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Agios stops developing drug for PK deficiency
Agios Pharmaceuticals, Inc. is no longer developing one of its pyruvate kinase-R (PKR) activators, AG-519, for the treatment of pyruvate kinase (PK) deficiency.
The company withdrew its investigational new drug application for AG-519 following a verbal notification of a clinical hold from the US Food and Drug Administration (FDA).
The hold resulted from an adverse event—cholestatic hepatitis—observed in a phase 1 trial of healthy volunteers.
“[W]e received feedback from the FDA that AG-519 no longer has an appropriate risk-benefit ratio to move forward in clinical development and was placed on clinical hold due to that case of cholestatic hepatitis,” said David Schenkein, MD, chief executive officer at Agios.
“We made the decision to withdraw the IND [investigational new drug application] and discontinue development of AG-519 and advance AG-348, our first-in-class and lead pyruvate kinase activator into pivotal development. We share the FDA’s commitment to patient safety and believe this is the right decision to ultimately help people with PK deficiency.”
About AG-519
Agios has described AG-519 as a potent, highly selective, and orally bioavailable PKR activator devoid of the aromatase inhibitory effects that were observed with the company’s other PKR activator, AG-348.
AG-519 was evaluated in a phase 1 study of healthy volunteers in the UK. The goal of this study was to assess the drug’s safety, tolerability, pharmacokinetics, pharmacodynamics, and bioavailability.
A case of drug-induced cholestatic hepatitis occurred in the bioavailability portion of the study. This volunteer continues to be monitored and is showing improvement, according to Dr Schenkein.
Agios said other adverse events observed in this trial were largely mild or moderate (grade 1/2). The most common of these was headache.
The company did note a case of grade 2 thrombocytopenia that resolved spontaneously within 7 days after the last dose of AG-519.
Results from this trial were presented at the 2015 ASH Annual Meeting (abstract 1264).
AG-519 was also under investigation in a palatability study of volunteers in the US. The goal of this study was to develop a formulation of the drug for potential future development.
In total, 98 volunteers have received AG-519. No volunteers or patients are currently receiving the drug.
About AG-348
Agios’s decision to stop developing AG-519 does not affect the company’s ongoing phase 2 study (DRIVE PK) of AG-348, an activator of both wild-type and mutated PKR enzymes.
“AG-348 and AG-519 are different molecules with different structures,” Dr Schenkein noted.
Agios is advancing AG-348 into development as the first potential disease-modifying treatment for PK deficiency.
Results from a pair of phase 1 studies of AG-348 were presented at the 2014 ASH Annual Meeting (abstract 4007).
About PK deficiency
PK deficiency is a rare inherited disease that presents as hemolytic anemia. The inherited mutations in PKR enzymes cause a deficit in cellular energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate levels, and a build-up of upstream metabolites, including 2,3-DPG.
The current standard of care for PK deficiency is supportive care, including blood transfusions, splenectomy, chelation therapy to address iron overload, and/or interventions for other treatment- and disease-related morbidities.
There is, at present, no approved therapy to treat the underlying cause of PK deficiency. 
Agios Pharmaceuticals, Inc. is no longer developing one of its pyruvate kinase-R (PKR) activators, AG-519, for the treatment of pyruvate kinase (PK) deficiency.
The company withdrew its investigational new drug application for AG-519 following a verbal notification of a clinical hold from the US Food and Drug Administration (FDA).
The hold resulted from an adverse event—cholestatic hepatitis—observed in a phase 1 trial of healthy volunteers.
“[W]e received feedback from the FDA that AG-519 no longer has an appropriate risk-benefit ratio to move forward in clinical development and was placed on clinical hold due to that case of cholestatic hepatitis,” said David Schenkein, MD, chief executive officer at Agios.
“We made the decision to withdraw the IND [investigational new drug application] and discontinue development of AG-519 and advance AG-348, our first-in-class and lead pyruvate kinase activator into pivotal development. We share the FDA’s commitment to patient safety and believe this is the right decision to ultimately help people with PK deficiency.”
About AG-519
Agios has described AG-519 as a potent, highly selective, and orally bioavailable PKR activator devoid of the aromatase inhibitory effects that were observed with the company’s other PKR activator, AG-348.
AG-519 was evaluated in a phase 1 study of healthy volunteers in the UK. The goal of this study was to assess the drug’s safety, tolerability, pharmacokinetics, pharmacodynamics, and bioavailability.
A case of drug-induced cholestatic hepatitis occurred in the bioavailability portion of the study. This volunteer continues to be monitored and is showing improvement, according to Dr Schenkein.
Agios said other adverse events observed in this trial were largely mild or moderate (grade 1/2). The most common of these was headache.
The company did note a case of grade 2 thrombocytopenia that resolved spontaneously within 7 days after the last dose of AG-519.
Results from this trial were presented at the 2015 ASH Annual Meeting (abstract 1264).
AG-519 was also under investigation in a palatability study of volunteers in the US. The goal of this study was to develop a formulation of the drug for potential future development.
In total, 98 volunteers have received AG-519. No volunteers or patients are currently receiving the drug.
About AG-348
Agios’s decision to stop developing AG-519 does not affect the company’s ongoing phase 2 study (DRIVE PK) of AG-348, an activator of both wild-type and mutated PKR enzymes.
“AG-348 and AG-519 are different molecules with different structures,” Dr Schenkein noted.
Agios is advancing AG-348 into development as the first potential disease-modifying treatment for PK deficiency.
Results from a pair of phase 1 studies of AG-348 were presented at the 2014 ASH Annual Meeting (abstract 4007).
About PK deficiency
PK deficiency is a rare inherited disease that presents as hemolytic anemia. The inherited mutations in PKR enzymes cause a deficit in cellular energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate levels, and a build-up of upstream metabolites, including 2,3-DPG.
The current standard of care for PK deficiency is supportive care, including blood transfusions, splenectomy, chelation therapy to address iron overload, and/or interventions for other treatment- and disease-related morbidities.
There is, at present, no approved therapy to treat the underlying cause of PK deficiency.
Agios Pharmaceuticals, Inc. is no longer developing one of its pyruvate kinase-R (PKR) activators, AG-519, for the treatment of pyruvate kinase (PK) deficiency.
The company withdrew its investigational new drug application for AG-519 following a verbal notification of a clinical hold from the US Food and Drug Administration (FDA).
The hold resulted from an adverse event—cholestatic hepatitis—observed in a phase 1 trial of healthy volunteers.
“[W]e received feedback from the FDA that AG-519 no longer has an appropriate risk-benefit ratio to move forward in clinical development and was placed on clinical hold due to that case of cholestatic hepatitis,” said David Schenkein, MD, chief executive officer at Agios.
“We made the decision to withdraw the IND [investigational new drug application] and discontinue development of AG-519 and advance AG-348, our first-in-class and lead pyruvate kinase activator into pivotal development. We share the FDA’s commitment to patient safety and believe this is the right decision to ultimately help people with PK deficiency.”
About AG-519
Agios has described AG-519 as a potent, highly selective, and orally bioavailable PKR activator devoid of the aromatase inhibitory effects that were observed with the company’s other PKR activator, AG-348.
AG-519 was evaluated in a phase 1 study of healthy volunteers in the UK. The goal of this study was to assess the drug’s safety, tolerability, pharmacokinetics, pharmacodynamics, and bioavailability.
A case of drug-induced cholestatic hepatitis occurred in the bioavailability portion of the study. This volunteer continues to be monitored and is showing improvement, according to Dr Schenkein.
Agios said other adverse events observed in this trial were largely mild or moderate (grade 1/2). The most common of these was headache.
The company did note a case of grade 2 thrombocytopenia that resolved spontaneously within 7 days after the last dose of AG-519.
Results from this trial were presented at the 2015 ASH Annual Meeting (abstract 1264).
AG-519 was also under investigation in a palatability study of volunteers in the US. The goal of this study was to develop a formulation of the drug for potential future development.
In total, 98 volunteers have received AG-519. No volunteers or patients are currently receiving the drug.
About AG-348
Agios’s decision to stop developing AG-519 does not affect the company’s ongoing phase 2 study (DRIVE PK) of AG-348, an activator of both wild-type and mutated PKR enzymes.
“AG-348 and AG-519 are different molecules with different structures,” Dr Schenkein noted.
Agios is advancing AG-348 into development as the first potential disease-modifying treatment for PK deficiency.
Results from a pair of phase 1 studies of AG-348 were presented at the 2014 ASH Annual Meeting (abstract 4007).
About PK deficiency
PK deficiency is a rare inherited disease that presents as hemolytic anemia. The inherited mutations in PKR enzymes cause a deficit in cellular energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate levels, and a build-up of upstream metabolites, including 2,3-DPG.
The current standard of care for PK deficiency is supportive care, including blood transfusions, splenectomy, chelation therapy to address iron overload, and/or interventions for other treatment- and disease-related morbidities.
There is, at present, no approved therapy to treat the underlying cause of PK deficiency.
Hospitalized patients may fare better with female doctors
Photo courtesy of CDC
New research suggests that hospitalized patients on Medicare may fare better when treated by female internists.
Researchers analyzed data on more than 1.5 million hospitalizations of Medicare beneficiaries and found that patients treated by female physicians had lower rates of 30-day mortality and hospital readmission than those treated by male physicians.
The results were published in JAMA Internal Medicine alongside a related editorial.
“There’s a lot of evidence out there that male and female physicians practice medicine differently,” noted study author Ashish K. Jha, MD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.
“Female physicians are more likely to adhere to clinical practice guidelines. They’re more likely to practice evidence-based medicine. And while that data has been out there, we don’t really know to what extent that actually matters for patient outcomes.”
So with this study, Dr Jha and his colleagues set out to determine if differences in practice patterns translate into differences in patient outcomes.
The researchers analyzed data on 1,583,028 hospitalizations to assess 30-day mortality rates and 1,540,797 hospitalizations to assess readmissions. The hospitalizations occurred from January 1, 2011, to December 31, 2014.
In the 30-day mortality analysis, the patients’ mean age was 80.2 years, 621,412 patients were male, and 961,616 were female.
In the hospital readmission analysis, the mean patient age was 80.1 years, 602,115 patients were male, and 938,682 were female.
Physician characteristics
During the study period, 58,344 internists treated at least 1 hospitalized Medicare beneficiary. Among those physicians, 18,751 were women (32.1%).
Female physicians tended to be younger than males, with mean ages of 42.8 and 47.8, respectively. Females were also more likely than males to have had osteopathic training—8.4% and 7.0%, respectively.
Females were more likely than males to work in large hospitals (41.9% vs 35.7%), nonprofit hospitals (78.2% vs 75.6%), major teaching hospitals (29.0% vs 21.1%), and hospitals located in the Northeast (26.8% vs 22.7%).
Female physicians tended to treat fewer patients than males—131.9 and 180.5 hospitalizations per year, respectively.
Patient characteristics were largely similar between male and female physicians. However, female physicians treated a higher proportion of female patients than male physicians did—62.1% and 60.2%, respectively.
Results
An adjusted analysis showed that patients treated by female physicians had lower 30-day mortality rates than those treated by males—11.07% and 11.49%, respectively (risk difference, –0.43%; 95% confidence interval, –0.57% to –0.28%; P<0.001; number needed to treat to prevent 1 death, 233).
An adjusted analysis for 30-day hospital readmission rates showed a lower rate for patients treated by females than those treated by males—15.02% and 15.57%, respectively (risk difference, –0.55%; 95% confidence interval, –0.71% to –0.39%; P<0.001; number needed to treat to prevent 1 readmission, 182).
These analyses were adjusted for patient characteristics, hospital-fixed effects, and physician characteristics.
The researchers noted that patients treated by female physicians had lower 30-day mortality and readmission rates regardless of their medical condition or the severity of their illness.
“Across a wide range of conditions, we see a very consistent pattern—that patients who are treated by female physicians had modest but consistently better outcomes than patients treated by male physicians,” Dr Jha said.
“That was true across conditions. It was also true across severity of illness. In fact, among the patients who were the sickest, that’s where we saw some of the largest gaps between female and male physicians.”
The researchers also adjusted their analyses for patients’ length of stay, use of care, discharge location, patient volume, and physicians’ years of practice. But this did not affect the results.
Dr Jha and his colleagues said the results of this study suggest differences in practice patterns between male and female physicians may have important clinical implications for patients. And understanding why these differences exist may provide valuable insights into improving the quality of patient care.
Photo courtesy of CDC
New research suggests that hospitalized patients on Medicare may fare better when treated by female internists.
Researchers analyzed data on more than 1.5 million hospitalizations of Medicare beneficiaries and found that patients treated by female physicians had lower rates of 30-day mortality and hospital readmission than those treated by male physicians.
The results were published in JAMA Internal Medicine alongside a related editorial.
“There’s a lot of evidence out there that male and female physicians practice medicine differently,” noted study author Ashish K. Jha, MD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.
“Female physicians are more likely to adhere to clinical practice guidelines. They’re more likely to practice evidence-based medicine. And while that data has been out there, we don’t really know to what extent that actually matters for patient outcomes.”
So with this study, Dr Jha and his colleagues set out to determine if differences in practice patterns translate into differences in patient outcomes.
The researchers analyzed data on 1,583,028 hospitalizations to assess 30-day mortality rates and 1,540,797 hospitalizations to assess readmissions. The hospitalizations occurred from January 1, 2011, to December 31, 2014.
In the 30-day mortality analysis, the patients’ mean age was 80.2 years, 621,412 patients were male, and 961,616 were female.
In the hospital readmission analysis, the mean patient age was 80.1 years, 602,115 patients were male, and 938,682 were female.
Physician characteristics
During the study period, 58,344 internists treated at least 1 hospitalized Medicare beneficiary. Among those physicians, 18,751 were women (32.1%).
Female physicians tended to be younger than males, with mean ages of 42.8 and 47.8, respectively. Females were also more likely than males to have had osteopathic training—8.4% and 7.0%, respectively.
Females were more likely than males to work in large hospitals (41.9% vs 35.7%), nonprofit hospitals (78.2% vs 75.6%), major teaching hospitals (29.0% vs 21.1%), and hospitals located in the Northeast (26.8% vs 22.7%).
Female physicians tended to treat fewer patients than males—131.9 and 180.5 hospitalizations per year, respectively.
Patient characteristics were largely similar between male and female physicians. However, female physicians treated a higher proportion of female patients than male physicians did—62.1% and 60.2%, respectively.
Results
An adjusted analysis showed that patients treated by female physicians had lower 30-day mortality rates than those treated by males—11.07% and 11.49%, respectively (risk difference, –0.43%; 95% confidence interval, –0.57% to –0.28%; P<0.001; number needed to treat to prevent 1 death, 233).
An adjusted analysis for 30-day hospital readmission rates showed a lower rate for patients treated by females than those treated by males—15.02% and 15.57%, respectively (risk difference, –0.55%; 95% confidence interval, –0.71% to –0.39%; P<0.001; number needed to treat to prevent 1 readmission, 182).
These analyses were adjusted for patient characteristics, hospital-fixed effects, and physician characteristics.
The researchers noted that patients treated by female physicians had lower 30-day mortality and readmission rates regardless of their medical condition or the severity of their illness.
“Across a wide range of conditions, we see a very consistent pattern—that patients who are treated by female physicians had modest but consistently better outcomes than patients treated by male physicians,” Dr Jha said.
“That was true across conditions. It was also true across severity of illness. In fact, among the patients who were the sickest, that’s where we saw some of the largest gaps between female and male physicians.”
The researchers also adjusted their analyses for patients’ length of stay, use of care, discharge location, patient volume, and physicians’ years of practice. But this did not affect the results.
Dr Jha and his colleagues said the results of this study suggest differences in practice patterns between male and female physicians may have important clinical implications for patients. And understanding why these differences exist may provide valuable insights into improving the quality of patient care.
Photo courtesy of CDC
New research suggests that hospitalized patients on Medicare may fare better when treated by female internists.
Researchers analyzed data on more than 1.5 million hospitalizations of Medicare beneficiaries and found that patients treated by female physicians had lower rates of 30-day mortality and hospital readmission than those treated by male physicians.
The results were published in JAMA Internal Medicine alongside a related editorial.
“There’s a lot of evidence out there that male and female physicians practice medicine differently,” noted study author Ashish K. Jha, MD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.
“Female physicians are more likely to adhere to clinical practice guidelines. They’re more likely to practice evidence-based medicine. And while that data has been out there, we don’t really know to what extent that actually matters for patient outcomes.”
So with this study, Dr Jha and his colleagues set out to determine if differences in practice patterns translate into differences in patient outcomes.
The researchers analyzed data on 1,583,028 hospitalizations to assess 30-day mortality rates and 1,540,797 hospitalizations to assess readmissions. The hospitalizations occurred from January 1, 2011, to December 31, 2014.
In the 30-day mortality analysis, the patients’ mean age was 80.2 years, 621,412 patients were male, and 961,616 were female.
In the hospital readmission analysis, the mean patient age was 80.1 years, 602,115 patients were male, and 938,682 were female.
Physician characteristics
During the study period, 58,344 internists treated at least 1 hospitalized Medicare beneficiary. Among those physicians, 18,751 were women (32.1%).
Female physicians tended to be younger than males, with mean ages of 42.8 and 47.8, respectively. Females were also more likely than males to have had osteopathic training—8.4% and 7.0%, respectively.
Females were more likely than males to work in large hospitals (41.9% vs 35.7%), nonprofit hospitals (78.2% vs 75.6%), major teaching hospitals (29.0% vs 21.1%), and hospitals located in the Northeast (26.8% vs 22.7%).
Female physicians tended to treat fewer patients than males—131.9 and 180.5 hospitalizations per year, respectively.
Patient characteristics were largely similar between male and female physicians. However, female physicians treated a higher proportion of female patients than male physicians did—62.1% and 60.2%, respectively.
Results
An adjusted analysis showed that patients treated by female physicians had lower 30-day mortality rates than those treated by males—11.07% and 11.49%, respectively (risk difference, –0.43%; 95% confidence interval, –0.57% to –0.28%; P<0.001; number needed to treat to prevent 1 death, 233).
An adjusted analysis for 30-day hospital readmission rates showed a lower rate for patients treated by females than those treated by males—15.02% and 15.57%, respectively (risk difference, –0.55%; 95% confidence interval, –0.71% to –0.39%; P<0.001; number needed to treat to prevent 1 readmission, 182).
These analyses were adjusted for patient characteristics, hospital-fixed effects, and physician characteristics.
The researchers noted that patients treated by female physicians had lower 30-day mortality and readmission rates regardless of their medical condition or the severity of their illness.
“Across a wide range of conditions, we see a very consistent pattern—that patients who are treated by female physicians had modest but consistently better outcomes than patients treated by male physicians,” Dr Jha said.
“That was true across conditions. It was also true across severity of illness. In fact, among the patients who were the sickest, that’s where we saw some of the largest gaps between female and male physicians.”
The researchers also adjusted their analyses for patients’ length of stay, use of care, discharge location, patient volume, and physicians’ years of practice. But this did not affect the results.
Dr Jha and his colleagues said the results of this study suggest differences in practice patterns between male and female physicians may have important clinical implications for patients. And understanding why these differences exist may provide valuable insights into improving the quality of patient care.
MDS patients with mutated IDH2 benefit from enasidenib
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Combo improves ORR, PFS in relapsed/refractory CLL
Image by Mary Ann Thompson
Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.
In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.
“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.
“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”
The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.
About otlertuzumab
Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.
Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.
According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.
Study design
This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.
Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.
Patients in both arms received intravenous bendamustine at 70 mg/m2 on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.
The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.
Patient characteristics
The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.
Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.
There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.
In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.
Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.
In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.
In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.
Response and survival
The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).
In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.
In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.
The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).
The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.
Safety
Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.
Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).
However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.
“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.
“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”
Image by Mary Ann Thompson
Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.
In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.
“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.
“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”
The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.
About otlertuzumab
Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.
Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.
According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.
Study design
This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.
Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.
Patients in both arms received intravenous bendamustine at 70 mg/m2 on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.
The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.
Patient characteristics
The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.
Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.
There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.
In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.
Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.
In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.
In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.
Response and survival
The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).
In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.
In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.
The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).
The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.
Safety
Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.
Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).
However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.
“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.
“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”
Image by Mary Ann Thompson
Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.
In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.
“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.
“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”
The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.
About otlertuzumab
Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.
Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.
According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.
Study design
This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.
Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.
Patients in both arms received intravenous bendamustine at 70 mg/m2 on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.
The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.
Patient characteristics
The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.
Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.
There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.
In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.
Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.
In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.
In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.
Response and survival
The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).
In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.
In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.
The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).
The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.
Safety
Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.
Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).
However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.
“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.
“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”
CHMP recommends authorization of rituximab biosimilar
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the rituximab biosimilar Truxima receive marketing authorization for the treatment of several conditions.
The CHMP said studies have shown that Truxima is comparable to the reference product, Mabthera, which was authorized for use in the European Union in 1998.
The active substance in both products is the anti-CD20 monoclonal antibody rituximab.
Truxima is being developed by Celltrion Healthcare Hungary Kft.
The CHMP’s recommendation for Truxima will be reviewed by the European Commission, which normally issues its decision on a product within 67 days of the time the CHMP adopts its opinion.
If the European Commission grants marketing authorization for Truxima, it will be available as a 500 mg concentrate for solution for infusion.
The CHMP has recommended marketing authorization for Truxima in the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.
The full indications are as follows.
Non-Hodgkin lymphoma
Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma.
Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
Chronic lymphocytic leukemia
Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.
The CHMP noted that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including Truxima, or patients refractory to previous Truxima plus chemotherapy.
Rheumatoid arthritis
Truxima in combination with methotrexate is indicated for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
The CHMP noted that Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active granulomatosis with polyangiitis and microscopic polyangiitis.
The CHMP proposed that Truxima be administered under the close supervision of an experienced healthcare professional and in an environment where full resuscitation facilities are immediately available.
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the rituximab biosimilar Truxima receive marketing authorization for the treatment of several conditions.
The CHMP said studies have shown that Truxima is comparable to the reference product, Mabthera, which was authorized for use in the European Union in 1998.
The active substance in both products is the anti-CD20 monoclonal antibody rituximab.
Truxima is being developed by Celltrion Healthcare Hungary Kft.
The CHMP’s recommendation for Truxima will be reviewed by the European Commission, which normally issues its decision on a product within 67 days of the time the CHMP adopts its opinion.
If the European Commission grants marketing authorization for Truxima, it will be available as a 500 mg concentrate for solution for infusion.
The CHMP has recommended marketing authorization for Truxima in the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.
The full indications are as follows.
Non-Hodgkin lymphoma
Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma.
Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
Chronic lymphocytic leukemia
Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.
The CHMP noted that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including Truxima, or patients refractory to previous Truxima plus chemotherapy.
Rheumatoid arthritis
Truxima in combination with methotrexate is indicated for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
The CHMP noted that Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active granulomatosis with polyangiitis and microscopic polyangiitis.
The CHMP proposed that Truxima be administered under the close supervision of an experienced healthcare professional and in an environment where full resuscitation facilities are immediately available.
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the rituximab biosimilar Truxima receive marketing authorization for the treatment of several conditions.
The CHMP said studies have shown that Truxima is comparable to the reference product, Mabthera, which was authorized for use in the European Union in 1998.
The active substance in both products is the anti-CD20 monoclonal antibody rituximab.
Truxima is being developed by Celltrion Healthcare Hungary Kft.
The CHMP’s recommendation for Truxima will be reviewed by the European Commission, which normally issues its decision on a product within 67 days of the time the CHMP adopts its opinion.
If the European Commission grants marketing authorization for Truxima, it will be available as a 500 mg concentrate for solution for infusion.
The CHMP has recommended marketing authorization for Truxima in the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.
The full indications are as follows.
Non-Hodgkin lymphoma
Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma.
Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
Chronic lymphocytic leukemia
Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.
The CHMP noted that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including Truxima, or patients refractory to previous Truxima plus chemotherapy.
Rheumatoid arthritis
Truxima in combination with methotrexate is indicated for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
The CHMP noted that Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active granulomatosis with polyangiitis and microscopic polyangiitis.
The CHMP proposed that Truxima be administered under the close supervision of an experienced healthcare professional and in an environment where full resuscitation facilities are immediately available.
CHMP recommends approval of topical gel for MF
mycosis fungoides
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that chlormethine gel (Ledaga®) be approved for use in adults with mycosis fungoides (MF).
Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.
Ledaga contains the same active substance as Caryolysine but is a gel intended for cutaneous use.
The active substance of Ledaga is chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells.
Hybrid drug applications rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.
The CHMP said studies have demonstrated the satisfactory quality of Ledaga. Since Ledaga is administered as a topical agent and results in no systemic exposure, a bioequivalence study versus the reference product, Caryolysine, was not required.
The CHMP’s recommendation for Ledaga will be reviewed by the European Commission, which is expected to issue a final decision by the end of February 2017.
If approved, Ledaga will be available as a 160 μg/g gel.
Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to a list of recommendations from the CHMP (post-authorization measures) with regard to the release of Ledaga in Europe.
Subject to the agreed recommendations and achieving market access in different countries, a potential first launch of Ledaga could occur at the end of 2017, at the earliest.
Phase 2 study
The CHMP’s positive opinion of Ledaga is based on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.
The study enrolled 260 patients who were randomized 1:1 to receive topical treatment with Ledaga or compounded control—chlormethine HCl 0.02% compounded in Aquaphor® ointment—once daily for up to 12 months.
A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.
In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.
Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.
Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.
The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, pain of the skin), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).
No systemic absorption of chlormethine was detected with treatment.
mycosis fungoides
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that chlormethine gel (Ledaga®) be approved for use in adults with mycosis fungoides (MF).
Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.
Ledaga contains the same active substance as Caryolysine but is a gel intended for cutaneous use.
The active substance of Ledaga is chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells.
Hybrid drug applications rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.
The CHMP said studies have demonstrated the satisfactory quality of Ledaga. Since Ledaga is administered as a topical agent and results in no systemic exposure, a bioequivalence study versus the reference product, Caryolysine, was not required.
The CHMP’s recommendation for Ledaga will be reviewed by the European Commission, which is expected to issue a final decision by the end of February 2017.
If approved, Ledaga will be available as a 160 μg/g gel.
Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to a list of recommendations from the CHMP (post-authorization measures) with regard to the release of Ledaga in Europe.
Subject to the agreed recommendations and achieving market access in different countries, a potential first launch of Ledaga could occur at the end of 2017, at the earliest.
Phase 2 study
The CHMP’s positive opinion of Ledaga is based on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.
The study enrolled 260 patients who were randomized 1:1 to receive topical treatment with Ledaga or compounded control—chlormethine HCl 0.02% compounded in Aquaphor® ointment—once daily for up to 12 months.
A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.
In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.
Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.
Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.
The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, pain of the skin), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).
No systemic absorption of chlormethine was detected with treatment.
mycosis fungoides
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that chlormethine gel (Ledaga®) be approved for use in adults with mycosis fungoides (MF).
Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.
Ledaga contains the same active substance as Caryolysine but is a gel intended for cutaneous use.
The active substance of Ledaga is chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells.
Hybrid drug applications rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.
The CHMP said studies have demonstrated the satisfactory quality of Ledaga. Since Ledaga is administered as a topical agent and results in no systemic exposure, a bioequivalence study versus the reference product, Caryolysine, was not required.
The CHMP’s recommendation for Ledaga will be reviewed by the European Commission, which is expected to issue a final decision by the end of February 2017.
If approved, Ledaga will be available as a 160 μg/g gel.
Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to a list of recommendations from the CHMP (post-authorization measures) with regard to the release of Ledaga in Europe.
Subject to the agreed recommendations and achieving market access in different countries, a potential first launch of Ledaga could occur at the end of 2017, at the earliest.
Phase 2 study
The CHMP’s positive opinion of Ledaga is based on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.
The study enrolled 260 patients who were randomized 1:1 to receive topical treatment with Ledaga or compounded control—chlormethine HCl 0.02% compounded in Aquaphor® ointment—once daily for up to 12 months.
A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.
In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.
Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.
Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.
The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, pain of the skin), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).
No systemic absorption of chlormethine was detected with treatment.
CAR met primary endpoint at interim analysis in DLBCL
2016 ASH Annual Meeting
SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.
DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.
ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).
A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.
Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).
Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.
Earlier data from the phase 2 study have been reported in Hematology Times.
Phase 2 interim analysis
The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.
“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.
Patients then received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.
Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg.
“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”
Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.
The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.
The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.
At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.
Patient characteristics
Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.
The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.
Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.
Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.
Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.
Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.
Results
Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.
At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.
For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.
Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.
The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.
Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.
After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.
Adverse events
Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.
Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.
CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.
In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.
Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.
There were no cases of cerebral edema.
Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.
Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.
Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.
The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).
Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.
AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.
Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.
The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.
The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
*Information in the abstract differs from that presented at the meeting.
2016 ASH Annual Meeting
SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.
DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.
ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).
A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.
Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).
Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.
Earlier data from the phase 2 study have been reported in Hematology Times.
Phase 2 interim analysis
The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.
“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.
Patients then received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.
Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg.
“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”
Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.
The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.
The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.
At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.
Patient characteristics
Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.
The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.
Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.
Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.
Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.
Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.
Results
Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.
At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.
For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.
Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.
The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.
Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.
After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.
Adverse events
Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.
Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.
CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.
In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.
Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.
There were no cases of cerebral edema.
Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.
Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.
Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.
The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).
Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.
AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.
Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.
The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.
The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
*Information in the abstract differs from that presented at the meeting.
2016 ASH Annual Meeting
SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.
DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.
ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).
A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.
Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).
Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.
Earlier data from the phase 2 study have been reported in Hematology Times.
Phase 2 interim analysis
The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.
“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.
Patients then received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.
Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg.
“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”
Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.
The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.
The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.
At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.
Patient characteristics
Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.
The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.
Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.
Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.
Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.
Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.
Results
Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.
At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.
For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.
Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.
The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.
Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.
After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.
Adverse events
Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.
Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.
CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.
In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.
Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.
There were no cases of cerebral edema.
Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.
Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.
Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.
The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).
Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.
AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.
Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.
The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.
The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
*Information in the abstract differs from that presented at the meeting.
Predicting the risk of CKD in sickle cell anemia
and normal red blood cells
Image by Graham Beards
Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).
The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.
The researchers reported these findings in Haematologica.
Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.
“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.
“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”
To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.
Stratification
The researchers used their genetic profile to stratify patients according to risk for CKD.
Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.
Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).
The researchers defined all other combinations as intermediate-risk.
The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m2.
The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.
Mechanisms
Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.
The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African
Americans by unknown mechanisms, but the team found an association with
hemolysis in SCA, as reflected by hemoglobinuria.
As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the
intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing
HbS polymerization.
Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.
“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”
“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.
“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”
The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.
and normal red blood cells
Image by Graham Beards
Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).
The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.
The researchers reported these findings in Haematologica.
Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.
“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.
“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”
To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.
Stratification
The researchers used their genetic profile to stratify patients according to risk for CKD.
Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.
Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).
The researchers defined all other combinations as intermediate-risk.
The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m2.
The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.
Mechanisms
Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.
The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African
Americans by unknown mechanisms, but the team found an association with
hemolysis in SCA, as reflected by hemoglobinuria.
As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the
intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing
HbS polymerization.
Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.
“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”
“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.
“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”
The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.
and normal red blood cells
Image by Graham Beards
Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).
The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.
The researchers reported these findings in Haematologica.
Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.
“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.
“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”
To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.
Stratification
The researchers used their genetic profile to stratify patients according to risk for CKD.
Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.
Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).
The researchers defined all other combinations as intermediate-risk.
The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m2.
The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.
Mechanisms
Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.
The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African
Americans by unknown mechanisms, but the team found an association with
hemolysis in SCA, as reflected by hemoglobinuria.
As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the
intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing
HbS polymerization.
Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.
“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”
“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.
“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”
The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.
Chemical could aid malaria control
Photo courtesy of the CDC
A chemical that disrupts hormone signaling in mosquitoes may reduce their ability to transmit malaria, according to a study published in PLOS Pathogens.
The findings suggest a potential new approach to combat spread of the disease.
“As insecticide resistance is spreading, new intervention methods to control mosquitoes are urgently needed,” said study author Flaminia Catteruccia, PhD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.
“Our study provides a new strategy based on the use of a non-toxic compound that prevents transmission of malaria parasites without killing the mosquito.”
Dr Catteruccia and her colleagues treated adult female Anopheles gambiae mosquitoes with a chemical known as dibenzoylhydrazine (DBH) to see how it would impact their biological processes.
DBH mimics the action of the steroid hormone 20-hydroxyecdysone, which plays a key role in the reproductive cycle of the female mosquito.
The researchers found various aspects of the mosquitoes’ life cycle to be disrupted after treatment with DBH.
DBH-treated mosquitoes produced and laid fewer eggs, didn’t mate successfully, and died more rapidly than non-treated mosquitoes. The effects were greater the higher the DBH dose.
And DBH-treated mosquitoes were less likely to be infected by malaria parasites.
To further explore the potential of hormone targeting as a malaria control tactic, the researchers fed their experimental results into a mathematical model of the mosquito life cycle.
The results suggest that applying DBH to bed nets or spraying it indoors could potentially reduce malaria transmission as effectively as insecticides.
The researchers noted that DBH compounds are not toxic to mammals, which would make them ideally suited for use in bed nets, where low toxicity is essential.
Photo courtesy of the CDC
A chemical that disrupts hormone signaling in mosquitoes may reduce their ability to transmit malaria, according to a study published in PLOS Pathogens.
The findings suggest a potential new approach to combat spread of the disease.
“As insecticide resistance is spreading, new intervention methods to control mosquitoes are urgently needed,” said study author Flaminia Catteruccia, PhD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.
“Our study provides a new strategy based on the use of a non-toxic compound that prevents transmission of malaria parasites without killing the mosquito.”
Dr Catteruccia and her colleagues treated adult female Anopheles gambiae mosquitoes with a chemical known as dibenzoylhydrazine (DBH) to see how it would impact their biological processes.
DBH mimics the action of the steroid hormone 20-hydroxyecdysone, which plays a key role in the reproductive cycle of the female mosquito.
The researchers found various aspects of the mosquitoes’ life cycle to be disrupted after treatment with DBH.
DBH-treated mosquitoes produced and laid fewer eggs, didn’t mate successfully, and died more rapidly than non-treated mosquitoes. The effects were greater the higher the DBH dose.
And DBH-treated mosquitoes were less likely to be infected by malaria parasites.
To further explore the potential of hormone targeting as a malaria control tactic, the researchers fed their experimental results into a mathematical model of the mosquito life cycle.
The results suggest that applying DBH to bed nets or spraying it indoors could potentially reduce malaria transmission as effectively as insecticides.
The researchers noted that DBH compounds are not toxic to mammals, which would make them ideally suited for use in bed nets, where low toxicity is essential.
Photo courtesy of the CDC
A chemical that disrupts hormone signaling in mosquitoes may reduce their ability to transmit malaria, according to a study published in PLOS Pathogens.
The findings suggest a potential new approach to combat spread of the disease.
“As insecticide resistance is spreading, new intervention methods to control mosquitoes are urgently needed,” said study author Flaminia Catteruccia, PhD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.
“Our study provides a new strategy based on the use of a non-toxic compound that prevents transmission of malaria parasites without killing the mosquito.”
Dr Catteruccia and her colleagues treated adult female Anopheles gambiae mosquitoes with a chemical known as dibenzoylhydrazine (DBH) to see how it would impact their biological processes.
DBH mimics the action of the steroid hormone 20-hydroxyecdysone, which plays a key role in the reproductive cycle of the female mosquito.
The researchers found various aspects of the mosquitoes’ life cycle to be disrupted after treatment with DBH.
DBH-treated mosquitoes produced and laid fewer eggs, didn’t mate successfully, and died more rapidly than non-treated mosquitoes. The effects were greater the higher the DBH dose.
And DBH-treated mosquitoes were less likely to be infected by malaria parasites.
To further explore the potential of hormone targeting as a malaria control tactic, the researchers fed their experimental results into a mathematical model of the mosquito life cycle.
The results suggest that applying DBH to bed nets or spraying it indoors could potentially reduce malaria transmission as effectively as insecticides.
The researchers noted that DBH compounds are not toxic to mammals, which would make them ideally suited for use in bed nets, where low toxicity is essential.
Congenital CMV linked to increased risk of ALL
Photo by Vera Kratochvil
Newborns with congenital cytomegalovirus (CMV) infection may have an increased risk of developing acute lymphoblastic leukemia (ALL), according to a study published in Blood.
The data also suggest the risk may be particularly high among Hispanic children.
Researchers said this is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children.
To conduct this study, the researchers first identified all known infections present in the bone marrow of 127 children diagnosed with ALL and 38 children diagnosed with acute myeloid leukemia (AML).
The team found CMV infection was prevalent in children with ALL but rare in those with AML.
Next, the researchers looked for CMV in newborn blood samples from 268 children who went on to develop ALL. The team compared the samples with samples from 270 healthy children.
“Our goal in tracking CMV back from the time of diagnosis to the womb was to establish that this infection occurred well before initiation of disease,” said lead study author Stephen Francis, PhD, of the University of Nevada and University of California, San Francisco.
He and his colleagues found that children who went on to develop ALL were nearly 4 times more likely than control subjects to be CMV-positive at birth. The odds ratio was 3.71 (P=0.0016).
The odds ratio was 5.9 in Hispanic children and 2.1 in non-Hispanic whites. The researchers said this finding is particularly interesting because of the high rate of ALL observed in Hispanics.
“If it’s true that in utero CMV is one of the initiating events in the development of childhood leukemia, then control of the virus has the potential to be a prevention target,” Dr Francis said. “That’s the real take-home message.”
While this research is in the early stages, the researchers hope these results will inspire more studies that will validate these findings and lead to the development of a CMV vaccine.
“This is the first step, but if we do end up finding a causal link to the most common childhood cancer, we hope that will light a fire in terms of stopping mother-to-child transmission of CMV,” Dr Francis said.
Photo by Vera Kratochvil
Newborns with congenital cytomegalovirus (CMV) infection may have an increased risk of developing acute lymphoblastic leukemia (ALL), according to a study published in Blood.
The data also suggest the risk may be particularly high among Hispanic children.
Researchers said this is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children.
To conduct this study, the researchers first identified all known infections present in the bone marrow of 127 children diagnosed with ALL and 38 children diagnosed with acute myeloid leukemia (AML).
The team found CMV infection was prevalent in children with ALL but rare in those with AML.
Next, the researchers looked for CMV in newborn blood samples from 268 children who went on to develop ALL. The team compared the samples with samples from 270 healthy children.
“Our goal in tracking CMV back from the time of diagnosis to the womb was to establish that this infection occurred well before initiation of disease,” said lead study author Stephen Francis, PhD, of the University of Nevada and University of California, San Francisco.
He and his colleagues found that children who went on to develop ALL were nearly 4 times more likely than control subjects to be CMV-positive at birth. The odds ratio was 3.71 (P=0.0016).
The odds ratio was 5.9 in Hispanic children and 2.1 in non-Hispanic whites. The researchers said this finding is particularly interesting because of the high rate of ALL observed in Hispanics.
“If it’s true that in utero CMV is one of the initiating events in the development of childhood leukemia, then control of the virus has the potential to be a prevention target,” Dr Francis said. “That’s the real take-home message.”
While this research is in the early stages, the researchers hope these results will inspire more studies that will validate these findings and lead to the development of a CMV vaccine.
“This is the first step, but if we do end up finding a causal link to the most common childhood cancer, we hope that will light a fire in terms of stopping mother-to-child transmission of CMV,” Dr Francis said.
Photo by Vera Kratochvil
Newborns with congenital cytomegalovirus (CMV) infection may have an increased risk of developing acute lymphoblastic leukemia (ALL), according to a study published in Blood.
The data also suggest the risk may be particularly high among Hispanic children.
Researchers said this is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children.
To conduct this study, the researchers first identified all known infections present in the bone marrow of 127 children diagnosed with ALL and 38 children diagnosed with acute myeloid leukemia (AML).
The team found CMV infection was prevalent in children with ALL but rare in those with AML.
Next, the researchers looked for CMV in newborn blood samples from 268 children who went on to develop ALL. The team compared the samples with samples from 270 healthy children.
“Our goal in tracking CMV back from the time of diagnosis to the womb was to establish that this infection occurred well before initiation of disease,” said lead study author Stephen Francis, PhD, of the University of Nevada and University of California, San Francisco.
He and his colleagues found that children who went on to develop ALL were nearly 4 times more likely than control subjects to be CMV-positive at birth. The odds ratio was 3.71 (P=0.0016).
The odds ratio was 5.9 in Hispanic children and 2.1 in non-Hispanic whites. The researchers said this finding is particularly interesting because of the high rate of ALL observed in Hispanics.
“If it’s true that in utero CMV is one of the initiating events in the development of childhood leukemia, then control of the virus has the potential to be a prevention target,” Dr Francis said. “That’s the real take-home message.”
While this research is in the early stages, the researchers hope these results will inspire more studies that will validate these findings and lead to the development of a CMV vaccine.
“This is the first step, but if we do end up finding a causal link to the most common childhood cancer, we hope that will light a fire in terms of stopping mother-to-child transmission of CMV,” Dr Francis said.