in the consensus statement, by Rupa Ahluwalia, MBBS, MD, of Norfolk and Norwich University Hospitals NHS Trust, United Kingdom, and colleagues, recently published in Clinical Endocrinology.
they wrote.
The ongoing debate over the use of LT3/LT4 combination therapy has persisted for more than 2 decades, with at least 16 randomized controlled trials and four meta-analyses failing to show any significant benefit of the combined regimen in key quality of life and cognitive function outcomes compared with LT4 monotherapy. However, many patients continue to report benefits with combination therapy, so the issue has not been laid to rest.
Wilmar M. Wiersinga, MD, PhD, emeritus professor of endocrinology at the University of Amsterdam, said in an interview: “The scientific community is divided as to whether or not the LT4/LT3 combination therapy has any value whatsoever, whereas the pressure from individual patients and patient associations on physicians – both general practitioners and specialists/endocrinologists – can be very high [in terms of] demanding prescriptions for the combination therapy.
“I welcome this joint statement very much because it provides guidance, especially for clinicians, on a hotly debated issue,” he said.
Persistent symptoms drive pursuit of alternatives
T4 refers to the hormone thyroxine made in the body, and LT4 to the pharmaceutical replacement product for that hormone, levothyroxine. Similarly, T3 refers to the hormone triiodothyronine, made in the body and a precursor to thyroxine, and LT3 refers to its pharmaceutical replacement, liothyronine.
Driving the continued demand from some patients with hypothyroidism and interest among clinicians is the relatively high proportion of patients who continue to experience symptoms even after the normalization of biochemical levels after treatment with LT4, which resolves symptoms in most patients within weeks of therapy.
Those who don’t improve report common ongoing symptoms: fatigue, sleepiness, memory problems, cognitive difficulties (brain fog), and weight gain.
However, with 60% of people commonly having one or more of the same symptoms even when their thyroid levels are normal, pinpointing the actual causes is a challenge, the societies report.
In the absence of other diagnoses, clinicians often turn to alternative treatment strategies, which, as well as addition of LT3 to LT4, also include the use of desiccated thyroid extract (DTE).
DTE was the medication first used to treat hypothyroidism years ago, originally made from pig glands. There are now several prescription medications made from the desiccated (dried) thyroid glands of animals, including brands such as Armour Thyroid, NP Thyroid, and WP Thyroid.
The practice of prescribing combination therapy has already been deemed acceptable by both the European Thyroid Association (ETA) and American Thyroid Association (ATA). The latter recommended in its 2014 guidelines that the combination of LT3/LT4 therapy may be trialed in exceptional circumstances or among patients who fail to improve with LT4 alone.
In following suit, the new Joint British Thyroid Association/Society consensus statement cautions that, first and foremost, “most patients with hypothyroidism should be treated with levothyroxine alone.”
However, combination LT3/LT4 therapy may be considered an option under key important conditions, including:
- When a diagnosis of overt hypothyroidism (documented TSH ≥ 10 mU/L and/or low FT4 pretreatment with thyroid replacement hormones) is established. If overt hypothyroidism cannot be confirmed, patients are recommended to first have a trial without LT4 and a repeat serum TSH after 6 weeks.
- For patients with overt hypothyroidism, prior to consideration of LT3, the dose of LT4 should be optimized to a TSH in the target range of 0.3-2.0 mU/L for 3 to 6 months. In some patients, it may be acceptable to have serum TSH below reference range (e.g., 0.1-0.3 mU/L), but not fully suppressed in the long term, instead of starting LT3.
- A trial of combination therapy may be warranted with confirmed overt hypothyroidism and persistent symptoms despite LT4 treatment and the exclusion of other comorbidities.
- Clinicians should not feel obliged to start LT3 or continue LT3 medication provided by other health care practitioners or accessed without medical advice if they judge this not to be in the patient’s best interest.
- When opting for LT3, a minimum of 3 to 6 months on the combination therapy should be considered before determining response to the trial, and for assessment, monitoring with serum TSH only is recommended.
- Patients should be counseled regarding the risk of arrhythmias, accelerated bone loss, and stroke associated with iatrogenic hyperthyroidism and the need for long-term monitoring.
- Given the short half-life of LT3, splitting doses across 24 hours is recommended for many people.
The joint association does not recommend the use of desiccated thyroid extract (which appears to be surprisingly on the rise, as recently reported).
Reasons for persistent symptoms are murky; don’t forget menopause
The key reason for the emphasis on making sure patients have overt hypothyroidism before trying LT3 is that patients are often treated with LT4 despite not even having hypothyroidism to begin with.
“In reality, many patients with subclinical hypothyroidism [TSH 5-10 mU/L] are now treated with levothyroxine, fueling a rise in its use, such that it is now the third most frequently prescribed medication in the United Kingdom,” the authors explained.
“In contrast, few patients are advised to seek lifestyle and exercise changes, despite the fact that there is positive evidence to support their benefits,” they continued.
In a recent podcast, Anthony Bianco, MD, a past president of the ATA, underscored another important factor complicating the ability to make conclusive hypothyroidism diagnoses in women: menopause.
“In my experience, the most confusing factor [in treatment decisions] is menopausal syndrome,” he said.
“The symptoms are very similar. Most patients with hypothyroidism are women. Are we getting close to menopause? Are we dealing with this? Is estrogen replacement therapy an option for this woman? Should we consult a colleague?” Dr. Bianco explained.
And there are other possibilities, including anemia, iron deficiency, other autoimmune diseases, and diabetes, he added.
“Exclude everything that you know,” Dr. Bianco said. “Use your common sense.”
Although the new statement echoes other guidelines, the recommendations are helpful amid the ever-present debate, said Dr. Wiersinga, the endocrinologist from the Netherlands.
Because of the pressure to try combination therapy, from patients and patient associations, the statement’s position that doctors must stand by their clinical judgment is important, he noted.
“I think many doctors would welcome the recommendation that doctors are not obliged to prescribe any medication that they believe is not in the patient’s best interest, and, in particular, that ‘doctors have no obligation to continue to provide prescriptions for LT3 or desiccated thyroid extract that have been started by other health care practitioners or accessed without medical advice if they judge this not to be in the patient’s best interest,’” he asserted.
“Also, the recommendation that an endocrinologist should be involved when a trial of T3 is considered is very valuable,” he added, noting the potential scenario of patients going to a general practitioner if turned down by a specialist for LT3.
An international consensus statement published by members of the ATA, ETA, and British Thyroid Association in 2021 further set forth recommendations for the development of future trials of LT3/LT4 combination therapy to establish more conclusive guidance.
Senior author Simon H. Pearce has reported receiving speaker fees from IBSA, Merck, Quidel, Berlin-Chemie, and consulting for Apitope/Worg and Immunovant/Roivant on issues unrelated to T3. The other authors of the consensus statement have reported no relevant financial relationships. Dr. Wiersinga has reporting consulting for Prolevi Bio.
A version of this article first appeared on Medscape.com.
FROM CLINICAL ENDOCRINOLOGY
New cancer survival calculator focuses on oral cancer
This represents the first cancer survival calculator that provides “personalized estimates of the likelihood of surviving or dying from oral cancer or other causes,” according to the experts who developed the tool.
An analysis evaluating the new calculator revealed that people with oral cancer are more likely to die from other causes, compared with their peers without oral cancer, and that noncancer survival worsens with cancer stage.
With its unique design, the calculator “represents perhaps one of the most sophisticated and comprehensive tools to date by integrating multiple population-level data sources to account for general health status [and] disease exposures,” such as alcohol and tobacco, socioeconomic status, and coexisting conditions, the authors of an accompanying commentary wrote.
This calculator may just be the beginning. The broader aim of developing the tool, the study authors explained, is for this new calculator approach to be “applicable for developing future prognostic models of cancer and noncancer aspects of a person’s health in other cancers.”
The analysis was published in JAMA Otolaryngology–Head and Neck Surgery.
When assessing survival, factors such as cancer stage and tumor size are key, but comorbidities also play a crucial role. For oral cancer in particular, where alcohol and tobacco use are notorious risk factors, comorbidities occur frequently and are often serious.
To create a model that provides more “holistic and personalized” estimates and includes a host of factors that can affect the risk of death, the authors tapped into data from the Surveillance, Epidemiology, and End Results database to develop the SEER Oral Cancer Survival Calculator.
Alongside data from the SEER database, the calculator used data from the National Health Interview Survey’s Longitudinal Mortality Files to obtain estimates of general health status, life expectancy without cancer, and the probability of dying from the cancer or from other causes within 1-10 years among people with newly diagnosed oral cancer.
Overall, the data included 22,392 patients, aged 20-94, with oral squamous cell carcinoma, 60.5% of whom were male and 78% White, as well as 402,626 interviewees from the survey. The calculator did not include patients with tonsil- or tongue-based cancers, which were not considered anatomically part of the oral cavity.
The most common conditions coexisting with oral cancer were diabetes and chronic obstructive pulmonary disease among older patients. Among those with oral cancer, more than half (52.8%) had none of the major coexisting conditions, which also included peripheral and cerebrovascular disease, compared with 80% of the Medicare population.
The researchers described and validated four models – one that estimated the probability of death due to oral cancer, and then three others that estimated the probability of death from other causes, with variations based on the specific data and covariates included.
Overall, the models in the calculator estimated that patients with oral cancer have a higher risk of death from other causes, compared with the general population, and survival estimates for noncancer causes got worse with more advanced cancer stage.
For instance, for a patient diagnosed with stage 3 oral cancer after age 50, the chances of being alive at age 70 were 60% for females and 44% for males in the absence of cancer, whereas the corresponding survival estimates in the general U.S. population were 86% for females and 79% for males – an absolute difference of 26 and 35 percentage points.
One key reason for this trend is that patients with later-stage cancers likely also have more coexisting health conditions, first author Louise Davies, MD, from the Geisel School of Medicine at Dartmouth, Lebanon, N.H., explained.
Another reason: For cancers with low enough mortality rates, people might be more likely to die from causes other than their cancer. This can also occur in ductal carcinoma in situ breast cancer or papillary thyroid cancer, noted Dr. Davies, also from the Department of Veterans Affairs Medical Center, White River Junction, Vt.
Commenting on the study, Eric Moore, MD, a head and neck surgeon with the Mayo Clinic in Rochester, Minn., said that while such prediction tools are important, they also come with caveats.
“I think these calculators are helpful and certainly having them widely available to people gives them another piece of knowledge that can be powerful,” he told this news organization. “But you want to make sure you don’t interpret them as the end-all, be-all message, because there are an infinite number of variables that could influence survival that aren’t available in some of these datasets.”
Neil D. Gross, MD, a professor of head and neck surgery at the University of Texas MD Anderson Cancer Center, Houston, agreed. Although this new calculator uses a large dataset, such tools “can be imperfect” and some factors simply can’t be calculated, such as a person’s priorities, Dr. Gross said.
That’s why there’s no substitute for having a “very personal discussion between a patient and a physician to decide what’s best.” And this calculator is just one tool to help with that process, Dr. Gross said.
The commentary authors echoed these sentiments. “This calculator can potentially bridge the gaps between the survival estimates in the literature, life tables, clinical gestalt, and physician attempts to contextualize the inherent limitations of applying survival curves and averages to the one patient with the diagnosis,” wrote Leila J. Mady, MD, PhD, MPH, Wayne M. Koch, MD, and Carole Fakhry, MD, MPH, all from Johns Hopkins School of Medicine, Baltimore.
But a caveat in providing such predictions is the possible psychological effect the news can have.
“Potential risks of revealing personalized prognostic survival estimates to patients include increased anxiety and distress surrounding competing causes of death [and] misinterpretation of data,” the commentary authors cautioned, adding that “we must present such information with grace and sensitivity.”
Dr. Davies recommends that clinicians ask patients what they want to know because that will vary by patient and potentially over time for the same patient.
“People are more than their cancer diagnosis,” said Dr. Davies. “Giving them the opportunity to consider their life as a whole is the aim.”
The oral cancer calculator can be publicly accessed through the National Cancer Institute. The study was supported by the Department of Veterans Affairs and the National Cancer Institute as part of an interagency agreement. The authors report no relevant financial relationships.
A version of this article appeared on Medscape.com.
This represents the first cancer survival calculator that provides “personalized estimates of the likelihood of surviving or dying from oral cancer or other causes,” according to the experts who developed the tool.
An analysis evaluating the new calculator revealed that people with oral cancer are more likely to die from other causes, compared with their peers without oral cancer, and that noncancer survival worsens with cancer stage.
With its unique design, the calculator “represents perhaps one of the most sophisticated and comprehensive tools to date by integrating multiple population-level data sources to account for general health status [and] disease exposures,” such as alcohol and tobacco, socioeconomic status, and coexisting conditions, the authors of an accompanying commentary wrote.
This calculator may just be the beginning. The broader aim of developing the tool, the study authors explained, is for this new calculator approach to be “applicable for developing future prognostic models of cancer and noncancer aspects of a person’s health in other cancers.”
The analysis was published in JAMA Otolaryngology–Head and Neck Surgery.
When assessing survival, factors such as cancer stage and tumor size are key, but comorbidities also play a crucial role. For oral cancer in particular, where alcohol and tobacco use are notorious risk factors, comorbidities occur frequently and are often serious.
To create a model that provides more “holistic and personalized” estimates and includes a host of factors that can affect the risk of death, the authors tapped into data from the Surveillance, Epidemiology, and End Results database to develop the SEER Oral Cancer Survival Calculator.
Alongside data from the SEER database, the calculator used data from the National Health Interview Survey’s Longitudinal Mortality Files to obtain estimates of general health status, life expectancy without cancer, and the probability of dying from the cancer or from other causes within 1-10 years among people with newly diagnosed oral cancer.
Overall, the data included 22,392 patients, aged 20-94, with oral squamous cell carcinoma, 60.5% of whom were male and 78% White, as well as 402,626 interviewees from the survey. The calculator did not include patients with tonsil- or tongue-based cancers, which were not considered anatomically part of the oral cavity.
The most common conditions coexisting with oral cancer were diabetes and chronic obstructive pulmonary disease among older patients. Among those with oral cancer, more than half (52.8%) had none of the major coexisting conditions, which also included peripheral and cerebrovascular disease, compared with 80% of the Medicare population.
The researchers described and validated four models – one that estimated the probability of death due to oral cancer, and then three others that estimated the probability of death from other causes, with variations based on the specific data and covariates included.
Overall, the models in the calculator estimated that patients with oral cancer have a higher risk of death from other causes, compared with the general population, and survival estimates for noncancer causes got worse with more advanced cancer stage.
For instance, for a patient diagnosed with stage 3 oral cancer after age 50, the chances of being alive at age 70 were 60% for females and 44% for males in the absence of cancer, whereas the corresponding survival estimates in the general U.S. population were 86% for females and 79% for males – an absolute difference of 26 and 35 percentage points.
One key reason for this trend is that patients with later-stage cancers likely also have more coexisting health conditions, first author Louise Davies, MD, from the Geisel School of Medicine at Dartmouth, Lebanon, N.H., explained.
Another reason: For cancers with low enough mortality rates, people might be more likely to die from causes other than their cancer. This can also occur in ductal carcinoma in situ breast cancer or papillary thyroid cancer, noted Dr. Davies, also from the Department of Veterans Affairs Medical Center, White River Junction, Vt.
Commenting on the study, Eric Moore, MD, a head and neck surgeon with the Mayo Clinic in Rochester, Minn., said that while such prediction tools are important, they also come with caveats.
“I think these calculators are helpful and certainly having them widely available to people gives them another piece of knowledge that can be powerful,” he told this news organization. “But you want to make sure you don’t interpret them as the end-all, be-all message, because there are an infinite number of variables that could influence survival that aren’t available in some of these datasets.”
Neil D. Gross, MD, a professor of head and neck surgery at the University of Texas MD Anderson Cancer Center, Houston, agreed. Although this new calculator uses a large dataset, such tools “can be imperfect” and some factors simply can’t be calculated, such as a person’s priorities, Dr. Gross said.
That’s why there’s no substitute for having a “very personal discussion between a patient and a physician to decide what’s best.” And this calculator is just one tool to help with that process, Dr. Gross said.
The commentary authors echoed these sentiments. “This calculator can potentially bridge the gaps between the survival estimates in the literature, life tables, clinical gestalt, and physician attempts to contextualize the inherent limitations of applying survival curves and averages to the one patient with the diagnosis,” wrote Leila J. Mady, MD, PhD, MPH, Wayne M. Koch, MD, and Carole Fakhry, MD, MPH, all from Johns Hopkins School of Medicine, Baltimore.
But a caveat in providing such predictions is the possible psychological effect the news can have.
“Potential risks of revealing personalized prognostic survival estimates to patients include increased anxiety and distress surrounding competing causes of death [and] misinterpretation of data,” the commentary authors cautioned, adding that “we must present such information with grace and sensitivity.”
Dr. Davies recommends that clinicians ask patients what they want to know because that will vary by patient and potentially over time for the same patient.
“People are more than their cancer diagnosis,” said Dr. Davies. “Giving them the opportunity to consider their life as a whole is the aim.”
The oral cancer calculator can be publicly accessed through the National Cancer Institute. The study was supported by the Department of Veterans Affairs and the National Cancer Institute as part of an interagency agreement. The authors report no relevant financial relationships.
A version of this article appeared on Medscape.com.
This represents the first cancer survival calculator that provides “personalized estimates of the likelihood of surviving or dying from oral cancer or other causes,” according to the experts who developed the tool.
An analysis evaluating the new calculator revealed that people with oral cancer are more likely to die from other causes, compared with their peers without oral cancer, and that noncancer survival worsens with cancer stage.
With its unique design, the calculator “represents perhaps one of the most sophisticated and comprehensive tools to date by integrating multiple population-level data sources to account for general health status [and] disease exposures,” such as alcohol and tobacco, socioeconomic status, and coexisting conditions, the authors of an accompanying commentary wrote.
This calculator may just be the beginning. The broader aim of developing the tool, the study authors explained, is for this new calculator approach to be “applicable for developing future prognostic models of cancer and noncancer aspects of a person’s health in other cancers.”
The analysis was published in JAMA Otolaryngology–Head and Neck Surgery.
When assessing survival, factors such as cancer stage and tumor size are key, but comorbidities also play a crucial role. For oral cancer in particular, where alcohol and tobacco use are notorious risk factors, comorbidities occur frequently and are often serious.
To create a model that provides more “holistic and personalized” estimates and includes a host of factors that can affect the risk of death, the authors tapped into data from the Surveillance, Epidemiology, and End Results database to develop the SEER Oral Cancer Survival Calculator.
Alongside data from the SEER database, the calculator used data from the National Health Interview Survey’s Longitudinal Mortality Files to obtain estimates of general health status, life expectancy without cancer, and the probability of dying from the cancer or from other causes within 1-10 years among people with newly diagnosed oral cancer.
Overall, the data included 22,392 patients, aged 20-94, with oral squamous cell carcinoma, 60.5% of whom were male and 78% White, as well as 402,626 interviewees from the survey. The calculator did not include patients with tonsil- or tongue-based cancers, which were not considered anatomically part of the oral cavity.
The most common conditions coexisting with oral cancer were diabetes and chronic obstructive pulmonary disease among older patients. Among those with oral cancer, more than half (52.8%) had none of the major coexisting conditions, which also included peripheral and cerebrovascular disease, compared with 80% of the Medicare population.
The researchers described and validated four models – one that estimated the probability of death due to oral cancer, and then three others that estimated the probability of death from other causes, with variations based on the specific data and covariates included.
Overall, the models in the calculator estimated that patients with oral cancer have a higher risk of death from other causes, compared with the general population, and survival estimates for noncancer causes got worse with more advanced cancer stage.
For instance, for a patient diagnosed with stage 3 oral cancer after age 50, the chances of being alive at age 70 were 60% for females and 44% for males in the absence of cancer, whereas the corresponding survival estimates in the general U.S. population were 86% for females and 79% for males – an absolute difference of 26 and 35 percentage points.
One key reason for this trend is that patients with later-stage cancers likely also have more coexisting health conditions, first author Louise Davies, MD, from the Geisel School of Medicine at Dartmouth, Lebanon, N.H., explained.
Another reason: For cancers with low enough mortality rates, people might be more likely to die from causes other than their cancer. This can also occur in ductal carcinoma in situ breast cancer or papillary thyroid cancer, noted Dr. Davies, also from the Department of Veterans Affairs Medical Center, White River Junction, Vt.
Commenting on the study, Eric Moore, MD, a head and neck surgeon with the Mayo Clinic in Rochester, Minn., said that while such prediction tools are important, they also come with caveats.
“I think these calculators are helpful and certainly having them widely available to people gives them another piece of knowledge that can be powerful,” he told this news organization. “But you want to make sure you don’t interpret them as the end-all, be-all message, because there are an infinite number of variables that could influence survival that aren’t available in some of these datasets.”
Neil D. Gross, MD, a professor of head and neck surgery at the University of Texas MD Anderson Cancer Center, Houston, agreed. Although this new calculator uses a large dataset, such tools “can be imperfect” and some factors simply can’t be calculated, such as a person’s priorities, Dr. Gross said.
That’s why there’s no substitute for having a “very personal discussion between a patient and a physician to decide what’s best.” And this calculator is just one tool to help with that process, Dr. Gross said.
The commentary authors echoed these sentiments. “This calculator can potentially bridge the gaps between the survival estimates in the literature, life tables, clinical gestalt, and physician attempts to contextualize the inherent limitations of applying survival curves and averages to the one patient with the diagnosis,” wrote Leila J. Mady, MD, PhD, MPH, Wayne M. Koch, MD, and Carole Fakhry, MD, MPH, all from Johns Hopkins School of Medicine, Baltimore.
But a caveat in providing such predictions is the possible psychological effect the news can have.
“Potential risks of revealing personalized prognostic survival estimates to patients include increased anxiety and distress surrounding competing causes of death [and] misinterpretation of data,” the commentary authors cautioned, adding that “we must present such information with grace and sensitivity.”
Dr. Davies recommends that clinicians ask patients what they want to know because that will vary by patient and potentially over time for the same patient.
“People are more than their cancer diagnosis,” said Dr. Davies. “Giving them the opportunity to consider their life as a whole is the aim.”
The oral cancer calculator can be publicly accessed through the National Cancer Institute. The study was supported by the Department of Veterans Affairs and the National Cancer Institute as part of an interagency agreement. The authors report no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM JAMA OTOLARYNGOLOGY–HEAD AND NECK SURGERY
Quizartinib boosts AML survival, regardless of SCT
The research shows that “FLT3 inhibitors are most effective in patients who are minimal residual disease (MRD) positive before allo-HCT,” first author Richard Schlenk, MD, of Heidelberg (Germany) University Hospital and the German Cancer Research Center, Heidelberg, said in an interview.
The findings are from a post-hoc analysis of the phase 3, multicenter QuANTUM-First trial, which involved patients with the FLT3-ITD mutation, who make up about a quarter of those with AML and who can have shorter survival and increased risk of relapse, compared with patients without the mutation. The current post-hoc analysis of the trial was presented at the European Hematology Association 2023 Congress.
The trial, published in April in The Lancet, showed significant benefits in newly diagnosed patients with FLT3-ITD AML who were treated with quizartinib and standard induction and consolidation therapy and then continued on quizartinib as monotherapy for up to 3 years.
In the trial, quizartinib, combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and continued as monotherapy following consolidation, was associated with a significant improvement in overall survival versus placebo (median 31.9 months versus 15.1 months, respectively; hazard ratio, 0.776; P = .0324).
For the post hoc analysis of the trial, the authors sought to evaluate if the effects were observed regardless of whether or not allo-HCT was received – which may not be recommended when patients go into remission after the first round of chemotherapy. The issue is important, as efficacy of other targeted therapy with the FLT3 inhibitors has been associated with allo-HCT treatment.
“Midostaurin, for example is mostly effective if [the drug] is followed by allo-HCT, and much less effective [no significant improvement] without allo-HCT,” Dr. Schlenk said.
The authors also sought to evaluate the relationship between minimal residual disease (MRD) prior to allo-HCT in FLT3-ITD and overall survival.
For the trial, 539 patients, with a median age of 56 were randomized to quizartinib (n = 268) or placebo (n = 271), and 147 patients (54.9%) in the quizartinib arm and 150 (55.4%) in the placebo arm achieved complete remission after induction. The rates of incomplete hematologic recovery (CRi) were 16.8% and 9.6%, respectively.
Of those achieving complete remission, 57.1% of patients on quizartinib and 48.7% of those receiving placebo underwent allo-HCT in the first complete remission. The median time to allo-HCT in the two groups was 3.5 months with quizartinib and 3.3 months for placebo.
Following the completion of allo-HCT, 61 patients (72.6%) receiving quizartinib and 36 (49.3%) receiving placebo started 3 years of continuation monotherapy.
In addition, 115 patients received allo-HCT outside of CR1, including 60 on quizartinib and 55 on placebo.
After adjustment for factors including region, age, and white blood count, patients treated with quizartinib treatment had a significantly higher overall survival (HR, 0.770; P = .0284), as did those receiving allo-HCT in CR1 (HR, 0.424; P < .0001).
Furthermore, patients receiving quizartinib had a longer overall survival regardless of whether they received allo-HCT in CR1 or not.
Of note, quizartinib-treated patients who were MRD positive prior to their allo-HCT transplant had a longer overall survival versus placebo (HR, 0.471); as did those who were MRD negative (HR, 0.717), to a lesser degree.
There were no new safety signals identified among patients undergoing allo-HCT.
Of note, cytomegalovirus infection was more common in the quizartinib group (11.8%) versus placebo (5.5%), while decreased appetite was less common with quizartinib (2.9%) versus placebo (12.1%).
Asked by an audience member about any risk of graft-versus-host disease (GVHD), Dr. Schlenk noted that “no difference between the quizartinib and placebo arms has been observed in GVHD acute and chronic.”
He added that patients “appear to benefit more from quizartinib if they have higher allelic frequency versus lower, overall,” and that younger patients, in general, showed greater benefit from quizartinib versus those over 60.
In general, “we see that for patients receiving allo-HCT transplantation, it’s beneficial to be randomized in the quizartinib arm [while] patients who did not undergo allo-HCT in first complete remission benefit equally when treated with quizartinib versus placebo,” he said in presenting the findings at the EHA meeting.
“And irrespective of pre–allo-HCT MRD status, longer survival was observed in those treated with quizartinib versus placebo, but most benefit was observed in those who were MRD positive.”
Quizartinib was approved in Japan this year in combination with chemotherapy for patients with newly diagnosed AML whose tumors harbor FLT3-ITD mutations.
The drug was granted a priority review by the U.S. Food and Drug Administration in October 2022. While the target action date was in April, a new decision date of July 21, 2023, is expected.
The study was sponsored by Daiichi Sankyo. Dr. Schlenk reported relationships with Daiichi Sankyo and other companies.
The research shows that “FLT3 inhibitors are most effective in patients who are minimal residual disease (MRD) positive before allo-HCT,” first author Richard Schlenk, MD, of Heidelberg (Germany) University Hospital and the German Cancer Research Center, Heidelberg, said in an interview.
The findings are from a post-hoc analysis of the phase 3, multicenter QuANTUM-First trial, which involved patients with the FLT3-ITD mutation, who make up about a quarter of those with AML and who can have shorter survival and increased risk of relapse, compared with patients without the mutation. The current post-hoc analysis of the trial was presented at the European Hematology Association 2023 Congress.
The trial, published in April in The Lancet, showed significant benefits in newly diagnosed patients with FLT3-ITD AML who were treated with quizartinib and standard induction and consolidation therapy and then continued on quizartinib as monotherapy for up to 3 years.
In the trial, quizartinib, combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and continued as monotherapy following consolidation, was associated with a significant improvement in overall survival versus placebo (median 31.9 months versus 15.1 months, respectively; hazard ratio, 0.776; P = .0324).
For the post hoc analysis of the trial, the authors sought to evaluate if the effects were observed regardless of whether or not allo-HCT was received – which may not be recommended when patients go into remission after the first round of chemotherapy. The issue is important, as efficacy of other targeted therapy with the FLT3 inhibitors has been associated with allo-HCT treatment.
“Midostaurin, for example is mostly effective if [the drug] is followed by allo-HCT, and much less effective [no significant improvement] without allo-HCT,” Dr. Schlenk said.
The authors also sought to evaluate the relationship between minimal residual disease (MRD) prior to allo-HCT in FLT3-ITD and overall survival.
For the trial, 539 patients, with a median age of 56 were randomized to quizartinib (n = 268) or placebo (n = 271), and 147 patients (54.9%) in the quizartinib arm and 150 (55.4%) in the placebo arm achieved complete remission after induction. The rates of incomplete hematologic recovery (CRi) were 16.8% and 9.6%, respectively.
Of those achieving complete remission, 57.1% of patients on quizartinib and 48.7% of those receiving placebo underwent allo-HCT in the first complete remission. The median time to allo-HCT in the two groups was 3.5 months with quizartinib and 3.3 months for placebo.
Following the completion of allo-HCT, 61 patients (72.6%) receiving quizartinib and 36 (49.3%) receiving placebo started 3 years of continuation monotherapy.
In addition, 115 patients received allo-HCT outside of CR1, including 60 on quizartinib and 55 on placebo.
After adjustment for factors including region, age, and white blood count, patients treated with quizartinib treatment had a significantly higher overall survival (HR, 0.770; P = .0284), as did those receiving allo-HCT in CR1 (HR, 0.424; P < .0001).
Furthermore, patients receiving quizartinib had a longer overall survival regardless of whether they received allo-HCT in CR1 or not.
Of note, quizartinib-treated patients who were MRD positive prior to their allo-HCT transplant had a longer overall survival versus placebo (HR, 0.471); as did those who were MRD negative (HR, 0.717), to a lesser degree.
There were no new safety signals identified among patients undergoing allo-HCT.
Of note, cytomegalovirus infection was more common in the quizartinib group (11.8%) versus placebo (5.5%), while decreased appetite was less common with quizartinib (2.9%) versus placebo (12.1%).
Asked by an audience member about any risk of graft-versus-host disease (GVHD), Dr. Schlenk noted that “no difference between the quizartinib and placebo arms has been observed in GVHD acute and chronic.”
He added that patients “appear to benefit more from quizartinib if they have higher allelic frequency versus lower, overall,” and that younger patients, in general, showed greater benefit from quizartinib versus those over 60.
In general, “we see that for patients receiving allo-HCT transplantation, it’s beneficial to be randomized in the quizartinib arm [while] patients who did not undergo allo-HCT in first complete remission benefit equally when treated with quizartinib versus placebo,” he said in presenting the findings at the EHA meeting.
“And irrespective of pre–allo-HCT MRD status, longer survival was observed in those treated with quizartinib versus placebo, but most benefit was observed in those who were MRD positive.”
Quizartinib was approved in Japan this year in combination with chemotherapy for patients with newly diagnosed AML whose tumors harbor FLT3-ITD mutations.
The drug was granted a priority review by the U.S. Food and Drug Administration in October 2022. While the target action date was in April, a new decision date of July 21, 2023, is expected.
The study was sponsored by Daiichi Sankyo. Dr. Schlenk reported relationships with Daiichi Sankyo and other companies.
The research shows that “FLT3 inhibitors are most effective in patients who are minimal residual disease (MRD) positive before allo-HCT,” first author Richard Schlenk, MD, of Heidelberg (Germany) University Hospital and the German Cancer Research Center, Heidelberg, said in an interview.
The findings are from a post-hoc analysis of the phase 3, multicenter QuANTUM-First trial, which involved patients with the FLT3-ITD mutation, who make up about a quarter of those with AML and who can have shorter survival and increased risk of relapse, compared with patients without the mutation. The current post-hoc analysis of the trial was presented at the European Hematology Association 2023 Congress.
The trial, published in April in The Lancet, showed significant benefits in newly diagnosed patients with FLT3-ITD AML who were treated with quizartinib and standard induction and consolidation therapy and then continued on quizartinib as monotherapy for up to 3 years.
In the trial, quizartinib, combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and continued as monotherapy following consolidation, was associated with a significant improvement in overall survival versus placebo (median 31.9 months versus 15.1 months, respectively; hazard ratio, 0.776; P = .0324).
For the post hoc analysis of the trial, the authors sought to evaluate if the effects were observed regardless of whether or not allo-HCT was received – which may not be recommended when patients go into remission after the first round of chemotherapy. The issue is important, as efficacy of other targeted therapy with the FLT3 inhibitors has been associated with allo-HCT treatment.
“Midostaurin, for example is mostly effective if [the drug] is followed by allo-HCT, and much less effective [no significant improvement] without allo-HCT,” Dr. Schlenk said.
The authors also sought to evaluate the relationship between minimal residual disease (MRD) prior to allo-HCT in FLT3-ITD and overall survival.
For the trial, 539 patients, with a median age of 56 were randomized to quizartinib (n = 268) or placebo (n = 271), and 147 patients (54.9%) in the quizartinib arm and 150 (55.4%) in the placebo arm achieved complete remission after induction. The rates of incomplete hematologic recovery (CRi) were 16.8% and 9.6%, respectively.
Of those achieving complete remission, 57.1% of patients on quizartinib and 48.7% of those receiving placebo underwent allo-HCT in the first complete remission. The median time to allo-HCT in the two groups was 3.5 months with quizartinib and 3.3 months for placebo.
Following the completion of allo-HCT, 61 patients (72.6%) receiving quizartinib and 36 (49.3%) receiving placebo started 3 years of continuation monotherapy.
In addition, 115 patients received allo-HCT outside of CR1, including 60 on quizartinib and 55 on placebo.
After adjustment for factors including region, age, and white blood count, patients treated with quizartinib treatment had a significantly higher overall survival (HR, 0.770; P = .0284), as did those receiving allo-HCT in CR1 (HR, 0.424; P < .0001).
Furthermore, patients receiving quizartinib had a longer overall survival regardless of whether they received allo-HCT in CR1 or not.
Of note, quizartinib-treated patients who were MRD positive prior to their allo-HCT transplant had a longer overall survival versus placebo (HR, 0.471); as did those who were MRD negative (HR, 0.717), to a lesser degree.
There were no new safety signals identified among patients undergoing allo-HCT.
Of note, cytomegalovirus infection was more common in the quizartinib group (11.8%) versus placebo (5.5%), while decreased appetite was less common with quizartinib (2.9%) versus placebo (12.1%).
Asked by an audience member about any risk of graft-versus-host disease (GVHD), Dr. Schlenk noted that “no difference between the quizartinib and placebo arms has been observed in GVHD acute and chronic.”
He added that patients “appear to benefit more from quizartinib if they have higher allelic frequency versus lower, overall,” and that younger patients, in general, showed greater benefit from quizartinib versus those over 60.
In general, “we see that for patients receiving allo-HCT transplantation, it’s beneficial to be randomized in the quizartinib arm [while] patients who did not undergo allo-HCT in first complete remission benefit equally when treated with quizartinib versus placebo,” he said in presenting the findings at the EHA meeting.
“And irrespective of pre–allo-HCT MRD status, longer survival was observed in those treated with quizartinib versus placebo, but most benefit was observed in those who were MRD positive.”
Quizartinib was approved in Japan this year in combination with chemotherapy for patients with newly diagnosed AML whose tumors harbor FLT3-ITD mutations.
The drug was granted a priority review by the U.S. Food and Drug Administration in October 2022. While the target action date was in April, a new decision date of July 21, 2023, is expected.
The study was sponsored by Daiichi Sankyo. Dr. Schlenk reported relationships with Daiichi Sankyo and other companies.
FROM THE EHA 2023 CONGRESS
SCD, beta-thalassemia: CRISPR-based gene therapy `transformative’
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
FROM EHA 2023
PV: Novel rusfertide shows ‘impressive’ efficacy
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
FROM EHA 2023
Multiple sclerosis has a misdiagnosis problem
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
AT CMSC 2023
‘Best’ for most APL patients: Chemo-free regimen
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
FROM EHA 2023
Antibiotic prophylaxis may lower SSIs in skin cancer surgery
Delivering s, compared with not using incision site antibiotics.
The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.
“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”
The study was published online in JAMA Surgery.
Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.
To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.
The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.
Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).
However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.
The results were similar after adjusting for baseline differences and lesion ulceration.
The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).
Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.
The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.
Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.
“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.
The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.
“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.
“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.
“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.
The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.
A version of this article first appeared on Medscape.com.
Delivering s, compared with not using incision site antibiotics.
The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.
“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”
The study was published online in JAMA Surgery.
Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.
To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.
The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.
Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).
However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.
The results were similar after adjusting for baseline differences and lesion ulceration.
The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).
Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.
The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.
Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.
“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.
The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.
“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.
“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.
“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.
The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.
A version of this article first appeared on Medscape.com.
Delivering s, compared with not using incision site antibiotics.
The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.
“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”
The study was published online in JAMA Surgery.
Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.
To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.
The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.
Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).
However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.
The results were similar after adjusting for baseline differences and lesion ulceration.
The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).
Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.
The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.
Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.
“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.
The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.
“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.
“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.
“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.
The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.
A version of this article first appeared on Medscape.com.
FROM JAMA SURGERY
‘Strikingly positive’ effect of novel MS agent
AURORA, COLO. –
“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.
The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Significant lesion reduction
With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.
To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.
Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.
The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).
Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.
In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.
In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.
Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.
In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”
Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
An intriguing mechanism
Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.
“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.
“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.
Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.
“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”
The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.
A version of this article first appears on Medscape.com.
AURORA, COLO. –
“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.
The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Significant lesion reduction
With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.
To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.
Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.
The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).
Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.
In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.
In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.
Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.
In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”
Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
An intriguing mechanism
Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.
“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.
“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.
Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.
“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”
The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.
A version of this article first appears on Medscape.com.
AURORA, COLO. –
“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.
The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Significant lesion reduction
With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.
To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.
Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.
The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).
Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.
In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.
In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.
Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.
In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”
Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
An intriguing mechanism
Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.
“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.
“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.
Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.
“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”
The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.
A version of this article first appears on Medscape.com.
At CMSC 2023
`Remarkable’: CAR T therapy for CLL/SLL
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
FROM ASCO 2023