Platelet inhibitor prasugrel has failed to show a significant reduction in the rate of vaso-occlusive crises events in children and adolescents with sickle cell anemia, according to data presented Dec. 8 at the annual meeting of the American Society of Hematology.

The phase III randomized placebo-controlled trial of 341 children and adolescents (aged 2-17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultaneously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduction among the older patients aged 12-17 years.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospitalizations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group (N Engl J Med. 2015, Dec 8. doi: 10.1056/NEJMoa1512021).

“Sickle cell anemia is a heterogeneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr. Matthew M. Heeney of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and his coauthors.

“However, the nonsignificant effect of prasugrel in the oldest age group may suggest that platelet activation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.”

Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceutical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

Platelet inhibitor prasugrel has failed to show a significant reduction in the rate of vaso-occlusive crises events in children and adolescents with sickle cell anemia, according to data presented Dec. 8 at the annual meeting of the American Society of Hematology.

The phase III randomized placebo-controlled trial of 341 children and adolescents (aged 2-17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultaneously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduction among the older patients aged 12-17 years.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospitalizations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group (N Engl J Med. 2015, Dec 8. doi: 10.1056/NEJMoa1512021).

“Sickle cell anemia is a heterogeneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr. Matthew M. Heeney of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and his coauthors.

“However, the nonsignificant effect of prasugrel in the oldest age group may suggest that platelet activation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.”

Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceutical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

Platelet inhibitor prasugrel has failed to show a significant reduction in the rate of vaso-occlusive crises events in children and adolescents with sickle cell anemia, according to data presented Dec. 8 at the annual meeting of the American Society of Hematology.

The phase III randomized placebo-controlled trial of 341 children and adolescents (aged 2-17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultaneously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduction among the older patients aged 12-17 years.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospitalizations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group (N Engl J Med. 2015, Dec 8. doi: 10.1056/NEJMoa1512021).

“Sickle cell anemia is a heterogeneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr. Matthew M. Heeney of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and his coauthors.

“However, the nonsignificant effect of prasugrel in the oldest age group may suggest that platelet activation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.”

Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceutical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

The estimated prevalence of depression or depressive symptoms was 28.8% among residents and interns worldwide in a meta-analysis of 54 studies of the issue, according to a report published online December 8 in JAMA.

The depression rate ranged from 20.9% to 43.2%, depending on the instrument used to assess symptoms. Eleven studies used the Beck Depression Inventory (BDI), 11 used the Center for Epidemiological Studies Depression Scale (CES-D), 8 used the two-item Primary Care Evaluation of Mental Disorders questionnaire (PRIME-MD), 7 used the nine-item Patient Health Questionnaire (PHQ-9), 4 used the Zung Self-Rating Depression Scale (SDS), 3 used the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), and 11 used other validated methods, said Dr. Douglas A. Mata of the department of pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

“It is important to note that the vast majority of participants were assessed through self-report inventories that measured depressive symptoms, rather than gold-standard diagnostic clinical interviews for major depressive disorder,” they said.

The meta-analysis included 31 cross-sectional and 23 longitudinal studies published in peer-reviewed journals since 1963 and involving 17,560 residents or interns in North America (35 studies), Asia (9 studies), Europe (5 studies), South America (4 studies), and Africa (1 study). When the results were pooled, the overall prevalence of depression or depressive symptoms was 28.8% (4,969 of 17,560 participants).

In a sensitivity analysis, no individual study affected the overall prevalence estimate by more than 1%. Further analyses showed no significant differences in the prevalence of depression between cross-sectional and longitudinal studies, between U.S. studies and those performed in other countries, between studies of nonsurgical residents only vs. studies of all types of residents, or between studies of interns only vs. studies of upper level residents only. This suggests that the underlying causes of depressive symptoms “are common to the residency experience,” Dr. Mata and his associates said (JAMA. 2015 Dec 8. doi: 10.1001/jama.2015.15845).

The prevalence of depression increased over time. Although this rise was characterized as modest, “it is notable, given efforts by the Accreditation Council for Graduate Medical Education, European Working Time Directive, and others to limit trainee duty hours and improve work conditions. [This] trend may reflect the medical community’s increased awareness of depression or developments external to medical education. Future studies should explore specific factors that may explain this trend,” the investigators said.

The study findings indicate that the long-term health of physicians may be affected, since depression has been linked to a higher risk of future depressive episodes and greater long-term morbidity. Patient care may also be affected, given the established association between physician depression and lower-quality care, they added.

The estimated prevalence of depression or depressive symptoms was 28.8% among residents and interns worldwide in a meta-analysis of 54 studies of the issue, according to a report published online December 8 in JAMA.

The depression rate ranged from 20.9% to 43.2%, depending on the instrument used to assess symptoms. Eleven studies used the Beck Depression Inventory (BDI), 11 used the Center for Epidemiological Studies Depression Scale (CES-D), 8 used the two-item Primary Care Evaluation of Mental Disorders questionnaire (PRIME-MD), 7 used the nine-item Patient Health Questionnaire (PHQ-9), 4 used the Zung Self-Rating Depression Scale (SDS), 3 used the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), and 11 used other validated methods, said Dr. Douglas A. Mata of the department of pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

“It is important to note that the vast majority of participants were assessed through self-report inventories that measured depressive symptoms, rather than gold-standard diagnostic clinical interviews for major depressive disorder,” they said.

The meta-analysis included 31 cross-sectional and 23 longitudinal studies published in peer-reviewed journals since 1963 and involving 17,560 residents or interns in North America (35 studies), Asia (9 studies), Europe (5 studies), South America (4 studies), and Africa (1 study). When the results were pooled, the overall prevalence of depression or depressive symptoms was 28.8% (4,969 of 17,560 participants).

In a sensitivity analysis, no individual study affected the overall prevalence estimate by more than 1%. Further analyses showed no significant differences in the prevalence of depression between cross-sectional and longitudinal studies, between U.S. studies and those performed in other countries, between studies of nonsurgical residents only vs. studies of all types of residents, or between studies of interns only vs. studies of upper level residents only. This suggests that the underlying causes of depressive symptoms “are common to the residency experience,” Dr. Mata and his associates said (JAMA. 2015 Dec 8. doi: 10.1001/jama.2015.15845).

The prevalence of depression increased over time. Although this rise was characterized as modest, “it is notable, given efforts by the Accreditation Council for Graduate Medical Education, European Working Time Directive, and others to limit trainee duty hours and improve work conditions. [This] trend may reflect the medical community’s increased awareness of depression or developments external to medical education. Future studies should explore specific factors that may explain this trend,” the investigators said.

The study findings indicate that the long-term health of physicians may be affected, since depression has been linked to a higher risk of future depressive episodes and greater long-term morbidity. Patient care may also be affected, given the established association between physician depression and lower-quality care, they added.

The estimated prevalence of depression or depressive symptoms was 28.8% among residents and interns worldwide in a meta-analysis of 54 studies of the issue, according to a report published online December 8 in JAMA.

The depression rate ranged from 20.9% to 43.2%, depending on the instrument used to assess symptoms. Eleven studies used the Beck Depression Inventory (BDI), 11 used the Center for Epidemiological Studies Depression Scale (CES-D), 8 used the two-item Primary Care Evaluation of Mental Disorders questionnaire (PRIME-MD), 7 used the nine-item Patient Health Questionnaire (PHQ-9), 4 used the Zung Self-Rating Depression Scale (SDS), 3 used the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), and 11 used other validated methods, said Dr. Douglas A. Mata of the department of pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

“It is important to note that the vast majority of participants were assessed through self-report inventories that measured depressive symptoms, rather than gold-standard diagnostic clinical interviews for major depressive disorder,” they said.

The meta-analysis included 31 cross-sectional and 23 longitudinal studies published in peer-reviewed journals since 1963 and involving 17,560 residents or interns in North America (35 studies), Asia (9 studies), Europe (5 studies), South America (4 studies), and Africa (1 study). When the results were pooled, the overall prevalence of depression or depressive symptoms was 28.8% (4,969 of 17,560 participants).

In a sensitivity analysis, no individual study affected the overall prevalence estimate by more than 1%. Further analyses showed no significant differences in the prevalence of depression between cross-sectional and longitudinal studies, between U.S. studies and those performed in other countries, between studies of nonsurgical residents only vs. studies of all types of residents, or between studies of interns only vs. studies of upper level residents only. This suggests that the underlying causes of depressive symptoms “are common to the residency experience,” Dr. Mata and his associates said (JAMA. 2015 Dec 8. doi: 10.1001/jama.2015.15845).

The prevalence of depression increased over time. Although this rise was characterized as modest, “it is notable, given efforts by the Accreditation Council for Graduate Medical Education, European Working Time Directive, and others to limit trainee duty hours and improve work conditions. [This] trend may reflect the medical community’s increased awareness of depression or developments external to medical education. Future studies should explore specific factors that may explain this trend,” the investigators said.

The study findings indicate that the long-term health of physicians may be affected, since depression has been linked to a higher risk of future depressive episodes and greater long-term morbidity. Patient care may also be affected, given the established association between physician depression and lower-quality care, they added.

The prevalence of obesity and obesity-related conditions in the United States is increasing. Many weight-loss prod­ucts and dietary supplements are used in an attempt to combat this epidemic, but little evi­dence exists of their efficacy and safety.

We present a case report of a middle-age woman who developed severe psychotic symptoms while taking phentermine hydro­chloride (HCl), a psychostimulant similar to amphetamine that is used as a weight-loss agent and for recreational purposes. Phentermine has been associated with mood and psychotic symptoms and has a tendency to cause psychological dependence and tolerance.

To investigate the risks and potential effects of using this drug, we searched OVID and PubMed databases using the search string “phentermine + psychosis.” We conclude that there is a need for awareness about early detection and treatment of reversible psy­chotic and mood symptoms caused by what might appear to be harmless weight-loss and energy pills.

Obesity epidemic, wide-ranging weight-loss effortsThere has been a dramatic increase in obesity in the United States in the past 20 years: More than one-third of adults and approximately 17% of children and adolescents are obese. Obesity-related conditions, such as heart dis­ease, stroke, and type 2 diabetes mellitus, are leading causes of preventable death.¹ Weight monitoring, a healthy lifestyle, surgical inter­vention, traditional herbs, and diet-pill sup­plements are some of the modalities used to address this epidemic.

Most so-called supplements for weight loss are exempt from FDA regulation. They do not undergo rigorous testing for safety. Furthermore, many contain controlled sub­stances; some supplements are anti-seizure medications or other prescription drugs; and some are drugs not approved in the United States.² Since the 1930s, such drugs as dini­trophenol, ephedrine, amphetamine, fenflu­ramine, and phentermine have flooded the market with the promise of quick weight loss.^3,4

Phentermine, a contraction of “phenyltertiary-butylamine,” and its various types (Table) is a psychostimu­lant of the phenethylamine class, with a pharmacologic profile similar to that of amphetamine. It is known to yield false-positive immunoassay screening results for amphetamines.
 

Speech is pressured, fast, and difficult to comprehend at times; affect is labile and irri­table. Ms. B denies suicidal ideation and is oriented to time, place, and person.

A urine drug screen is positive for amphetamine.

Pre-admission medications include alpra­zolam, 1 mg as needed, and zolpidem, 10 mg at bedtime, prescribed by Ms. B’s primary care physician for anxiety and insomnia. She discontinued these medications 3 weeks ago because of increased drowsiness at work. She denies other substance use and is unable to account for the positive urine drug screen.

Her medical history, physical examination, and a CT scan of the head are unremarkable. The components of a comprehensive meta­bolic panel and complete blood count are within normal limits.

After admission, in-depth assessment reveals that Ms. B has been taking phen­termine, 37.5 mg (under the brand name Adipex-P), once daily since age 16 for weight loss. She recently discontinued the drug, abruptly, for 1 month, then resumed taking it at an unspecified higher dosage 1 week before she came to the emergency room, for what she said was recreational use and to meet the demands of her job, which required shift work and long hours.

Over the next few days in the hospital, Ms. B’s symptoms resolve as the drug is eliminated from her body. Speech becomes comprehensible and sleep improves. Affective distress diminishes considerably after admission; slight mood lability per­sists. She no longer reports perceptual dis­turbances or distress secondary to intrusive thoughts.

Ms. B is discharged 1 week after admis­sion, with instructions to follow up at a dual-diagnosis outpatient program.
Pharmacologic profilePhentermine acts through sympathomi­metic pathways by increasing brain nor­adrenaline and dopamine. The drug has no effect on serotonin.^4,5 Phentermine can lead to elevated blood pressure and heart rate, palpitations, restlessness, and insomnia, and can suppress appetite. Increased sympatho­mimetic activity has been implicated in the ability of phentermine to induce psychotic symptoms.

The literature. Our PubMed search of “phentermine + psychosis” produced 13 results, including 6 case reports of phen­termine use. Five citations were more than 4 decades old^5-12; only 1 could be considered recent (2011).¹³

Patients in these reports developed psy­chotic or manic features after chronic or acute phentermine use, mainly for weight reduction. The most recent article¹³ men­tioned 4 patients who were abusing diet pills recreationally (including “for lethargy”). As with Ms. B, in all 4 of those patients, phen­termine precipitated the primary pathol­ogy (mania in bipolar disorder; depression in postpartum depression and substance abuse) or revealed underlying illness.
Changing landscape of use and abuseThere has been a trend observed in the pattern of diet pill use: Initially marketed as an appetite suppressant, these pills are now being abused across ethnic, racial, and socioeconomic groups, by males and females.¹⁴ There is also a scarcity of useful guidance for clinicians.

Not only are diet pills used by people with an eating disorder; their recreational use is an emerging problem. If reports^12,13 continue to reveal that phentermine is a substance of abuse and has catastrophic effects on the user’s psyche, the need for stronger warnings and guidelines might be warranted to allow consumers to make an informed choice about using the drug.
Call for awarenessThe case we presented here exemplifies the importance of tighter regulation of both over-the-counter and prescription stimu­lant analogs. There is a need for awareness among practitioners about early detection and treatment of reversible psychotic and mood symptoms secondary to what might be promoted as, or appear to be, “harmless” weight loss and energy pills.
 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

This unfunded study was presented as a case report poster at the Annual Meeting of the Academy of Psychosomatic Medicine, November 2013, Tucson, Arizona, and at the Colloquium of Scholars of the Philadelphia Psychiatric Society, March 2014, Philadelphia, Pennsylvania.
 

Drug Brand Names
Alprazolam • Xanax
Fenfluramine • Pondimin
Phentermine HCl • Adipex-P, Fen-Phen, Qsymia, Suprenza
Topiramate • Topamax, Trokendi XR                
Zolpidem • Ambien

The prevalence of obesity and obesity-related conditions in the United States is increasing. Many weight-loss prod­ucts and dietary supplements are used in an attempt to combat this epidemic, but little evi­dence exists of their efficacy and safety.

We present a case report of a middle-age woman who developed severe psychotic symptoms while taking phentermine hydro­chloride (HCl), a psychostimulant similar to amphetamine that is used as a weight-loss agent and for recreational purposes. Phentermine has been associated with mood and psychotic symptoms and has a tendency to cause psychological dependence and tolerance.

To investigate the risks and potential effects of using this drug, we searched OVID and PubMed databases using the search string “phentermine + psychosis.” We conclude that there is a need for awareness about early detection and treatment of reversible psy­chotic and mood symptoms caused by what might appear to be harmless weight-loss and energy pills.

Obesity epidemic, wide-ranging weight-loss effortsThere has been a dramatic increase in obesity in the United States in the past 20 years: More than one-third of adults and approximately 17% of children and adolescents are obese. Obesity-related conditions, such as heart dis­ease, stroke, and type 2 diabetes mellitus, are leading causes of preventable death.¹ Weight monitoring, a healthy lifestyle, surgical inter­vention, traditional herbs, and diet-pill sup­plements are some of the modalities used to address this epidemic.

Most so-called supplements for weight loss are exempt from FDA regulation. They do not undergo rigorous testing for safety. Furthermore, many contain controlled sub­stances; some supplements are anti-seizure medications or other prescription drugs; and some are drugs not approved in the United States.² Since the 1930s, such drugs as dini­trophenol, ephedrine, amphetamine, fenflu­ramine, and phentermine have flooded the market with the promise of quick weight loss.^3,4

Phentermine, a contraction of “phenyltertiary-butylamine,” and its various types (Table) is a psychostimu­lant of the phenethylamine class, with a pharmacologic profile similar to that of amphetamine. It is known to yield false-positive immunoassay screening results for amphetamines.
 

Speech is pressured, fast, and difficult to comprehend at times; affect is labile and irri­table. Ms. B denies suicidal ideation and is oriented to time, place, and person.

A urine drug screen is positive for amphetamine.

Pre-admission medications include alpra­zolam, 1 mg as needed, and zolpidem, 10 mg at bedtime, prescribed by Ms. B’s primary care physician for anxiety and insomnia. She discontinued these medications 3 weeks ago because of increased drowsiness at work. She denies other substance use and is unable to account for the positive urine drug screen.

Her medical history, physical examination, and a CT scan of the head are unremarkable. The components of a comprehensive meta­bolic panel and complete blood count are within normal limits.

After admission, in-depth assessment reveals that Ms. B has been taking phen­termine, 37.5 mg (under the brand name Adipex-P), once daily since age 16 for weight loss. She recently discontinued the drug, abruptly, for 1 month, then resumed taking it at an unspecified higher dosage 1 week before she came to the emergency room, for what she said was recreational use and to meet the demands of her job, which required shift work and long hours.

Over the next few days in the hospital, Ms. B’s symptoms resolve as the drug is eliminated from her body. Speech becomes comprehensible and sleep improves. Affective distress diminishes considerably after admission; slight mood lability per­sists. She no longer reports perceptual dis­turbances or distress secondary to intrusive thoughts.

Ms. B is discharged 1 week after admis­sion, with instructions to follow up at a dual-diagnosis outpatient program.
Pharmacologic profilePhentermine acts through sympathomi­metic pathways by increasing brain nor­adrenaline and dopamine. The drug has no effect on serotonin.^4,5 Phentermine can lead to elevated blood pressure and heart rate, palpitations, restlessness, and insomnia, and can suppress appetite. Increased sympatho­mimetic activity has been implicated in the ability of phentermine to induce psychotic symptoms.

The literature. Our PubMed search of “phentermine + psychosis” produced 13 results, including 6 case reports of phen­termine use. Five citations were more than 4 decades old^5-12; only 1 could be considered recent (2011).¹³

Patients in these reports developed psy­chotic or manic features after chronic or acute phentermine use, mainly for weight reduction. The most recent article¹³ men­tioned 4 patients who were abusing diet pills recreationally (including “for lethargy”). As with Ms. B, in all 4 of those patients, phen­termine precipitated the primary pathol­ogy (mania in bipolar disorder; depression in postpartum depression and substance abuse) or revealed underlying illness.
Changing landscape of use and abuseThere has been a trend observed in the pattern of diet pill use: Initially marketed as an appetite suppressant, these pills are now being abused across ethnic, racial, and socioeconomic groups, by males and females.¹⁴ There is also a scarcity of useful guidance for clinicians.

Not only are diet pills used by people with an eating disorder; their recreational use is an emerging problem. If reports^12,13 continue to reveal that phentermine is a substance of abuse and has catastrophic effects on the user’s psyche, the need for stronger warnings and guidelines might be warranted to allow consumers to make an informed choice about using the drug.
Call for awarenessThe case we presented here exemplifies the importance of tighter regulation of both over-the-counter and prescription stimu­lant analogs. There is a need for awareness among practitioners about early detection and treatment of reversible psychotic and mood symptoms secondary to what might be promoted as, or appear to be, “harmless” weight loss and energy pills.
 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

This unfunded study was presented as a case report poster at the Annual Meeting of the Academy of Psychosomatic Medicine, November 2013, Tucson, Arizona, and at the Colloquium of Scholars of the Philadelphia Psychiatric Society, March 2014, Philadelphia, Pennsylvania.
 

Drug Brand Names
Alprazolam • Xanax
Fenfluramine • Pondimin
Phentermine HCl • Adipex-P, Fen-Phen, Qsymia, Suprenza
Topiramate • Topamax, Trokendi XR                
Zolpidem • Ambien

The prevalence of obesity and obesity-related conditions in the United States is increasing. Many weight-loss prod­ucts and dietary supplements are used in an attempt to combat this epidemic, but little evi­dence exists of their efficacy and safety.

We present a case report of a middle-age woman who developed severe psychotic symptoms while taking phentermine hydro­chloride (HCl), a psychostimulant similar to amphetamine that is used as a weight-loss agent and for recreational purposes. Phentermine has been associated with mood and psychotic symptoms and has a tendency to cause psychological dependence and tolerance.

To investigate the risks and potential effects of using this drug, we searched OVID and PubMed databases using the search string “phentermine + psychosis.” We conclude that there is a need for awareness about early detection and treatment of reversible psy­chotic and mood symptoms caused by what might appear to be harmless weight-loss and energy pills.

Obesity epidemic, wide-ranging weight-loss effortsThere has been a dramatic increase in obesity in the United States in the past 20 years: More than one-third of adults and approximately 17% of children and adolescents are obese. Obesity-related conditions, such as heart dis­ease, stroke, and type 2 diabetes mellitus, are leading causes of preventable death.¹ Weight monitoring, a healthy lifestyle, surgical inter­vention, traditional herbs, and diet-pill sup­plements are some of the modalities used to address this epidemic.

Most so-called supplements for weight loss are exempt from FDA regulation. They do not undergo rigorous testing for safety. Furthermore, many contain controlled sub­stances; some supplements are anti-seizure medications or other prescription drugs; and some are drugs not approved in the United States.² Since the 1930s, such drugs as dini­trophenol, ephedrine, amphetamine, fenflu­ramine, and phentermine have flooded the market with the promise of quick weight loss.^3,4

Phentermine, a contraction of “phenyltertiary-butylamine,” and its various types (Table) is a psychostimu­lant of the phenethylamine class, with a pharmacologic profile similar to that of amphetamine. It is known to yield false-positive immunoassay screening results for amphetamines.
 

Speech is pressured, fast, and difficult to comprehend at times; affect is labile and irri­table. Ms. B denies suicidal ideation and is oriented to time, place, and person.

A urine drug screen is positive for amphetamine.

Pre-admission medications include alpra­zolam, 1 mg as needed, and zolpidem, 10 mg at bedtime, prescribed by Ms. B’s primary care physician for anxiety and insomnia. She discontinued these medications 3 weeks ago because of increased drowsiness at work. She denies other substance use and is unable to account for the positive urine drug screen.

Her medical history, physical examination, and a CT scan of the head are unremarkable. The components of a comprehensive meta­bolic panel and complete blood count are within normal limits.

After admission, in-depth assessment reveals that Ms. B has been taking phen­termine, 37.5 mg (under the brand name Adipex-P), once daily since age 16 for weight loss. She recently discontinued the drug, abruptly, for 1 month, then resumed taking it at an unspecified higher dosage 1 week before she came to the emergency room, for what she said was recreational use and to meet the demands of her job, which required shift work and long hours.

Over the next few days in the hospital, Ms. B’s symptoms resolve as the drug is eliminated from her body. Speech becomes comprehensible and sleep improves. Affective distress diminishes considerably after admission; slight mood lability per­sists. She no longer reports perceptual dis­turbances or distress secondary to intrusive thoughts.

Ms. B is discharged 1 week after admis­sion, with instructions to follow up at a dual-diagnosis outpatient program.
Pharmacologic profilePhentermine acts through sympathomi­metic pathways by increasing brain nor­adrenaline and dopamine. The drug has no effect on serotonin.^4,5 Phentermine can lead to elevated blood pressure and heart rate, palpitations, restlessness, and insomnia, and can suppress appetite. Increased sympatho­mimetic activity has been implicated in the ability of phentermine to induce psychotic symptoms.

The literature. Our PubMed search of “phentermine + psychosis” produced 13 results, including 6 case reports of phen­termine use. Five citations were more than 4 decades old^5-12; only 1 could be considered recent (2011).¹³

Patients in these reports developed psy­chotic or manic features after chronic or acute phentermine use, mainly for weight reduction. The most recent article¹³ men­tioned 4 patients who were abusing diet pills recreationally (including “for lethargy”). As with Ms. B, in all 4 of those patients, phen­termine precipitated the primary pathol­ogy (mania in bipolar disorder; depression in postpartum depression and substance abuse) or revealed underlying illness.
Changing landscape of use and abuseThere has been a trend observed in the pattern of diet pill use: Initially marketed as an appetite suppressant, these pills are now being abused across ethnic, racial, and socioeconomic groups, by males and females.¹⁴ There is also a scarcity of useful guidance for clinicians.

Not only are diet pills used by people with an eating disorder; their recreational use is an emerging problem. If reports^12,13 continue to reveal that phentermine is a substance of abuse and has catastrophic effects on the user’s psyche, the need for stronger warnings and guidelines might be warranted to allow consumers to make an informed choice about using the drug.
Call for awarenessThe case we presented here exemplifies the importance of tighter regulation of both over-the-counter and prescription stimu­lant analogs. There is a need for awareness among practitioners about early detection and treatment of reversible psychotic and mood symptoms secondary to what might be promoted as, or appear to be, “harmless” weight loss and energy pills.
 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

This unfunded study was presented as a case report poster at the Annual Meeting of the Academy of Psychosomatic Medicine, November 2013, Tucson, Arizona, and at the Colloquium of Scholars of the Philadelphia Psychiatric Society, March 2014, Philadelphia, Pennsylvania.
 

Drug Brand Names
Alprazolam • Xanax
Fenfluramine • Pondimin
Phentermine HCl • Adipex-P, Fen-Phen, Qsymia, Suprenza
Topiramate • Topamax, Trokendi XR                
Zolpidem • Ambien

ORLANDO – Five “Choosing Wisely” initiatives selected from other specialties were featured at the annual meeting of the American Society of Hematology.

Dr. Lisa Hicks of St. Michael’s Hospital in Toronto led ASH’s Choosing Wisely list and moderated their presentation and the discussion of this year’s recommendations at the meeting. In a video interview, Dr. Hicks discussed the five recommendations and how hematologists can influence better patient care through cross-specialty collaborations. The complete Choosing Wisely list is available at www.hematology.org/choosingwisely

The 2015 Choosing Wisely recommendations, selected from recommendations made previously by other organizations, are:

• Don’t image for suspected pulmonary embolism (PE) without moderate or high pre-test probability of PE. (American College of Radiology)

• Don’t perform repetitive CBC and chemistry testing in the face of clinical and lab stability. (Society of Hospital Medicine)

• Don’t routinely order thrombophilia testing on patients undergoing a routine infertility evaluation. (American Society of Reproductive Medicine)

• Don’t transfuse red blood cells for iron deficiency without hemodynamic instability. (American Association of Blood Banks)

• Avoid using PET or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome. (American Society of Clinical Oncology)

Choosing Wisely is an initiative of the ABIM Foundation. Dr. Hicks had no relevant financial disclosures.

ORLANDO – Five “Choosing Wisely” initiatives selected from other specialties were featured at the annual meeting of the American Society of Hematology.

Dr. Lisa Hicks of St. Michael’s Hospital in Toronto led ASH’s Choosing Wisely list and moderated their presentation and the discussion of this year’s recommendations at the meeting. In a video interview, Dr. Hicks discussed the five recommendations and how hematologists can influence better patient care through cross-specialty collaborations. The complete Choosing Wisely list is available at www.hematology.org/choosingwisely

The 2015 Choosing Wisely recommendations, selected from recommendations made previously by other organizations, are:

• Don’t image for suspected pulmonary embolism (PE) without moderate or high pre-test probability of PE. (American College of Radiology)

• Don’t perform repetitive CBC and chemistry testing in the face of clinical and lab stability. (Society of Hospital Medicine)

• Don’t routinely order thrombophilia testing on patients undergoing a routine infertility evaluation. (American Society of Reproductive Medicine)

• Don’t transfuse red blood cells for iron deficiency without hemodynamic instability. (American Association of Blood Banks)

• Avoid using PET or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome. (American Society of Clinical Oncology)

Choosing Wisely is an initiative of the ABIM Foundation. Dr. Hicks had no relevant financial disclosures.

ORLANDO – Five “Choosing Wisely” initiatives selected from other specialties were featured at the annual meeting of the American Society of Hematology.

Dr. Lisa Hicks of St. Michael’s Hospital in Toronto led ASH’s Choosing Wisely list and moderated their presentation and the discussion of this year’s recommendations at the meeting. In a video interview, Dr. Hicks discussed the five recommendations and how hematologists can influence better patient care through cross-specialty collaborations. The complete Choosing Wisely list is available at www.hematology.org/choosingwisely

The 2015 Choosing Wisely recommendations, selected from recommendations made previously by other organizations, are:

• Don’t image for suspected pulmonary embolism (PE) without moderate or high pre-test probability of PE. (American College of Radiology)

• Don’t perform repetitive CBC and chemistry testing in the face of clinical and lab stability. (Society of Hospital Medicine)

• Don’t routinely order thrombophilia testing on patients undergoing a routine infertility evaluation. (American Society of Reproductive Medicine)

• Don’t transfuse red blood cells for iron deficiency without hemodynamic instability. (American Association of Blood Banks)

• Avoid using PET or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome. (American Society of Clinical Oncology)

Choosing Wisely is an initiative of the ABIM Foundation. Dr. Hicks had no relevant financial disclosures.

ORLANDO – A second, confirmatory major study has shown that chronic obstructive pulmonary disease independently increases the risk of sudden cardiac death severalfold.

COPD was associated with a roughly twofold increased risk of sudden cardiac death (SCD) in hypertensive patients with COPD, compared with those without the pulmonary disease, in the Scandinavian Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, Dr. Peter M. Okin reported at the American Heart Association scientific sessions.

Moreover, aggressive blood pressure lowering in the hypertensive COPD patients didn’t negate this risk, added Dr. Okin of Cornell University in New York.

The impetus for his secondary analysis of LIFE data was an earlier report from the landmark, population-based Rotterdam Heart Study. Among 1,615 participants with COPD, the age- and sex-adjusted risk of SCD was 1.34-fold greater than in nearly 12,000 controls. This increased SCD risk climbed to 2.12-fold during the first 2,000 days following diagnosis of COPD and reached 3.58-fold among those with frequent COPD exacerbations during this period (Eur Heart J. 2015 Jul 14;36[27]:1754-61).

Dr. Okin’s secondary analysis of LIFE data included 9,193 hypertensive subjects with ECG evidence of left ventricular hypertrophy who were randomized to lisinopril- or atenolol-based blood pressure lowering to a target of 140/90 mm Hg or less. A history of COPD was present in 385 patients (4.2%) at enrollment.

During a mean 4.8 years of prospective follow-up, 178 patients experienced SCD, a prespecified secondary endpoint in the LIFE trial. The incidence rate was 9 cases per 1,000 patient-years in those with COPD and 3.8 per 1,000 person-years in those without the pulmonary disease.

In a univariate analysis, a history of COPD was associated with a 2.36-fold increased risk of SCD during follow-up. In a multivariate analysis extensively adjusted for potential confounders – treatment arm, age, race, gender, history of atrial fibrillation, baseline serum creatinine and serum glucose, stroke or TIA, as well as on-treatment blood pressure, heart rate, QRS duration, HDL cholesterol level, use of a statin or hydrochlorothiazide, and incident MI or heart failure – COPD remained associated with a 1.82-fold increased risk of SCD, the cardiologist reported.

“These results suggest the need for additional studies to assess whether there are targeted therapies that can reduce the risk of SCD in patients with COPD,” he concluded.

As previously reported, the main finding in LIFE was that losartan conferred benefits beyond blood pressure control (Lancet. 2002 Mar 23;359[9311]:995-1003).

Dr. Okin reported serving as a consultant to Novartis.

[email protected]

ORLANDO – A second, confirmatory major study has shown that chronic obstructive pulmonary disease independently increases the risk of sudden cardiac death severalfold.

COPD was associated with a roughly twofold increased risk of sudden cardiac death (SCD) in hypertensive patients with COPD, compared with those without the pulmonary disease, in the Scandinavian Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, Dr. Peter M. Okin reported at the American Heart Association scientific sessions.

Moreover, aggressive blood pressure lowering in the hypertensive COPD patients didn’t negate this risk, added Dr. Okin of Cornell University in New York.

The impetus for his secondary analysis of LIFE data was an earlier report from the landmark, population-based Rotterdam Heart Study. Among 1,615 participants with COPD, the age- and sex-adjusted risk of SCD was 1.34-fold greater than in nearly 12,000 controls. This increased SCD risk climbed to 2.12-fold during the first 2,000 days following diagnosis of COPD and reached 3.58-fold among those with frequent COPD exacerbations during this period (Eur Heart J. 2015 Jul 14;36[27]:1754-61).

Dr. Okin’s secondary analysis of LIFE data included 9,193 hypertensive subjects with ECG evidence of left ventricular hypertrophy who were randomized to lisinopril- or atenolol-based blood pressure lowering to a target of 140/90 mm Hg or less. A history of COPD was present in 385 patients (4.2%) at enrollment.

During a mean 4.8 years of prospective follow-up, 178 patients experienced SCD, a prespecified secondary endpoint in the LIFE trial. The incidence rate was 9 cases per 1,000 patient-years in those with COPD and 3.8 per 1,000 person-years in those without the pulmonary disease.

In a univariate analysis, a history of COPD was associated with a 2.36-fold increased risk of SCD during follow-up. In a multivariate analysis extensively adjusted for potential confounders – treatment arm, age, race, gender, history of atrial fibrillation, baseline serum creatinine and serum glucose, stroke or TIA, as well as on-treatment blood pressure, heart rate, QRS duration, HDL cholesterol level, use of a statin or hydrochlorothiazide, and incident MI or heart failure – COPD remained associated with a 1.82-fold increased risk of SCD, the cardiologist reported.

“These results suggest the need for additional studies to assess whether there are targeted therapies that can reduce the risk of SCD in patients with COPD,” he concluded.

As previously reported, the main finding in LIFE was that losartan conferred benefits beyond blood pressure control (Lancet. 2002 Mar 23;359[9311]:995-1003).

Dr. Okin reported serving as a consultant to Novartis.

[email protected]

ORLANDO – A second, confirmatory major study has shown that chronic obstructive pulmonary disease independently increases the risk of sudden cardiac death severalfold.

COPD was associated with a roughly twofold increased risk of sudden cardiac death (SCD) in hypertensive patients with COPD, compared with those without the pulmonary disease, in the Scandinavian Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, Dr. Peter M. Okin reported at the American Heart Association scientific sessions.

Moreover, aggressive blood pressure lowering in the hypertensive COPD patients didn’t negate this risk, added Dr. Okin of Cornell University in New York.

The impetus for his secondary analysis of LIFE data was an earlier report from the landmark, population-based Rotterdam Heart Study. Among 1,615 participants with COPD, the age- and sex-adjusted risk of SCD was 1.34-fold greater than in nearly 12,000 controls. This increased SCD risk climbed to 2.12-fold during the first 2,000 days following diagnosis of COPD and reached 3.58-fold among those with frequent COPD exacerbations during this period (Eur Heart J. 2015 Jul 14;36[27]:1754-61).

Dr. Okin’s secondary analysis of LIFE data included 9,193 hypertensive subjects with ECG evidence of left ventricular hypertrophy who were randomized to lisinopril- or atenolol-based blood pressure lowering to a target of 140/90 mm Hg or less. A history of COPD was present in 385 patients (4.2%) at enrollment.

During a mean 4.8 years of prospective follow-up, 178 patients experienced SCD, a prespecified secondary endpoint in the LIFE trial. The incidence rate was 9 cases per 1,000 patient-years in those with COPD and 3.8 per 1,000 person-years in those without the pulmonary disease.

In a univariate analysis, a history of COPD was associated with a 2.36-fold increased risk of SCD during follow-up. In a multivariate analysis extensively adjusted for potential confounders – treatment arm, age, race, gender, history of atrial fibrillation, baseline serum creatinine and serum glucose, stroke or TIA, as well as on-treatment blood pressure, heart rate, QRS duration, HDL cholesterol level, use of a statin or hydrochlorothiazide, and incident MI or heart failure – COPD remained associated with a 1.82-fold increased risk of SCD, the cardiologist reported.

“These results suggest the need for additional studies to assess whether there are targeted therapies that can reduce the risk of SCD in patients with COPD,” he concluded.

As previously reported, the main finding in LIFE was that losartan conferred benefits beyond blood pressure control (Lancet. 2002 Mar 23;359[9311]:995-1003).

Dr. Okin reported serving as a consultant to Novartis.

[email protected]

Blood for transfusion

Photo by Elise Amendola

ORLANDO, FL—The storage duration of red blood cells (RBCs) doesn’t affect transfusion outcomes in children with lactic acidosis due to severe anemia, according to a new study.

Investigators found no significant differences in lactate levels, 30-day recovery, survival, or adverse events between children who received RBCs stored for 25 to 35 days and children who received RBCs stored for 1 to 10 days.

These results were published in JAMA and presented at the 2015 ASH Annual Meeting as abstract 769.

Christine Cserti-Gazdewich, MD, of University Health Network in Toronto, Canada, provided insights on the data during a press conference at ASH.

A concern of the investigators, according to Dr Cserti-Gazdewich, was that previous studies on blood storage were conducted in “high-income countries in high-technology care settings with blood inventory wealth, and findings may not be generalizable to the other half of the world.”

She pointed out that, in less developed countries, the shortfall in blood availability compared to the need is up to 3-fold.

So the investigators examined whether longer-stored red blood cells actually deliver oxygen in a manner not worse than shorter-stored or fresh blood and examined it at the extremes of storage duration in the context of a very high-dose need.

The team evaluated 290 children (aged 6 months to 60 months) with elevated blood lactate levels due to severe anemia who presented at a university-affiliated national referral hospital in Kampala, Uganda.

The children were randomized to receive RBC units stored for 25 to 35 days (longer-storage group, n=145) or RBCs stored for 1 to 10 days (shorter-storage group, n=145).

All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.

In the entire population, the mean presenting hemoglobin level was 3.7 g/dL, and the mean lactate level was 9.3 mmol/L. The median RBC unit storage duration was 8 days (range, 7-9) for the shorter-storage group and 32 days (range, 30-34) for the longer-storage group.

Results

The investigators found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days.

The study’s primary endpoint was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours, using a margin of noninferiority equal to an absolute difference of 25%.

The proportion of patients meeting this endpoint was 0.61 in the longer-storage group and 0.58 in the shorter-storage group (P<0.001 for noninferiority).

Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. And there was no statistical difference in the median time to achieve a blood lactate of 3 mmol/L or lower at 4 hours (hazard ratio=0.99, P=0.92).

Cerebral tissue oxygen saturation rose significantly during transfusion, but there was no significant difference between the 2 storage groups. The median area under the curve of cerebral tissue oxygen saturation during transfusion was 679 (range, 334-1156) for the longer-storage group and 521 (range, 303-835) for the shorter-storage group (P=0.25).

There was no significant difference between the longer-storage group and the shorter-storage group in the persistence of stupor or coma 8 hours after transfusion (12.6% and 19.6%, respectively, P=0.11) or the persistence of respiratory distress at 8 hours (28.7% and 30%, respectively, P=0.79).

The median length of hospital stay was 4 days (range, 2-6) in the longer-storage group and 4 days (range, 3-7) in the shorter-storage group.

There were 8 deaths, 3 in the longer-storage group and 5 in the shorter-storage group, during the 24 hours from the start of transfusion. Four additional patients, 2 in each group, died in the hospital after the initial 24-hour observation period.

The proportion of patients who had returned to good health by 30 days was 86% of the longer-storage group and 93% of the shorter-storage group (P=0.13).

“By every single measure we explored, and we explored many, we found that long-stored blood was not inferior . . . ,” Dr Csert-Gazdewich said. “We truly found no justification to shorten the current storage duration of red cells as judged by the fundamental role to deliver oxygen.”

Blood for transfusion

Photo by Elise Amendola

ORLANDO, FL—The storage duration of red blood cells (RBCs) doesn’t affect transfusion outcomes in children with lactic acidosis due to severe anemia, according to a new study.

Investigators found no significant differences in lactate levels, 30-day recovery, survival, or adverse events between children who received RBCs stored for 25 to 35 days and children who received RBCs stored for 1 to 10 days.

These results were published in JAMA and presented at the 2015 ASH Annual Meeting as abstract 769.

Christine Cserti-Gazdewich, MD, of University Health Network in Toronto, Canada, provided insights on the data during a press conference at ASH.

A concern of the investigators, according to Dr Cserti-Gazdewich, was that previous studies on blood storage were conducted in “high-income countries in high-technology care settings with blood inventory wealth, and findings may not be generalizable to the other half of the world.”

She pointed out that, in less developed countries, the shortfall in blood availability compared to the need is up to 3-fold.

So the investigators examined whether longer-stored red blood cells actually deliver oxygen in a manner not worse than shorter-stored or fresh blood and examined it at the extremes of storage duration in the context of a very high-dose need.

The team evaluated 290 children (aged 6 months to 60 months) with elevated blood lactate levels due to severe anemia who presented at a university-affiliated national referral hospital in Kampala, Uganda.

The children were randomized to receive RBC units stored for 25 to 35 days (longer-storage group, n=145) or RBCs stored for 1 to 10 days (shorter-storage group, n=145).

All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.

In the entire population, the mean presenting hemoglobin level was 3.7 g/dL, and the mean lactate level was 9.3 mmol/L. The median RBC unit storage duration was 8 days (range, 7-9) for the shorter-storage group and 32 days (range, 30-34) for the longer-storage group.

Results

The investigators found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days.

The study’s primary endpoint was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours, using a margin of noninferiority equal to an absolute difference of 25%.

The proportion of patients meeting this endpoint was 0.61 in the longer-storage group and 0.58 in the shorter-storage group (P<0.001 for noninferiority).

Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. And there was no statistical difference in the median time to achieve a blood lactate of 3 mmol/L or lower at 4 hours (hazard ratio=0.99, P=0.92).

Cerebral tissue oxygen saturation rose significantly during transfusion, but there was no significant difference between the 2 storage groups. The median area under the curve of cerebral tissue oxygen saturation during transfusion was 679 (range, 334-1156) for the longer-storage group and 521 (range, 303-835) for the shorter-storage group (P=0.25).

There was no significant difference between the longer-storage group and the shorter-storage group in the persistence of stupor or coma 8 hours after transfusion (12.6% and 19.6%, respectively, P=0.11) or the persistence of respiratory distress at 8 hours (28.7% and 30%, respectively, P=0.79).

The median length of hospital stay was 4 days (range, 2-6) in the longer-storage group and 4 days (range, 3-7) in the shorter-storage group.

There were 8 deaths, 3 in the longer-storage group and 5 in the shorter-storage group, during the 24 hours from the start of transfusion. Four additional patients, 2 in each group, died in the hospital after the initial 24-hour observation period.

The proportion of patients who had returned to good health by 30 days was 86% of the longer-storage group and 93% of the shorter-storage group (P=0.13).

“By every single measure we explored, and we explored many, we found that long-stored blood was not inferior . . . ,” Dr Csert-Gazdewich said. “We truly found no justification to shorten the current storage duration of red cells as judged by the fundamental role to deliver oxygen.”

Blood for transfusion

Photo by Elise Amendola

ORLANDO, FL—The storage duration of red blood cells (RBCs) doesn’t affect transfusion outcomes in children with lactic acidosis due to severe anemia, according to a new study.

Investigators found no significant differences in lactate levels, 30-day recovery, survival, or adverse events between children who received RBCs stored for 25 to 35 days and children who received RBCs stored for 1 to 10 days.

These results were published in JAMA and presented at the 2015 ASH Annual Meeting as abstract 769.

Christine Cserti-Gazdewich, MD, of University Health Network in Toronto, Canada, provided insights on the data during a press conference at ASH.

A concern of the investigators, according to Dr Cserti-Gazdewich, was that previous studies on blood storage were conducted in “high-income countries in high-technology care settings with blood inventory wealth, and findings may not be generalizable to the other half of the world.”

She pointed out that, in less developed countries, the shortfall in blood availability compared to the need is up to 3-fold.

So the investigators examined whether longer-stored red blood cells actually deliver oxygen in a manner not worse than shorter-stored or fresh blood and examined it at the extremes of storage duration in the context of a very high-dose need.

The team evaluated 290 children (aged 6 months to 60 months) with elevated blood lactate levels due to severe anemia who presented at a university-affiliated national referral hospital in Kampala, Uganda.

The children were randomized to receive RBC units stored for 25 to 35 days (longer-storage group, n=145) or RBCs stored for 1 to 10 days (shorter-storage group, n=145).

All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.

In the entire population, the mean presenting hemoglobin level was 3.7 g/dL, and the mean lactate level was 9.3 mmol/L. The median RBC unit storage duration was 8 days (range, 7-9) for the shorter-storage group and 32 days (range, 30-34) for the longer-storage group.

Results

The investigators found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days.

The study’s primary endpoint was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours, using a margin of noninferiority equal to an absolute difference of 25%.

The proportion of patients meeting this endpoint was 0.61 in the longer-storage group and 0.58 in the shorter-storage group (P<0.001 for noninferiority).

Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. And there was no statistical difference in the median time to achieve a blood lactate of 3 mmol/L or lower at 4 hours (hazard ratio=0.99, P=0.92).

Cerebral tissue oxygen saturation rose significantly during transfusion, but there was no significant difference between the 2 storage groups. The median area under the curve of cerebral tissue oxygen saturation during transfusion was 679 (range, 334-1156) for the longer-storage group and 521 (range, 303-835) for the shorter-storage group (P=0.25).

There was no significant difference between the longer-storage group and the shorter-storage group in the persistence of stupor or coma 8 hours after transfusion (12.6% and 19.6%, respectively, P=0.11) or the persistence of respiratory distress at 8 hours (28.7% and 30%, respectively, P=0.79).

The median length of hospital stay was 4 days (range, 2-6) in the longer-storage group and 4 days (range, 3-7) in the shorter-storage group.

There were 8 deaths, 3 in the longer-storage group and 5 in the shorter-storage group, during the 24 hours from the start of transfusion. Four additional patients, 2 in each group, died in the hospital after the initial 24-hour observation period.

The proportion of patients who had returned to good health by 30 days was 86% of the longer-storage group and 93% of the shorter-storage group (P=0.13).

“By every single measure we explored, and we explored many, we found that long-stored blood was not inferior . . . ,” Dr Csert-Gazdewich said. “We truly found no justification to shorten the current storage duration of red cells as judged by the fundamental role to deliver oxygen.”

Crowd at 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.

Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.

There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.

A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.

Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.

The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.

Study design

The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.

The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.

Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.

Patient characteristics

Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).

The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.

The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.

About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).

Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.

PFS

The study’s primary endpoint was PFS, as assessed by an independent review committee.

At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.

Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.

“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”

Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.

Secondary endpoints

The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.

This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.

The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.

The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).

And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.

Timing counts

Dr Rule also presented response and PFS data according to the number of prior therapies patients received.

He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.

In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.

Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.

At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.

“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”

Safety

“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.

Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.

Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.

Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.

Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).

The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).

The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).

The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).

Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.

At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.

Crowd at 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.

Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.

There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.

A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.

Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.

The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.

Study design

The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.

The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.

Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.

Patient characteristics

Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).

The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.

The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.

About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).

Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.

PFS

The study’s primary endpoint was PFS, as assessed by an independent review committee.

At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.

Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.

“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”

Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.

Secondary endpoints

The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.

This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.

The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.

The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).

And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.

Timing counts

Dr Rule also presented response and PFS data according to the number of prior therapies patients received.

He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.

In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.

Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.

At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.

“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”

Safety

“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.

Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.

Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.

Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.

Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).

The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).

The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).

The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).

Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.

At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.

Crowd at 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.

Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.

There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.

A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.

Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.

The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.

Study design

The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.

The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.

Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.

Patient characteristics

Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).

The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.

The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.

About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).

Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.

PFS

The study’s primary endpoint was PFS, as assessed by an independent review committee.

At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.

Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.

“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”

Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.

Secondary endpoints

The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.

This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.

The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.

The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).

And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.

Timing counts

Dr Rule also presented response and PFS data according to the number of prior therapies patients received.

He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.

In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.

Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.

At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.

“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”

Safety

“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.

Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.

Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.

Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.

Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).

The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).

The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).

The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).

Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.

At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Sheet of hydrogel bonded to

a matrix of polymer islands

(red) that can encapsulate

electronic components

Photo by Melanie Gonick/MIT

Engineers say they have designed “smart wound dressing,” a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels.

The dressing releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.

When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.

The key to the design is a hydrogel matrix designed by Xuanhe Zhao, PhD, of the Massachusetts Institute of Technology in Cambridge.

The hydrogel, which was describe in Nature Materials last month, is a rubbery material, mostly composed of water, designed to bond strongly to surfaces such as gold, titanium, aluminum, silicon, glass, and ceramic.

In a paper published in Advanced Materials, Dr Zhao and his colleagues described embedding various electronics within the hydrogel, such as conductive wires, semiconductor chips, LED lights, and temperature sensors.

Dr Zhao said electronics coated in hydrogel may be used not just on the surface of the skin but also inside the body; for example, as implanted, biocompatible glucose sensors, or even soft, compliant neural probes.

“Electronics are usually hard and dry, but the human body is soft and wet,” Dr Zhao said. “These two systems have drastically different properties. If you want to put electronics in close contact with the human body for applications such as healthcare monitoring and drug delivery, it is highly desirable to make the electronic devices soft and stretchable to fit the environment of the human body. That’s the motivation for stretchable hydrogel electronics.”

A strong and stretchy bond

Typical synthetic hydrogels are brittle, barely stretchable, and adhere weakly to other surfaces.

“They’re often used as degradable biomaterials at the current stage,” Dr Zhao said. “If you want to make an electronic device out of hydrogels, you need to think of long-term stability of the hydrogels and interfaces.”

To get around these challenges, his team came up with a design strategy for robust hydrogels, mixing water with a small amount of selected biopolymers to create soft, stretchy materials with a stiffness of 10 to 100 kilopascals—about the range of human soft tissues. The researchers also devised a method to strongly bond the hydrogel to various nonporous surfaces.

In the new study, the researchers applied their techniques to demonstrate several uses for the hydrogel, including encapsulating a titanium wire to form a transparent, stretchable conductor. In experiments, they stretched the encapsulated wire multiple times and found it maintained constant electrical conductivity.

Dr Zhao also created an array of LED lights embedded in a sheet of hydrogel. When attached to different regions of the body, the array continued working, even when stretched across highly deformable areas such as the knee and elbow.

A versatile matrix

Finally, the group embedded various electronic components within a sheet of hydrogel to create a “smart wound dressing,” comprising regularly spaced temperature sensors and tiny drug reservoirs.

The researchers also created pathways for drugs to flow through the hydrogel, by either inserting patterned tubes or drilling tiny holes through the matrix. They placed the dressing over various regions of the body and found that, even when highly stretched, the dressing continued to monitor skin temperature and release drugs according to the sensor readings.

An immediate application of the technology may be as a stretchable, on-demand treatment for burns or other skin conditions, said Hyunwoo Yuk, a graduate student at MIT.

“It’s a very versatile matrix,” Yuk said. “The unique capability here is, when a sensor senses something different, like an abnormal increase in temperature, the device can, on demand, release drugs to that specific location and select a specific drug from one of the reservoirs, which can diffuse in the hydrogel matrix for sustained release over time.”

Delving deeper, Dr Zhao envisions hydrogel to be an ideal, biocompatible vehicle for delivering electronics inside the body. He is currently exploring hydrogel’s potential as a carrier for glucose sensors as well as neural probes.

Sheet of hydrogel bonded to

a matrix of polymer islands

(red) that can encapsulate

electronic components

Photo by Melanie Gonick/MIT

Engineers say they have designed “smart wound dressing,” a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels.

The dressing releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.

When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.

The key to the design is a hydrogel matrix designed by Xuanhe Zhao, PhD, of the Massachusetts Institute of Technology in Cambridge.

The hydrogel, which was describe in Nature Materials last month, is a rubbery material, mostly composed of water, designed to bond strongly to surfaces such as gold, titanium, aluminum, silicon, glass, and ceramic.

In a paper published in Advanced Materials, Dr Zhao and his colleagues described embedding various electronics within the hydrogel, such as conductive wires, semiconductor chips, LED lights, and temperature sensors.

Dr Zhao said electronics coated in hydrogel may be used not just on the surface of the skin but also inside the body; for example, as implanted, biocompatible glucose sensors, or even soft, compliant neural probes.

“Electronics are usually hard and dry, but the human body is soft and wet,” Dr Zhao said. “These two systems have drastically different properties. If you want to put electronics in close contact with the human body for applications such as healthcare monitoring and drug delivery, it is highly desirable to make the electronic devices soft and stretchable to fit the environment of the human body. That’s the motivation for stretchable hydrogel electronics.”

A strong and stretchy bond

Typical synthetic hydrogels are brittle, barely stretchable, and adhere weakly to other surfaces.

“They’re often used as degradable biomaterials at the current stage,” Dr Zhao said. “If you want to make an electronic device out of hydrogels, you need to think of long-term stability of the hydrogels and interfaces.”

To get around these challenges, his team came up with a design strategy for robust hydrogels, mixing water with a small amount of selected biopolymers to create soft, stretchy materials with a stiffness of 10 to 100 kilopascals—about the range of human soft tissues. The researchers also devised a method to strongly bond the hydrogel to various nonporous surfaces.

In the new study, the researchers applied their techniques to demonstrate several uses for the hydrogel, including encapsulating a titanium wire to form a transparent, stretchable conductor. In experiments, they stretched the encapsulated wire multiple times and found it maintained constant electrical conductivity.

Dr Zhao also created an array of LED lights embedded in a sheet of hydrogel. When attached to different regions of the body, the array continued working, even when stretched across highly deformable areas such as the knee and elbow.

A versatile matrix

Finally, the group embedded various electronic components within a sheet of hydrogel to create a “smart wound dressing,” comprising regularly spaced temperature sensors and tiny drug reservoirs.

The researchers also created pathways for drugs to flow through the hydrogel, by either inserting patterned tubes or drilling tiny holes through the matrix. They placed the dressing over various regions of the body and found that, even when highly stretched, the dressing continued to monitor skin temperature and release drugs according to the sensor readings.

An immediate application of the technology may be as a stretchable, on-demand treatment for burns or other skin conditions, said Hyunwoo Yuk, a graduate student at MIT.

“It’s a very versatile matrix,” Yuk said. “The unique capability here is, when a sensor senses something different, like an abnormal increase in temperature, the device can, on demand, release drugs to that specific location and select a specific drug from one of the reservoirs, which can diffuse in the hydrogel matrix for sustained release over time.”

Delving deeper, Dr Zhao envisions hydrogel to be an ideal, biocompatible vehicle for delivering electronics inside the body. He is currently exploring hydrogel’s potential as a carrier for glucose sensors as well as neural probes.

Sheet of hydrogel bonded to

a matrix of polymer islands

(red) that can encapsulate

electronic components

Photo by Melanie Gonick/MIT

Engineers say they have designed “smart wound dressing,” a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels.

The dressing releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.

When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.

The key to the design is a hydrogel matrix designed by Xuanhe Zhao, PhD, of the Massachusetts Institute of Technology in Cambridge.

The hydrogel, which was describe in Nature Materials last month, is a rubbery material, mostly composed of water, designed to bond strongly to surfaces such as gold, titanium, aluminum, silicon, glass, and ceramic.

In a paper published in Advanced Materials, Dr Zhao and his colleagues described embedding various electronics within the hydrogel, such as conductive wires, semiconductor chips, LED lights, and temperature sensors.

Dr Zhao said electronics coated in hydrogel may be used not just on the surface of the skin but also inside the body; for example, as implanted, biocompatible glucose sensors, or even soft, compliant neural probes.

“Electronics are usually hard and dry, but the human body is soft and wet,” Dr Zhao said. “These two systems have drastically different properties. If you want to put electronics in close contact with the human body for applications such as healthcare monitoring and drug delivery, it is highly desirable to make the electronic devices soft and stretchable to fit the environment of the human body. That’s the motivation for stretchable hydrogel electronics.”

A strong and stretchy bond

Typical synthetic hydrogels are brittle, barely stretchable, and adhere weakly to other surfaces.

“They’re often used as degradable biomaterials at the current stage,” Dr Zhao said. “If you want to make an electronic device out of hydrogels, you need to think of long-term stability of the hydrogels and interfaces.”

To get around these challenges, his team came up with a design strategy for robust hydrogels, mixing water with a small amount of selected biopolymers to create soft, stretchy materials with a stiffness of 10 to 100 kilopascals—about the range of human soft tissues. The researchers also devised a method to strongly bond the hydrogel to various nonporous surfaces.

In the new study, the researchers applied their techniques to demonstrate several uses for the hydrogel, including encapsulating a titanium wire to form a transparent, stretchable conductor. In experiments, they stretched the encapsulated wire multiple times and found it maintained constant electrical conductivity.

Dr Zhao also created an array of LED lights embedded in a sheet of hydrogel. When attached to different regions of the body, the array continued working, even when stretched across highly deformable areas such as the knee and elbow.

A versatile matrix

Finally, the group embedded various electronic components within a sheet of hydrogel to create a “smart wound dressing,” comprising regularly spaced temperature sensors and tiny drug reservoirs.

The researchers also created pathways for drugs to flow through the hydrogel, by either inserting patterned tubes or drilling tiny holes through the matrix. They placed the dressing over various regions of the body and found that, even when highly stretched, the dressing continued to monitor skin temperature and release drugs according to the sensor readings.

An immediate application of the technology may be as a stretchable, on-demand treatment for burns or other skin conditions, said Hyunwoo Yuk, a graduate student at MIT.

“It’s a very versatile matrix,” Yuk said. “The unique capability here is, when a sensor senses something different, like an abnormal increase in temperature, the device can, on demand, release drugs to that specific location and select a specific drug from one of the reservoirs, which can diffuse in the hydrogel matrix for sustained release over time.”

Delving deeper, Dr Zhao envisions hydrogel to be an ideal, biocompatible vehicle for delivering electronics inside the body. He is currently exploring hydrogel’s potential as a carrier for glucose sensors as well as neural probes.

ORLANDO – The combination of the oral proteasome inhibitor ixazomib (Ninlaro, recently approved by the Food and Drug Administration) with lenalidomide and dexamethasone was associated with a 35% improvement in progression free survival in the Tourmaline trial.

In a video interview, Tourmaline investigator Dr. Shaji Kumar, professor of medicine at the Mayo Clinic, Rochester, Minn., discussed the top-line study results, the status of ongoing trials with ixazomib in other combination regimens, and the decision rationales that will need to be considered in selecting one of the newly approved multiple myeloma therapies.

Dr. Kumar has received funding from Takeda, the makers of ixazomib; he has also received funding from Celgene, Onyx, Janssen, and Sanofi.

[email protected]

ORLANDO – The combination of the oral proteasome inhibitor ixazomib (Ninlaro, recently approved by the Food and Drug Administration) with lenalidomide and dexamethasone was associated with a 35% improvement in progression free survival in the Tourmaline trial.

In a video interview, Tourmaline investigator Dr. Shaji Kumar, professor of medicine at the Mayo Clinic, Rochester, Minn., discussed the top-line study results, the status of ongoing trials with ixazomib in other combination regimens, and the decision rationales that will need to be considered in selecting one of the newly approved multiple myeloma therapies.

Dr. Kumar has received funding from Takeda, the makers of ixazomib; he has also received funding from Celgene, Onyx, Janssen, and Sanofi.

[email protected]

ORLANDO – The combination of the oral proteasome inhibitor ixazomib (Ninlaro, recently approved by the Food and Drug Administration) with lenalidomide and dexamethasone was associated with a 35% improvement in progression free survival in the Tourmaline trial.

In a video interview, Tourmaline investigator Dr. Shaji Kumar, professor of medicine at the Mayo Clinic, Rochester, Minn., discussed the top-line study results, the status of ongoing trials with ixazomib in other combination regimens, and the decision rationales that will need to be considered in selecting one of the newly approved multiple myeloma therapies.

Dr. Kumar has received funding from Takeda, the makers of ixazomib; he has also received funding from Celgene, Onyx, Janssen, and Sanofi.

[email protected]