This week in MDedge Cardiocast: Most tPA-eligible stroke patients now get treated within an hour, atrial fib patients with prior hemorrhagic stroke who get their LAA closed can be safely treated, SGLT2 inhibitors are quickly morphing from diabetes to heart failure drugs, and the MESA cardiovascular disease risk calculator can be an improvement on the ACC/AHA version.

Amazon AlexaApple Podcasts

Google Podcasts

TuneIn

This week in MDedge Cardiocast: Most tPA-eligible stroke patients now get treated within an hour, atrial fib patients with prior hemorrhagic stroke who get their LAA closed can be safely treated, SGLT2 inhibitors are quickly morphing from diabetes to heart failure drugs, and the MESA cardiovascular disease risk calculator can be an improvement on the ACC/AHA version.

Amazon AlexaApple Podcasts

Google Podcasts

TuneIn

This week in MDedge Cardiocast: Most tPA-eligible stroke patients now get treated within an hour, atrial fib patients with prior hemorrhagic stroke who get their LAA closed can be safely treated, SGLT2 inhibitors are quickly morphing from diabetes to heart failure drugs, and the MESA cardiovascular disease risk calculator can be an improvement on the ACC/AHA version.

Amazon AlexaApple Podcasts

Google Podcasts

TuneIn

Among older adults, adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease, according to research published in Movement Disorders.

snyferok/Thinkstock

“Recommending the Mediterranean diet pattern, either to reduce the risk or lessen the effects ... of prodromal Parkinson’s disease, needs to be considered and further explored,” said lead author Maria I. Maraki, PhD, of the department of nutrition and dietetics at Harokopio University in Athens, Greece, and her research colleagues.

Evidence regarding the effect of a Mediterranean diet on Parkinson’s disease risk remains limited, however, and physicians should be cautious in interpreting the data, researchers noted in accompanying editorials.

“There is a puzzling constellation of information and data that cannot be reconciled with a simple model accounting for the role of diet, vascular risk factors, and the neurodegenerative process and mechanisms underlying Parkinson’s disease,” Connie Marras, MD, PhD, and Jose A. Obeso, MD, PhD, said in an editorial. Given Maraki et al.’s findings, “most of us would be glad to accept that such a causal inverse association exists and can therefore be strongly recommended to our patients,” but “further work is needed before definitive conclusions can be reached,” Dr. Marras and Dr. Obeso wrote. Dr. Marras is affiliated with the University Health Network and the University of Toronto. Dr. Obeso is affiliated with University Hospital HM Puerta del Sur, CEU San Pablo University, Móstoles, Spain.


 

The role of diet

Prior research has suggested that adherence to the Mediterranean diet – characterized by consumption of nonrefined cereals, fruits, vegetables, legumes, potatoes, fish, and olive oil – may be associated with reduced risk of Parkinson’s disease. In addition, studies have found that adherence to the Mediterranean diet may be protective in other diseases, including dementia and cardiovascular disease. Dr. Maraki and her colleagues sought to assess whether adherence to the Mediterranean diet is associated with the likelihood of prodromal Parkinson’s disease or its manifestations. To calculate the probability of prodromal Parkinson’s disease, the investigators used a tool created by the International Parkinson and Movement Disorder Society (MDS) that takes into account baseline risk factors as well as prodromal markers such as constipation and motor slowing.

They analyzed data from 1,731 participants in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece. Participants, 41% of whom were male, were aged 65 years or older and did not have Parkinson’s disease. They completed a detailed food frequency questionnaire, and the researchers calculated how closely each participant’s diet adhered to the Mediterranean diet. Diet adherence scores ranged from 0 to 55, with higher scores indicating greater adherence.

The median probability of prodromal Parkinson’s disease was 1.9% (range, 0.2%-96.7%), and the probability was lower among those with greater adherence to the Mediterranean diet. This difference was “driven mostly by nonmotor markers of prodromal Parkinson’s disease,” including depression, constipation, urinary dysfunction, and daytime somnolence, the researchers said. “Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.” Compared with participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile had an approximately 21% lower probability for prodromal Parkinson’s disease.
 

Potential confounding

“This study pushes the prodromal criteria into performing a job they were never designed to do,” which presents potential pitfalls, Ronald B. Postuma, MD, of the department of neurology at Montreal General Hospital in Quebec, said in an accompanying editorial.

While the MDS criteria were designed to assess the likelihood that any person over age 50 years is in a state of prodromal Parkinson’s disease, the present study aimed to evaluate whether a single putative risk factor for Parkinson’s disease is associated with the likelihood of its prodromal state.

In addition, the analysis did not include some of the prodromal markers that are part of the MDS criteria, including olfaction, polysomnographic-proven REM sleep behavior disorder, and dopaminergic functional neuroimaging.

“As pointed out by the researchers, many of the risk factors in the prodromal criteria are potentially confounded by factors other than Parkinson’s disease; for example, one could imagine that older people, men, or farmers (with their higher pesticide exposure) are less likely to follow the Mediterranean diet simply because of different cultural lifestyle patterns,” Dr. Postuma said.

It is also possible that the Mediterranean diet affects prodromal markers such as constipation, sleep, or depression without affecting underlying neurodegenerative disease. In any case, the effect sizes observed in the study were small, and there was no evidence that participants who adhered most closely to a Mediterranean diet had less parkinsonism, Dr. Postuma said.

These limitations do not preclude physicians from recommending the diet for other reasons. “Numerous studies, reviews, meta-analyses, and randomized controlled trials consistently rank the Mediterranean diet as among the healthiest diets available,” Dr. Postuma said. “So, one can clearly recommend diets such as these, even if not necessarily for Parkinson’s disease prevention.”
 

Adding insights

The researchers used a Mediterranean diet score that was developed in a population of adults from metropolitan Athens, “an area not unlike the one in which the score is being applied in the HELIAD study,” Christy C. Tangney, PhD, professor of clinical nutrition and preventive medicine and associate dean for research at Rush University Medical Center, Chicago, said in a separate editorial. As expected, the average Mediterranean diet adherence score in this study was higher than that in the Chicago Health and Aging Project (33.2 vs. 28.2).

“If we can identify differences in diet or lifestyle patterns and risk of this latent phase of Parkinson’s disease neurodegeneration, we may be one step closer to identifying preventive measures,” she said. Follow-up reports from HELIAD and other cohorts may allow researchers to assess how changes in dietary patterns relate to changes in Parkinson’s disease markers, the probability of prodromal Parkinson’s disease, and incident Parkinson’s disease, Dr. Tangney said.

The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation. Dr. Tangney and Dr. Postuma had no conflicts of interest.

jremaly@mdedge.com

SOURCE: Maraki MI et al. Mov Disord. 2018 Oct 10. doi: 10.1002/mds.27489.

Among older adults, adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease, according to research published in Movement Disorders.

snyferok/Thinkstock

“Recommending the Mediterranean diet pattern, either to reduce the risk or lessen the effects ... of prodromal Parkinson’s disease, needs to be considered and further explored,” said lead author Maria I. Maraki, PhD, of the department of nutrition and dietetics at Harokopio University in Athens, Greece, and her research colleagues.

Evidence regarding the effect of a Mediterranean diet on Parkinson’s disease risk remains limited, however, and physicians should be cautious in interpreting the data, researchers noted in accompanying editorials.

“There is a puzzling constellation of information and data that cannot be reconciled with a simple model accounting for the role of diet, vascular risk factors, and the neurodegenerative process and mechanisms underlying Parkinson’s disease,” Connie Marras, MD, PhD, and Jose A. Obeso, MD, PhD, said in an editorial. Given Maraki et al.’s findings, “most of us would be glad to accept that such a causal inverse association exists and can therefore be strongly recommended to our patients,” but “further work is needed before definitive conclusions can be reached,” Dr. Marras and Dr. Obeso wrote. Dr. Marras is affiliated with the University Health Network and the University of Toronto. Dr. Obeso is affiliated with University Hospital HM Puerta del Sur, CEU San Pablo University, Móstoles, Spain.


 

The role of diet

Prior research has suggested that adherence to the Mediterranean diet – characterized by consumption of nonrefined cereals, fruits, vegetables, legumes, potatoes, fish, and olive oil – may be associated with reduced risk of Parkinson’s disease. In addition, studies have found that adherence to the Mediterranean diet may be protective in other diseases, including dementia and cardiovascular disease. Dr. Maraki and her colleagues sought to assess whether adherence to the Mediterranean diet is associated with the likelihood of prodromal Parkinson’s disease or its manifestations. To calculate the probability of prodromal Parkinson’s disease, the investigators used a tool created by the International Parkinson and Movement Disorder Society (MDS) that takes into account baseline risk factors as well as prodromal markers such as constipation and motor slowing.

They analyzed data from 1,731 participants in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece. Participants, 41% of whom were male, were aged 65 years or older and did not have Parkinson’s disease. They completed a detailed food frequency questionnaire, and the researchers calculated how closely each participant’s diet adhered to the Mediterranean diet. Diet adherence scores ranged from 0 to 55, with higher scores indicating greater adherence.

The median probability of prodromal Parkinson’s disease was 1.9% (range, 0.2%-96.7%), and the probability was lower among those with greater adherence to the Mediterranean diet. This difference was “driven mostly by nonmotor markers of prodromal Parkinson’s disease,” including depression, constipation, urinary dysfunction, and daytime somnolence, the researchers said. “Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.” Compared with participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile had an approximately 21% lower probability for prodromal Parkinson’s disease.
 

Potential confounding

“This study pushes the prodromal criteria into performing a job they were never designed to do,” which presents potential pitfalls, Ronald B. Postuma, MD, of the department of neurology at Montreal General Hospital in Quebec, said in an accompanying editorial.

While the MDS criteria were designed to assess the likelihood that any person over age 50 years is in a state of prodromal Parkinson’s disease, the present study aimed to evaluate whether a single putative risk factor for Parkinson’s disease is associated with the likelihood of its prodromal state.

In addition, the analysis did not include some of the prodromal markers that are part of the MDS criteria, including olfaction, polysomnographic-proven REM sleep behavior disorder, and dopaminergic functional neuroimaging.

“As pointed out by the researchers, many of the risk factors in the prodromal criteria are potentially confounded by factors other than Parkinson’s disease; for example, one could imagine that older people, men, or farmers (with their higher pesticide exposure) are less likely to follow the Mediterranean diet simply because of different cultural lifestyle patterns,” Dr. Postuma said.

It is also possible that the Mediterranean diet affects prodromal markers such as constipation, sleep, or depression without affecting underlying neurodegenerative disease. In any case, the effect sizes observed in the study were small, and there was no evidence that participants who adhered most closely to a Mediterranean diet had less parkinsonism, Dr. Postuma said.

These limitations do not preclude physicians from recommending the diet for other reasons. “Numerous studies, reviews, meta-analyses, and randomized controlled trials consistently rank the Mediterranean diet as among the healthiest diets available,” Dr. Postuma said. “So, one can clearly recommend diets such as these, even if not necessarily for Parkinson’s disease prevention.”
 

Adding insights

The researchers used a Mediterranean diet score that was developed in a population of adults from metropolitan Athens, “an area not unlike the one in which the score is being applied in the HELIAD study,” Christy C. Tangney, PhD, professor of clinical nutrition and preventive medicine and associate dean for research at Rush University Medical Center, Chicago, said in a separate editorial. As expected, the average Mediterranean diet adherence score in this study was higher than that in the Chicago Health and Aging Project (33.2 vs. 28.2).

“If we can identify differences in diet or lifestyle patterns and risk of this latent phase of Parkinson’s disease neurodegeneration, we may be one step closer to identifying preventive measures,” she said. Follow-up reports from HELIAD and other cohorts may allow researchers to assess how changes in dietary patterns relate to changes in Parkinson’s disease markers, the probability of prodromal Parkinson’s disease, and incident Parkinson’s disease, Dr. Tangney said.

The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation. Dr. Tangney and Dr. Postuma had no conflicts of interest.

jremaly@mdedge.com

SOURCE: Maraki MI et al. Mov Disord. 2018 Oct 10. doi: 10.1002/mds.27489.

Among older adults, adherence to a Mediterranean diet is associated with lower probability of prodromal Parkinson’s disease, according to research published in Movement Disorders.

snyferok/Thinkstock

“Recommending the Mediterranean diet pattern, either to reduce the risk or lessen the effects ... of prodromal Parkinson’s disease, needs to be considered and further explored,” said lead author Maria I. Maraki, PhD, of the department of nutrition and dietetics at Harokopio University in Athens, Greece, and her research colleagues.

Evidence regarding the effect of a Mediterranean diet on Parkinson’s disease risk remains limited, however, and physicians should be cautious in interpreting the data, researchers noted in accompanying editorials.

“There is a puzzling constellation of information and data that cannot be reconciled with a simple model accounting for the role of diet, vascular risk factors, and the neurodegenerative process and mechanisms underlying Parkinson’s disease,” Connie Marras, MD, PhD, and Jose A. Obeso, MD, PhD, said in an editorial. Given Maraki et al.’s findings, “most of us would be glad to accept that such a causal inverse association exists and can therefore be strongly recommended to our patients,” but “further work is needed before definitive conclusions can be reached,” Dr. Marras and Dr. Obeso wrote. Dr. Marras is affiliated with the University Health Network and the University of Toronto. Dr. Obeso is affiliated with University Hospital HM Puerta del Sur, CEU San Pablo University, Móstoles, Spain.


 

The role of diet

Prior research has suggested that adherence to the Mediterranean diet – characterized by consumption of nonrefined cereals, fruits, vegetables, legumes, potatoes, fish, and olive oil – may be associated with reduced risk of Parkinson’s disease. In addition, studies have found that adherence to the Mediterranean diet may be protective in other diseases, including dementia and cardiovascular disease. Dr. Maraki and her colleagues sought to assess whether adherence to the Mediterranean diet is associated with the likelihood of prodromal Parkinson’s disease or its manifestations. To calculate the probability of prodromal Parkinson’s disease, the investigators used a tool created by the International Parkinson and Movement Disorder Society (MDS) that takes into account baseline risk factors as well as prodromal markers such as constipation and motor slowing.

They analyzed data from 1,731 participants in the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort in Greece. Participants, 41% of whom were male, were aged 65 years or older and did not have Parkinson’s disease. They completed a detailed food frequency questionnaire, and the researchers calculated how closely each participant’s diet adhered to the Mediterranean diet. Diet adherence scores ranged from 0 to 55, with higher scores indicating greater adherence.

The median probability of prodromal Parkinson’s disease was 1.9% (range, 0.2%-96.7%), and the probability was lower among those with greater adherence to the Mediterranean diet. This difference was “driven mostly by nonmotor markers of prodromal Parkinson’s disease,” including depression, constipation, urinary dysfunction, and daytime somnolence, the researchers said. “Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal Parkinson’s disease.” Compared with participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile had an approximately 21% lower probability for prodromal Parkinson’s disease.
 

Potential confounding

“This study pushes the prodromal criteria into performing a job they were never designed to do,” which presents potential pitfalls, Ronald B. Postuma, MD, of the department of neurology at Montreal General Hospital in Quebec, said in an accompanying editorial.

While the MDS criteria were designed to assess the likelihood that any person over age 50 years is in a state of prodromal Parkinson’s disease, the present study aimed to evaluate whether a single putative risk factor for Parkinson’s disease is associated with the likelihood of its prodromal state.

In addition, the analysis did not include some of the prodromal markers that are part of the MDS criteria, including olfaction, polysomnographic-proven REM sleep behavior disorder, and dopaminergic functional neuroimaging.

“As pointed out by the researchers, many of the risk factors in the prodromal criteria are potentially confounded by factors other than Parkinson’s disease; for example, one could imagine that older people, men, or farmers (with their higher pesticide exposure) are less likely to follow the Mediterranean diet simply because of different cultural lifestyle patterns,” Dr. Postuma said.

It is also possible that the Mediterranean diet affects prodromal markers such as constipation, sleep, or depression without affecting underlying neurodegenerative disease. In any case, the effect sizes observed in the study were small, and there was no evidence that participants who adhered most closely to a Mediterranean diet had less parkinsonism, Dr. Postuma said.

These limitations do not preclude physicians from recommending the diet for other reasons. “Numerous studies, reviews, meta-analyses, and randomized controlled trials consistently rank the Mediterranean diet as among the healthiest diets available,” Dr. Postuma said. “So, one can clearly recommend diets such as these, even if not necessarily for Parkinson’s disease prevention.”
 

Adding insights

The researchers used a Mediterranean diet score that was developed in a population of adults from metropolitan Athens, “an area not unlike the one in which the score is being applied in the HELIAD study,” Christy C. Tangney, PhD, professor of clinical nutrition and preventive medicine and associate dean for research at Rush University Medical Center, Chicago, said in a separate editorial. As expected, the average Mediterranean diet adherence score in this study was higher than that in the Chicago Health and Aging Project (33.2 vs. 28.2).

“If we can identify differences in diet or lifestyle patterns and risk of this latent phase of Parkinson’s disease neurodegeneration, we may be one step closer to identifying preventive measures,” she said. Follow-up reports from HELIAD and other cohorts may allow researchers to assess how changes in dietary patterns relate to changes in Parkinson’s disease markers, the probability of prodromal Parkinson’s disease, and incident Parkinson’s disease, Dr. Tangney said.

The study authors had no conflicts of interest or financial disclosures. The study was supported by a grant from the Alzheimer’s Association, an ESPA‐EU grant cofunded by the European Social Fund and Greek National resources, and a grant from the Ministry for Health and Social Solidarity (Greece). Dr. Maraki and a coauthor have received financial support from the Greek State Scholarships Foundation. Dr. Tangney and Dr. Postuma had no conflicts of interest.

jremaly@mdedge.com

SOURCE: Maraki MI et al. Mov Disord. 2018 Oct 10. doi: 10.1002/mds.27489.

HONOLULU – Deferoxamine mesylate does not significantly improve 90-day outcomes after intracranial hemorrhage (ICH), according to trial results described at the International Stroke Conference sponsored by the American Heart Association. However, the drug is safe and well tolerated and data suggest that it may improve outcomes at 180 days.

Animal studies indicate that iron, which is released from hemolyzed red blood cells, accumulates in the brain after ICH and is associated with secondary neuronal injury and death. Researchers have found that deferoxamine, an iron chelator, provides neuroprotection and improves recovery after experimental ICH. The drug also has anti-inflammatory, antiapoptotic, and BP-lowering effects. Deferoxamine has been approved since the 1960s.

Magdy H. Selim, MD, PhD, a neurologist at Beth Israel Deaconess Medical Center in Boston, and colleagues hypothesized that treatment with deferoxamine could improve outcomes in patients with ICH. The researchers conducted a phase 2 clinical trial to evaluate whether deferoxamine should be studied in a phase 3 efficacy trial. In their multicenter, double-blind study, Dr. Selim and his colleagues randomized patients with spontaneous supratentorial ICH in equal groups to 32 mg/kg per day of deferoxamine or saline placebo. Treatments were administered as intravenous infusions for 3 consecutive days, and therapy was initiated within 24 hours after ICH onset. The follow-up period was 6 months.

Eligible participants had an National Institutes of Health Stroke Scale score of 6 or higher, a Glasgow Coma Scale score greater than 6, and had been functionally independent before the hemorrhage. The researchers excluded patients with a secondary cause for ICH or coagulopathy.

The primary endpoint in the futility analysis was the proportion of participants with a good clinical outcome – defined as a modified Rankin Scale (mRS) score of 0-2 – at 90 days and 180 days. The secondary endpoint was good outcome, defined as an mRS score of 0-3, at 90 days. Safety endpoints included all deferoxamine-related adverse events until day 7 or discharge (whichever was earlier) and serious adverse events through day 90.

Dr. Selim and his colleagues enrolled 294 participants in their trial, 3 of whom did not receive treatment. Of these included participants, 147 (50.5%) were randomized to placebo and 144 (49.5%) were randomized to deferoxamine. Participants’ mean age was 60.3 years, and 38.5% of the population was female.

Overall, the two study arms did not differ significantly according to demographic and clinical characteristics, however, there were more nonwhite patients in the deferoxamine arm than in the placebo arm, however. In addition, thalamic hemorrhage and intraventricular hemorrhage were more common in the placebo-treated group and hemorrhages in the putamen and basal ganglia were more common in the deferoxamine-treated group.

The rates of adverse events were comparable between the two study arms. Dr. Selim and his colleagues found no unexpected safety issues. Mortality was low, and the 90-day and 180-day mortality rates were comparable between the two treatment arms.

Approximately 34% of deferoxamine-treated patients and 33% of placebo-treated patients had an mRS score of 0-2 at 90 days. The adjusted absolute risk difference between arms was 0.6%; this result did not surpass the predefined futility threshold. The risk difference between groups for mRS score of 0-2 at 180 days was 8.6% in favor of deferoxamine, which did surpass the futility threshold.

The risk difference for meeting the secondary endpoint was 6.2% in favor of deferoxamine; this result did not surpass the futility threshold. Patients in both treatment groups improved between day 90 and day 180. The likelihood of good outcome was approximately 10% higher in the deferoxamine group at day 90 and 26% higher in the deferoxamine group at day 180.

“It is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as mRS score of 0-2 at 90 days,” said Dr. Selim. “These data, together with the data from MISTIE and CLEAR, suggest that ICH trials need to have a longer follow-up period to capture the full extent of recovery after ICH. Several of our secondary analyses tended to favor deferoxamine over the placebo arm and leave open the possibility that deferoxamine might lead to improved outcome at 180 days.”

The researchers received support from the NIH and the National Institute of Neurological Disorders and Stroke.

egreb@mdedge.com

SOURCE: Selim MH et al. ISC 2019, Abstract LB22.

HONOLULU – Deferoxamine mesylate does not significantly improve 90-day outcomes after intracranial hemorrhage (ICH), according to trial results described at the International Stroke Conference sponsored by the American Heart Association. However, the drug is safe and well tolerated and data suggest that it may improve outcomes at 180 days.

Animal studies indicate that iron, which is released from hemolyzed red blood cells, accumulates in the brain after ICH and is associated with secondary neuronal injury and death. Researchers have found that deferoxamine, an iron chelator, provides neuroprotection and improves recovery after experimental ICH. The drug also has anti-inflammatory, antiapoptotic, and BP-lowering effects. Deferoxamine has been approved since the 1960s.

Magdy H. Selim, MD, PhD, a neurologist at Beth Israel Deaconess Medical Center in Boston, and colleagues hypothesized that treatment with deferoxamine could improve outcomes in patients with ICH. The researchers conducted a phase 2 clinical trial to evaluate whether deferoxamine should be studied in a phase 3 efficacy trial. In their multicenter, double-blind study, Dr. Selim and his colleagues randomized patients with spontaneous supratentorial ICH in equal groups to 32 mg/kg per day of deferoxamine or saline placebo. Treatments were administered as intravenous infusions for 3 consecutive days, and therapy was initiated within 24 hours after ICH onset. The follow-up period was 6 months.

Eligible participants had an National Institutes of Health Stroke Scale score of 6 or higher, a Glasgow Coma Scale score greater than 6, and had been functionally independent before the hemorrhage. The researchers excluded patients with a secondary cause for ICH or coagulopathy.

The primary endpoint in the futility analysis was the proportion of participants with a good clinical outcome – defined as a modified Rankin Scale (mRS) score of 0-2 – at 90 days and 180 days. The secondary endpoint was good outcome, defined as an mRS score of 0-3, at 90 days. Safety endpoints included all deferoxamine-related adverse events until day 7 or discharge (whichever was earlier) and serious adverse events through day 90.

Dr. Selim and his colleagues enrolled 294 participants in their trial, 3 of whom did not receive treatment. Of these included participants, 147 (50.5%) were randomized to placebo and 144 (49.5%) were randomized to deferoxamine. Participants’ mean age was 60.3 years, and 38.5% of the population was female.

Overall, the two study arms did not differ significantly according to demographic and clinical characteristics, however, there were more nonwhite patients in the deferoxamine arm than in the placebo arm, however. In addition, thalamic hemorrhage and intraventricular hemorrhage were more common in the placebo-treated group and hemorrhages in the putamen and basal ganglia were more common in the deferoxamine-treated group.

The rates of adverse events were comparable between the two study arms. Dr. Selim and his colleagues found no unexpected safety issues. Mortality was low, and the 90-day and 180-day mortality rates were comparable between the two treatment arms.

Approximately 34% of deferoxamine-treated patients and 33% of placebo-treated patients had an mRS score of 0-2 at 90 days. The adjusted absolute risk difference between arms was 0.6%; this result did not surpass the predefined futility threshold. The risk difference between groups for mRS score of 0-2 at 180 days was 8.6% in favor of deferoxamine, which did surpass the futility threshold.

The risk difference for meeting the secondary endpoint was 6.2% in favor of deferoxamine; this result did not surpass the futility threshold. Patients in both treatment groups improved between day 90 and day 180. The likelihood of good outcome was approximately 10% higher in the deferoxamine group at day 90 and 26% higher in the deferoxamine group at day 180.

“It is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as mRS score of 0-2 at 90 days,” said Dr. Selim. “These data, together with the data from MISTIE and CLEAR, suggest that ICH trials need to have a longer follow-up period to capture the full extent of recovery after ICH. Several of our secondary analyses tended to favor deferoxamine over the placebo arm and leave open the possibility that deferoxamine might lead to improved outcome at 180 days.”

The researchers received support from the NIH and the National Institute of Neurological Disorders and Stroke.

egreb@mdedge.com

SOURCE: Selim MH et al. ISC 2019, Abstract LB22.

HONOLULU – Deferoxamine mesylate does not significantly improve 90-day outcomes after intracranial hemorrhage (ICH), according to trial results described at the International Stroke Conference sponsored by the American Heart Association. However, the drug is safe and well tolerated and data suggest that it may improve outcomes at 180 days.

Animal studies indicate that iron, which is released from hemolyzed red blood cells, accumulates in the brain after ICH and is associated with secondary neuronal injury and death. Researchers have found that deferoxamine, an iron chelator, provides neuroprotection and improves recovery after experimental ICH. The drug also has anti-inflammatory, antiapoptotic, and BP-lowering effects. Deferoxamine has been approved since the 1960s.

Magdy H. Selim, MD, PhD, a neurologist at Beth Israel Deaconess Medical Center in Boston, and colleagues hypothesized that treatment with deferoxamine could improve outcomes in patients with ICH. The researchers conducted a phase 2 clinical trial to evaluate whether deferoxamine should be studied in a phase 3 efficacy trial. In their multicenter, double-blind study, Dr. Selim and his colleagues randomized patients with spontaneous supratentorial ICH in equal groups to 32 mg/kg per day of deferoxamine or saline placebo. Treatments were administered as intravenous infusions for 3 consecutive days, and therapy was initiated within 24 hours after ICH onset. The follow-up period was 6 months.

Eligible participants had an National Institutes of Health Stroke Scale score of 6 or higher, a Glasgow Coma Scale score greater than 6, and had been functionally independent before the hemorrhage. The researchers excluded patients with a secondary cause for ICH or coagulopathy.

The primary endpoint in the futility analysis was the proportion of participants with a good clinical outcome – defined as a modified Rankin Scale (mRS) score of 0-2 – at 90 days and 180 days. The secondary endpoint was good outcome, defined as an mRS score of 0-3, at 90 days. Safety endpoints included all deferoxamine-related adverse events until day 7 or discharge (whichever was earlier) and serious adverse events through day 90.

Dr. Selim and his colleagues enrolled 294 participants in their trial, 3 of whom did not receive treatment. Of these included participants, 147 (50.5%) were randomized to placebo and 144 (49.5%) were randomized to deferoxamine. Participants’ mean age was 60.3 years, and 38.5% of the population was female.

Overall, the two study arms did not differ significantly according to demographic and clinical characteristics, however, there were more nonwhite patients in the deferoxamine arm than in the placebo arm, however. In addition, thalamic hemorrhage and intraventricular hemorrhage were more common in the placebo-treated group and hemorrhages in the putamen and basal ganglia were more common in the deferoxamine-treated group.

The rates of adverse events were comparable between the two study arms. Dr. Selim and his colleagues found no unexpected safety issues. Mortality was low, and the 90-day and 180-day mortality rates were comparable between the two treatment arms.

Approximately 34% of deferoxamine-treated patients and 33% of placebo-treated patients had an mRS score of 0-2 at 90 days. The adjusted absolute risk difference between arms was 0.6%; this result did not surpass the predefined futility threshold. The risk difference between groups for mRS score of 0-2 at 180 days was 8.6% in favor of deferoxamine, which did surpass the futility threshold.

The risk difference for meeting the secondary endpoint was 6.2% in favor of deferoxamine; this result did not surpass the futility threshold. Patients in both treatment groups improved between day 90 and day 180. The likelihood of good outcome was approximately 10% higher in the deferoxamine group at day 90 and 26% higher in the deferoxamine group at day 180.

“It is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as mRS score of 0-2 at 90 days,” said Dr. Selim. “These data, together with the data from MISTIE and CLEAR, suggest that ICH trials need to have a longer follow-up period to capture the full extent of recovery after ICH. Several of our secondary analyses tended to favor deferoxamine over the placebo arm and leave open the possibility that deferoxamine might lead to improved outcome at 180 days.”

The researchers received support from the NIH and the National Institute of Neurological Disorders and Stroke.

egreb@mdedge.com

SOURCE: Selim MH et al. ISC 2019, Abstract LB22.

WASHINGTON – Kim Schrier, MD, the first pediatrician elected to the U.S. House of Representatives, describes her decision to seek a seat in Congress as a natural extension of her work caring for children.

Nick Piegari/MDedge News

Following the 2016 election, she said she became concerned about what she saw as rising threats to the health of families. The Republican congressional majority made several attempts to undo the Affordable Care Act. In an interview with Pediatric News, Dr. Schrier, a Democrat who represents Washington’s 8th district, said she worried about a rollback of the insurance protections the 2010 law created for people with preexisting conditions. She understood the need for these guarantees of access to care both as a physician and as a patient – Dr. Schrier was diagnosed with type 1 diabetes as a teenager.

Her concerns extended beyond the health care and insurance. Efforts to weaken environmental protections could create new risks for children’s health, she said. Dr. Schrier also worried about attempts to erode Roe v. Wade and to reduce funding for programs such as SNAP supplemental food assistance.

“I felt like every one of those elements was under assault and so who better to speak to that than the pediatrician with her own preexisting condition?” she said.

Dr. Schrier currently is the only female physician serving in Congress. “It’s exciting to be here and it’s exciting to bring that lens that no one else really has,” she said.

Still, the decision to run was not easy.

“I’ve left a practice that I love. I had no intention to run for office ever in my life.”

Dr. Schrier earned an undergraduate degree in astrophysics at the University of California, Berkeley. She worked for about a year at the Environmental Protection Agency before earning her medical degree at the University of California, Davis, and completing her residency at Stanford (Calif.) University. She was working as a pediatrician in the Seattle-based Virginia Mason Health System when she decided to run for Congress.

Her husband, David, and son, Sam, are staying on in the family’s home of Sammamish as she settles into her new work as a legislator. She said she returns home often.

“I go back and forth every week. I just didn’t see it working all that well with having them here,” she said. “I work from 8:00 or 9:00 in the morning until 9:00 at night and would never see them anyway.”

Dr. Schrier has long used an insulin pump and glucose monitors to keep her diabetes in check.

“It is a bit more difficult because my days are less predictable” when working in the Capitol, she said. “So I carry granola bars around in my purse.”
 

Bipartisan bill

Dr. Schrier said she is taking her time in deciding on the first health care legislation that she will introduce in the House. She’s considering measures that would focus on children’s health, possibly in connection with nutrition or with protection of those in immigrant communities.

“I’m looking at something that is uniquely me and know that a lot of my colleagues are going to be working on things like affordability of medications and I will partner with them,” she said.

Dr. Schrier said that she supports creating a way for people to buy into Medicare coverage, paying for this government insurance on a sliding scale. The American public is getting more comfortable with the idea of expanding access to Medicare, which “is incredibly popular but now exclusively available for seniors and other selected groups,” she said.

In her view, an expanded Medicare would stand among private insurance options, allowing for a gradual change.

“It’s a way that we could start tomorrow to let people buy in, as opposed to having a 5- or 10-year rollout that something as big and daunting as a Medicare-for-all plan would require,” she said.

But Dr. Schrier said she won’t start her legislative career with such a sweeping goal as a Medicare buy-in bill.

“I think it would be jumping the gun to come in right away with my own health plan because I really want to collaborate” with fellow lawmakers, she said.

Winning Republican support for her future legislation also is important to Dr. Schrier. “I want to make sure that I have the support of a lot of my colleagues,” she said. “I would like to see a successful first bill.

“The advantage of coming at this as a pediatrician and taking on a first bill or bills that relate to children is that both sides of the aisle can get behind what is good for families and children,” Dr. Schrier said. “I think that’s hard to really argue with.”

Dr. Schrier cosponsored her first piece of legislation in February, reaching across the aisle to work with Rep. Dan Newhouse (R-Wash.) to introduce H.R. 1048, a bill to authorize the next phase of a water resource management plan for Washington’s Yakima River basin.

Beyond that effort, Dr. Schrier said she’s seeking areas of common ground with Republican members of her state delegation. She had dinner in January with two Republican members of the Washington delegation – Rep. Cathy McMorris Rodgers and Rep. Jaime Herrera Beutler. Rep. McMorris Rodgers’ website describes her as a leader in the disabilities community and the only member of Congress to give birth three times while in office, while Rep. Herrera Beutler has spoken openly about her daughter’s battle with Potter’s syndrome, in which the kidneys fail to develop.

Within her party, Dr. Schrier is allied with the moderate New Democrat Coalition. Also in the coalition are two fellow physicians, Ami Bera, MD, and Raul Ruiz, MD, both from California. The New Democrat Coalition also has several lawmakers who flipped House seats from Republican control to Democratic in the 2018 election, a group that includes Dr. Schrier and Reps. Jennifer Wexton (D-VA) and Mikie Sherrill (D-NJ). It was the victories of these moderates that gave the Democrats control of the House. Yet, they get far less media attention than do House Democratic freshmen who are politically further to the left. These members, including Rep. Alexandria Ocasio-Cortez (D-N.Y.), tend to hail from districts where Republicans stand little chance of winning.

Dr. Schrier said the Democratic party, and Congress as a whole, should focus on issues such as affordable health care, on which the country can unite.

“If you’re looking for collaboration, that just doesn’t make the headlines and yet it is the absolute best thing for the country,” she said, adding that most Americans have more centrist views. “So we should really be governing to the middle and that’s how we can move our country forward.”

WASHINGTON – Kim Schrier, MD, the first pediatrician elected to the U.S. House of Representatives, describes her decision to seek a seat in Congress as a natural extension of her work caring for children.

Nick Piegari/MDedge News

Following the 2016 election, she said she became concerned about what she saw as rising threats to the health of families. The Republican congressional majority made several attempts to undo the Affordable Care Act. In an interview with Pediatric News, Dr. Schrier, a Democrat who represents Washington’s 8th district, said she worried about a rollback of the insurance protections the 2010 law created for people with preexisting conditions. She understood the need for these guarantees of access to care both as a physician and as a patient – Dr. Schrier was diagnosed with type 1 diabetes as a teenager.

Her concerns extended beyond the health care and insurance. Efforts to weaken environmental protections could create new risks for children’s health, she said. Dr. Schrier also worried about attempts to erode Roe v. Wade and to reduce funding for programs such as SNAP supplemental food assistance.

“I felt like every one of those elements was under assault and so who better to speak to that than the pediatrician with her own preexisting condition?” she said.

Dr. Schrier currently is the only female physician serving in Congress. “It’s exciting to be here and it’s exciting to bring that lens that no one else really has,” she said.

Still, the decision to run was not easy.

“I’ve left a practice that I love. I had no intention to run for office ever in my life.”

Dr. Schrier earned an undergraduate degree in astrophysics at the University of California, Berkeley. She worked for about a year at the Environmental Protection Agency before earning her medical degree at the University of California, Davis, and completing her residency at Stanford (Calif.) University. She was working as a pediatrician in the Seattle-based Virginia Mason Health System when she decided to run for Congress.

Her husband, David, and son, Sam, are staying on in the family’s home of Sammamish as she settles into her new work as a legislator. She said she returns home often.

“I go back and forth every week. I just didn’t see it working all that well with having them here,” she said. “I work from 8:00 or 9:00 in the morning until 9:00 at night and would never see them anyway.”

Dr. Schrier has long used an insulin pump and glucose monitors to keep her diabetes in check.

“It is a bit more difficult because my days are less predictable” when working in the Capitol, she said. “So I carry granola bars around in my purse.”
 

Bipartisan bill

Dr. Schrier said she is taking her time in deciding on the first health care legislation that she will introduce in the House. She’s considering measures that would focus on children’s health, possibly in connection with nutrition or with protection of those in immigrant communities.

“I’m looking at something that is uniquely me and know that a lot of my colleagues are going to be working on things like affordability of medications and I will partner with them,” she said.

Dr. Schrier said that she supports creating a way for people to buy into Medicare coverage, paying for this government insurance on a sliding scale. The American public is getting more comfortable with the idea of expanding access to Medicare, which “is incredibly popular but now exclusively available for seniors and other selected groups,” she said.

In her view, an expanded Medicare would stand among private insurance options, allowing for a gradual change.

“It’s a way that we could start tomorrow to let people buy in, as opposed to having a 5- or 10-year rollout that something as big and daunting as a Medicare-for-all plan would require,” she said.

But Dr. Schrier said she won’t start her legislative career with such a sweeping goal as a Medicare buy-in bill.

“I think it would be jumping the gun to come in right away with my own health plan because I really want to collaborate” with fellow lawmakers, she said.

Winning Republican support for her future legislation also is important to Dr. Schrier. “I want to make sure that I have the support of a lot of my colleagues,” she said. “I would like to see a successful first bill.

“The advantage of coming at this as a pediatrician and taking on a first bill or bills that relate to children is that both sides of the aisle can get behind what is good for families and children,” Dr. Schrier said. “I think that’s hard to really argue with.”

Dr. Schrier cosponsored her first piece of legislation in February, reaching across the aisle to work with Rep. Dan Newhouse (R-Wash.) to introduce H.R. 1048, a bill to authorize the next phase of a water resource management plan for Washington’s Yakima River basin.

Beyond that effort, Dr. Schrier said she’s seeking areas of common ground with Republican members of her state delegation. She had dinner in January with two Republican members of the Washington delegation – Rep. Cathy McMorris Rodgers and Rep. Jaime Herrera Beutler. Rep. McMorris Rodgers’ website describes her as a leader in the disabilities community and the only member of Congress to give birth three times while in office, while Rep. Herrera Beutler has spoken openly about her daughter’s battle with Potter’s syndrome, in which the kidneys fail to develop.

Within her party, Dr. Schrier is allied with the moderate New Democrat Coalition. Also in the coalition are two fellow physicians, Ami Bera, MD, and Raul Ruiz, MD, both from California. The New Democrat Coalition also has several lawmakers who flipped House seats from Republican control to Democratic in the 2018 election, a group that includes Dr. Schrier and Reps. Jennifer Wexton (D-VA) and Mikie Sherrill (D-NJ). It was the victories of these moderates that gave the Democrats control of the House. Yet, they get far less media attention than do House Democratic freshmen who are politically further to the left. These members, including Rep. Alexandria Ocasio-Cortez (D-N.Y.), tend to hail from districts where Republicans stand little chance of winning.

Dr. Schrier said the Democratic party, and Congress as a whole, should focus on issues such as affordable health care, on which the country can unite.

“If you’re looking for collaboration, that just doesn’t make the headlines and yet it is the absolute best thing for the country,” she said, adding that most Americans have more centrist views. “So we should really be governing to the middle and that’s how we can move our country forward.”

WASHINGTON – Kim Schrier, MD, the first pediatrician elected to the U.S. House of Representatives, describes her decision to seek a seat in Congress as a natural extension of her work caring for children.

Nick Piegari/MDedge News

Following the 2016 election, she said she became concerned about what she saw as rising threats to the health of families. The Republican congressional majority made several attempts to undo the Affordable Care Act. In an interview with Pediatric News, Dr. Schrier, a Democrat who represents Washington’s 8th district, said she worried about a rollback of the insurance protections the 2010 law created for people with preexisting conditions. She understood the need for these guarantees of access to care both as a physician and as a patient – Dr. Schrier was diagnosed with type 1 diabetes as a teenager.

Her concerns extended beyond the health care and insurance. Efforts to weaken environmental protections could create new risks for children’s health, she said. Dr. Schrier also worried about attempts to erode Roe v. Wade and to reduce funding for programs such as SNAP supplemental food assistance.

“I felt like every one of those elements was under assault and so who better to speak to that than the pediatrician with her own preexisting condition?” she said.

Dr. Schrier currently is the only female physician serving in Congress. “It’s exciting to be here and it’s exciting to bring that lens that no one else really has,” she said.

Still, the decision to run was not easy.

“I’ve left a practice that I love. I had no intention to run for office ever in my life.”

Dr. Schrier earned an undergraduate degree in astrophysics at the University of California, Berkeley. She worked for about a year at the Environmental Protection Agency before earning her medical degree at the University of California, Davis, and completing her residency at Stanford (Calif.) University. She was working as a pediatrician in the Seattle-based Virginia Mason Health System when she decided to run for Congress.

Her husband, David, and son, Sam, are staying on in the family’s home of Sammamish as she settles into her new work as a legislator. She said she returns home often.

“I go back and forth every week. I just didn’t see it working all that well with having them here,” she said. “I work from 8:00 or 9:00 in the morning until 9:00 at night and would never see them anyway.”

Dr. Schrier has long used an insulin pump and glucose monitors to keep her diabetes in check.

“It is a bit more difficult because my days are less predictable” when working in the Capitol, she said. “So I carry granola bars around in my purse.”
 

Bipartisan bill

Dr. Schrier said she is taking her time in deciding on the first health care legislation that she will introduce in the House. She’s considering measures that would focus on children’s health, possibly in connection with nutrition or with protection of those in immigrant communities.

“I’m looking at something that is uniquely me and know that a lot of my colleagues are going to be working on things like affordability of medications and I will partner with them,” she said.

Dr. Schrier said that she supports creating a way for people to buy into Medicare coverage, paying for this government insurance on a sliding scale. The American public is getting more comfortable with the idea of expanding access to Medicare, which “is incredibly popular but now exclusively available for seniors and other selected groups,” she said.

In her view, an expanded Medicare would stand among private insurance options, allowing for a gradual change.

“It’s a way that we could start tomorrow to let people buy in, as opposed to having a 5- or 10-year rollout that something as big and daunting as a Medicare-for-all plan would require,” she said.

But Dr. Schrier said she won’t start her legislative career with such a sweeping goal as a Medicare buy-in bill.

“I think it would be jumping the gun to come in right away with my own health plan because I really want to collaborate” with fellow lawmakers, she said.

Winning Republican support for her future legislation also is important to Dr. Schrier. “I want to make sure that I have the support of a lot of my colleagues,” she said. “I would like to see a successful first bill.

“The advantage of coming at this as a pediatrician and taking on a first bill or bills that relate to children is that both sides of the aisle can get behind what is good for families and children,” Dr. Schrier said. “I think that’s hard to really argue with.”

Dr. Schrier cosponsored her first piece of legislation in February, reaching across the aisle to work with Rep. Dan Newhouse (R-Wash.) to introduce H.R. 1048, a bill to authorize the next phase of a water resource management plan for Washington’s Yakima River basin.

Beyond that effort, Dr. Schrier said she’s seeking areas of common ground with Republican members of her state delegation. She had dinner in January with two Republican members of the Washington delegation – Rep. Cathy McMorris Rodgers and Rep. Jaime Herrera Beutler. Rep. McMorris Rodgers’ website describes her as a leader in the disabilities community and the only member of Congress to give birth three times while in office, while Rep. Herrera Beutler has spoken openly about her daughter’s battle with Potter’s syndrome, in which the kidneys fail to develop.

Within her party, Dr. Schrier is allied with the moderate New Democrat Coalition. Also in the coalition are two fellow physicians, Ami Bera, MD, and Raul Ruiz, MD, both from California. The New Democrat Coalition also has several lawmakers who flipped House seats from Republican control to Democratic in the 2018 election, a group that includes Dr. Schrier and Reps. Jennifer Wexton (D-VA) and Mikie Sherrill (D-NJ). It was the victories of these moderates that gave the Democrats control of the House. Yet, they get far less media attention than do House Democratic freshmen who are politically further to the left. These members, including Rep. Alexandria Ocasio-Cortez (D-N.Y.), tend to hail from districts where Republicans stand little chance of winning.

Dr. Schrier said the Democratic party, and Congress as a whole, should focus on issues such as affordable health care, on which the country can unite.

“If you’re looking for collaboration, that just doesn’t make the headlines and yet it is the absolute best thing for the country,” she said, adding that most Americans have more centrist views. “So we should really be governing to the middle and that’s how we can move our country forward.”

In this episode, David Henry, MD, welcomes Daniel G. Haller, MD, to rehash research from ESMO 2018 as well as the way the meeting itself was run.

And Ilana Yurkiewicz, MD, stops by for this week’s Clinical Correlation. Dr. Yurkiewicz is a hematology fellow at Stanford and also is a columnist at MDedge Hematology/Oncology. More from Dr. Yurkiewicz here.

Subscribe to Blood & Cancer here:

Apple Podcasts
Google Podcasts

SHOW NOTES

By Emily Bryer, DO
Resident in the department of internal medicine, University of Pennsylvania Health System

• CheckMate 142: Durable clinical benefit with nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite high (MSI-H) and non-MSI-H colon cancer
  • Phase 2 study included 45 patients with metastatic colorectal cancer
  • Overall response rate (primary end point) was 60% and disease control rate was 84%
  • Almost every patient had some response and the therapy was well-tolerated
  • https://academic.oup.com/annonc/article/29/suppl_8/mdy424.019/5141601?searchresult=1

• Tribe 2: FOLFOXIRI plus bevacizumab followed by reintroduction of FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab
  • Phase 3 study of 654 patients with unresectable metastatic colorectal cancer
  • Progression free survival (primary end point) of FOLFOXIRI regimen was 18.9 months, compared with 16.2 months of the FOLFOX then FOLFIRI regimen
  • Side effects of FOLFOXIRI: febrile neutropenia, neutropenia, GI toxicities
  • https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext

• Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial
  • Phase 3 study included 506 patients with metastatic gastric cancer
  • Trifluridine/tipiracil (oral drug) provided a 2-month overall survival advantage (primary end point), compared with placebo
  • Major side effect: neutropenia
  • https://www.ncbi.nlm.nih.gov/pubmed/30355453

• Safety and clinical activity of 1L atezolizumab plus bevacizumab in a phase 1b study in hepatocellular carcinoma (HCC)
  • Phase 1B study included 100 patients with HCC who had not received prior therapy
  • Disease control rate was high as was duration of response
  • Primary outcomes included safety and efficacy
  • The overall response rate was 34% and the most common side effect was hypertension
  • http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.4074

In this episode, David Henry, MD, welcomes Daniel G. Haller, MD, to rehash research from ESMO 2018 as well as the way the meeting itself was run.

And Ilana Yurkiewicz, MD, stops by for this week’s Clinical Correlation. Dr. Yurkiewicz is a hematology fellow at Stanford and also is a columnist at MDedge Hematology/Oncology. More from Dr. Yurkiewicz here.

Subscribe to Blood & Cancer here:

Apple Podcasts
Google Podcasts

SHOW NOTES

By Emily Bryer, DO
Resident in the department of internal medicine, University of Pennsylvania Health System

• CheckMate 142: Durable clinical benefit with nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite high (MSI-H) and non-MSI-H colon cancer
  • Phase 2 study included 45 patients with metastatic colorectal cancer
  • Overall response rate (primary end point) was 60% and disease control rate was 84%
  • Almost every patient had some response and the therapy was well-tolerated
  • https://academic.oup.com/annonc/article/29/suppl_8/mdy424.019/5141601?searchresult=1

• Tribe 2: FOLFOXIRI plus bevacizumab followed by reintroduction of FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab
  • Phase 3 study of 654 patients with unresectable metastatic colorectal cancer
  • Progression free survival (primary end point) of FOLFOXIRI regimen was 18.9 months, compared with 16.2 months of the FOLFOX then FOLFIRI regimen
  • Side effects of FOLFOXIRI: febrile neutropenia, neutropenia, GI toxicities
  • https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext

• Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial
  • Phase 3 study included 506 patients with metastatic gastric cancer
  • Trifluridine/tipiracil (oral drug) provided a 2-month overall survival advantage (primary end point), compared with placebo
  • Major side effect: neutropenia
  • https://www.ncbi.nlm.nih.gov/pubmed/30355453

• Safety and clinical activity of 1L atezolizumab plus bevacizumab in a phase 1b study in hepatocellular carcinoma (HCC)
  • Phase 1B study included 100 patients with HCC who had not received prior therapy
  • Disease control rate was high as was duration of response
  • Primary outcomes included safety and efficacy
  • The overall response rate was 34% and the most common side effect was hypertension
  • http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.4074

In this episode, David Henry, MD, welcomes Daniel G. Haller, MD, to rehash research from ESMO 2018 as well as the way the meeting itself was run.

And Ilana Yurkiewicz, MD, stops by for this week’s Clinical Correlation. Dr. Yurkiewicz is a hematology fellow at Stanford and also is a columnist at MDedge Hematology/Oncology. More from Dr. Yurkiewicz here.

Subscribe to Blood & Cancer here:

Apple Podcasts
Google Podcasts

SHOW NOTES

By Emily Bryer, DO
Resident in the department of internal medicine, University of Pennsylvania Health System

• CheckMate 142: Durable clinical benefit with nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite high (MSI-H) and non-MSI-H colon cancer
  • Phase 2 study included 45 patients with metastatic colorectal cancer
  • Overall response rate (primary end point) was 60% and disease control rate was 84%
  • Almost every patient had some response and the therapy was well-tolerated
  • https://academic.oup.com/annonc/article/29/suppl_8/mdy424.019/5141601?searchresult=1

• Tribe 2: FOLFOXIRI plus bevacizumab followed by reintroduction of FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab
  • Phase 3 study of 654 patients with unresectable metastatic colorectal cancer
  • Progression free survival (primary end point) of FOLFOXIRI regimen was 18.9 months, compared with 16.2 months of the FOLFOX then FOLFIRI regimen
  • Side effects of FOLFOXIRI: febrile neutropenia, neutropenia, GI toxicities
  • https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext

• Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial
  • Phase 3 study included 506 patients with metastatic gastric cancer
  • Trifluridine/tipiracil (oral drug) provided a 2-month overall survival advantage (primary end point), compared with placebo
  • Major side effect: neutropenia
  • https://www.ncbi.nlm.nih.gov/pubmed/30355453

• Safety and clinical activity of 1L atezolizumab plus bevacizumab in a phase 1b study in hepatocellular carcinoma (HCC)
  • Phase 1B study included 100 patients with HCC who had not received prior therapy
  • Disease control rate was high as was duration of response
  • Primary outcomes included safety and efficacy
  • The overall response rate was 34% and the most common side effect was hypertension
  • http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.4074

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

sworcester@mdedge.com

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

sworcester@mdedge.com

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

sworcester@mdedge.com

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

Screen-based activities and sleep behaviors could be “intervention targets” for adolescents with depressive symptoms, results of a study of almost 3,000 U.S. adolescents suggest.

maewjpho/Thinkstock

“Overall, our results indicated that [social messaging, Web surfing, TV/movie watching, and video gaming] ... were associated with greater depressive symptoms and poorer sleep characteristics,” Xian Li, PhD, and her associates reported in Sleep Medicine.

Numerous studies previously have demonstrated a positive link between adolescent depression and exposure to electronic devices, although little is known about the precise mechanism(s) of action involved and to what extent sleep plays a role. To address those gaps, Dr. Li, of the State University of New York at Stony Brook, and her associates examined four types of screen activities to determine whether symptoms of adolescent depression, sleep duration, and symptoms of insomnia – including problems falling asleep and staying asleep – are influenced in any way by those activities.

Using data from the Fragile Families and Child Wellbeing Study, a longitudinal urban birth cohort study that included an “oversampling of nonmarital births,” Dr. Li and her associates evaluated a total of 2,865 adolescents (mean 15.53 years of age; 48.2% female) self-identifying as African American (47.4%), Hispanic/Latino (23.7%), white (16.8%), or other/multiracial (12.1%). In participant interviews conducted with adolescents and caregivers during 2014-2016, 17.5% of caregivers reported having less than a high school education; 31.1% of teens lived in households below 100% of poverty; 32.8% came from single-mother families; and just 26.9% lived with both biological parents. The investigators assessed depressive symptoms at age 15 years by using five items from Center for Epidemiologic Studies Depression Scale.

Overall, Dr. Li and her associates found greater depressive symptoms associated with all four of the screen-based activities (P less than .01). In addition, more problems were observed with falling and staying asleep as well as shortened duration of sleep during the week for each of the activities monitored.

Social messaging, Web surfing, and time spent watching TV and movies appeared to be directly correlated with sleep characteristics, but the same could not be said for gaming, which showed only partial correlation with sleep characteristics. In that case, the authors speculated that the association between gaming and depression could be at least partly explained by individual characteristics such as trait neuroticism and self-control or a self-selection behavior in which those exhibiting greater signs of depression turn to gaming as an escape. “Thus, interventions among heavy gamers to reduce depression may need to consider other mechanisms,” Dr. Li and her associates wrote. The authors also noted a significant link between depressive symptoms at age 9 years and gaming behavior at age 15 years.

Several study limitations were noted. Causality and temporality could not be teased apart given that screen activities, sleep, and depressive symptoms all were measured concurrently at age 15 years. Screen activities also were noted to have captured only duration and not content or interactivity of the activities. Self-reports of screen time also might have been inaccurate because of general error in recall or even overlap in cases where participants were using more than one device simultaneously.

It is important to consider that while the relationships in the models might have statistical significance, “the effect size in the study as a whole are small.”

Nevertheless, they wrote, their findings “suggest that screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”

Future studies should examine the “temporal sequencing” of those three limitations as well as adding more informants, including parent and teacher reports, and methods for objectively measuring screen activities and sleep, the authors cautioned.

The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor in chief of the journal Sleep Health.

SOURCE: Li X et al. Sleep Med. 2019 Feb 2. doi: 10.1016/j.sleep.2019.01.029.

Screen-based activities and sleep behaviors could be “intervention targets” for adolescents with depressive symptoms, results of a study of almost 3,000 U.S. adolescents suggest.

maewjpho/Thinkstock

“Overall, our results indicated that [social messaging, Web surfing, TV/movie watching, and video gaming] ... were associated with greater depressive symptoms and poorer sleep characteristics,” Xian Li, PhD, and her associates reported in Sleep Medicine.

Numerous studies previously have demonstrated a positive link between adolescent depression and exposure to electronic devices, although little is known about the precise mechanism(s) of action involved and to what extent sleep plays a role. To address those gaps, Dr. Li, of the State University of New York at Stony Brook, and her associates examined four types of screen activities to determine whether symptoms of adolescent depression, sleep duration, and symptoms of insomnia – including problems falling asleep and staying asleep – are influenced in any way by those activities.

Using data from the Fragile Families and Child Wellbeing Study, a longitudinal urban birth cohort study that included an “oversampling of nonmarital births,” Dr. Li and her associates evaluated a total of 2,865 adolescents (mean 15.53 years of age; 48.2% female) self-identifying as African American (47.4%), Hispanic/Latino (23.7%), white (16.8%), or other/multiracial (12.1%). In participant interviews conducted with adolescents and caregivers during 2014-2016, 17.5% of caregivers reported having less than a high school education; 31.1% of teens lived in households below 100% of poverty; 32.8% came from single-mother families; and just 26.9% lived with both biological parents. The investigators assessed depressive symptoms at age 15 years by using five items from Center for Epidemiologic Studies Depression Scale.

Overall, Dr. Li and her associates found greater depressive symptoms associated with all four of the screen-based activities (P less than .01). In addition, more problems were observed with falling and staying asleep as well as shortened duration of sleep during the week for each of the activities monitored.

Social messaging, Web surfing, and time spent watching TV and movies appeared to be directly correlated with sleep characteristics, but the same could not be said for gaming, which showed only partial correlation with sleep characteristics. In that case, the authors speculated that the association between gaming and depression could be at least partly explained by individual characteristics such as trait neuroticism and self-control or a self-selection behavior in which those exhibiting greater signs of depression turn to gaming as an escape. “Thus, interventions among heavy gamers to reduce depression may need to consider other mechanisms,” Dr. Li and her associates wrote. The authors also noted a significant link between depressive symptoms at age 9 years and gaming behavior at age 15 years.

Several study limitations were noted. Causality and temporality could not be teased apart given that screen activities, sleep, and depressive symptoms all were measured concurrently at age 15 years. Screen activities also were noted to have captured only duration and not content or interactivity of the activities. Self-reports of screen time also might have been inaccurate because of general error in recall or even overlap in cases where participants were using more than one device simultaneously.

It is important to consider that while the relationships in the models might have statistical significance, “the effect size in the study as a whole are small.”

Nevertheless, they wrote, their findings “suggest that screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”

Future studies should examine the “temporal sequencing” of those three limitations as well as adding more informants, including parent and teacher reports, and methods for objectively measuring screen activities and sleep, the authors cautioned.

The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor in chief of the journal Sleep Health.

SOURCE: Li X et al. Sleep Med. 2019 Feb 2. doi: 10.1016/j.sleep.2019.01.029.

Screen-based activities and sleep behaviors could be “intervention targets” for adolescents with depressive symptoms, results of a study of almost 3,000 U.S. adolescents suggest.

maewjpho/Thinkstock

“Overall, our results indicated that [social messaging, Web surfing, TV/movie watching, and video gaming] ... were associated with greater depressive symptoms and poorer sleep characteristics,” Xian Li, PhD, and her associates reported in Sleep Medicine.

Numerous studies previously have demonstrated a positive link between adolescent depression and exposure to electronic devices, although little is known about the precise mechanism(s) of action involved and to what extent sleep plays a role. To address those gaps, Dr. Li, of the State University of New York at Stony Brook, and her associates examined four types of screen activities to determine whether symptoms of adolescent depression, sleep duration, and symptoms of insomnia – including problems falling asleep and staying asleep – are influenced in any way by those activities.

Using data from the Fragile Families and Child Wellbeing Study, a longitudinal urban birth cohort study that included an “oversampling of nonmarital births,” Dr. Li and her associates evaluated a total of 2,865 adolescents (mean 15.53 years of age; 48.2% female) self-identifying as African American (47.4%), Hispanic/Latino (23.7%), white (16.8%), or other/multiracial (12.1%). In participant interviews conducted with adolescents and caregivers during 2014-2016, 17.5% of caregivers reported having less than a high school education; 31.1% of teens lived in households below 100% of poverty; 32.8% came from single-mother families; and just 26.9% lived with both biological parents. The investigators assessed depressive symptoms at age 15 years by using five items from Center for Epidemiologic Studies Depression Scale.

Overall, Dr. Li and her associates found greater depressive symptoms associated with all four of the screen-based activities (P less than .01). In addition, more problems were observed with falling and staying asleep as well as shortened duration of sleep during the week for each of the activities monitored.

Social messaging, Web surfing, and time spent watching TV and movies appeared to be directly correlated with sleep characteristics, but the same could not be said for gaming, which showed only partial correlation with sleep characteristics. In that case, the authors speculated that the association between gaming and depression could be at least partly explained by individual characteristics such as trait neuroticism and self-control or a self-selection behavior in which those exhibiting greater signs of depression turn to gaming as an escape. “Thus, interventions among heavy gamers to reduce depression may need to consider other mechanisms,” Dr. Li and her associates wrote. The authors also noted a significant link between depressive symptoms at age 9 years and gaming behavior at age 15 years.

Several study limitations were noted. Causality and temporality could not be teased apart given that screen activities, sleep, and depressive symptoms all were measured concurrently at age 15 years. Screen activities also were noted to have captured only duration and not content or interactivity of the activities. Self-reports of screen time also might have been inaccurate because of general error in recall or even overlap in cases where participants were using more than one device simultaneously.

It is important to consider that while the relationships in the models might have statistical significance, “the effect size in the study as a whole are small.”

Nevertheless, they wrote, their findings “suggest that screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”

Future studies should examine the “temporal sequencing” of those three limitations as well as adding more informants, including parent and teacher reports, and methods for objectively measuring screen activities and sleep, the authors cautioned.

The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor in chief of the journal Sleep Health.

SOURCE: Li X et al. Sleep Med. 2019 Feb 2. doi: 10.1016/j.sleep.2019.01.029.

A new study published in JAMA Internal Medicine offers yet more evidence that the opioid epidemic affects a large proportion of low-income majority-white communities. Also today, undervaccination poses a particular danger to patients with HIV, patients with inflammatory bowl disease aren’t getting appropriate reproductive counseling, and the type of exercise does matter when it comes to preventing falls among elderly patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

A new study published in JAMA Internal Medicine offers yet more evidence that the opioid epidemic affects a large proportion of low-income majority-white communities. Also today, undervaccination poses a particular danger to patients with HIV, patients with inflammatory bowl disease aren’t getting appropriate reproductive counseling, and the type of exercise does matter when it comes to preventing falls among elderly patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

A new study published in JAMA Internal Medicine offers yet more evidence that the opioid epidemic affects a large proportion of low-income majority-white communities. Also today, undervaccination poses a particular danger to patients with HIV, patients with inflammatory bowl disease aren’t getting appropriate reproductive counseling, and the type of exercise does matter when it comes to preventing falls among elderly patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed. 

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

• What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴ 

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷  

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷ 

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations. 

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial. 

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in  the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹ 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7%  in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹² 

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴ 

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy. 

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶ 

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷ 

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes  elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷ 

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR. 

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed. 

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

• What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴ 

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷  

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷ 

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations. 

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial. 

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in  the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹ 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7%  in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹² 

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴ 

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy. 

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶ 

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷ 

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes  elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷ 

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR. 

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed. 

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

• What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴ 

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷  

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷ 

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations. 

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial. 

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in  the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹ 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7%  in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹² 

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴ 

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy. 

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶ 

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷ 

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes  elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷ 

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR. 

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML.