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Gene variants associated with high-risk pediatric ALL
New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.
Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.
These variants were associated with inferior survival and an increased risk of developing second malignancies.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.
The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).
The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.
The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).
Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).
The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).
The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.
And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).
“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”
The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.
“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”
Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.
“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.” 
New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.
Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.
These variants were associated with inferior survival and an increased risk of developing second malignancies.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.
The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).
The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.
The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).
Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).
The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).
The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.
And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).
“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”
The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.
“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”
Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.
“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”
New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.
Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.
These variants were associated with inferior survival and an increased risk of developing second malignancies.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.
The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).
The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.
The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).
Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).
The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).
The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.
And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).
“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”
The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.
“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”
Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.
“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”
Combo produces responses in R/R Ph+ ALL
ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).
He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.
The patients received inotuzumab ozogamicin at 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m2 once every 4 weeks for subsequent cycles. Six cycles were planned.
Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).
The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.
The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.
Response and survival
The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.
All responses occurred among the patients with ALL.
Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.
The median duration of response was 8.8 months.
Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.
The median overall survival was 10.7 months.
“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”
Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.
*Data in the presentation differ from the abstract.
ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).
He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.
The patients received inotuzumab ozogamicin at 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m2 once every 4 weeks for subsequent cycles. Six cycles were planned.
Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).
The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.
The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.
Response and survival
The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.
All responses occurred among the patients with ALL.
Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.
The median duration of response was 8.8 months.
Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.
The median overall survival was 10.7 months.
“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”
Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.
*Data in the presentation differ from the abstract.
ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).
He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.
The patients received inotuzumab ozogamicin at 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m2 once every 4 weeks for subsequent cycles. Six cycles were planned.
Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).
The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.
The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.
Response and survival
The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.
All responses occurred among the patients with ALL.
Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.
The median duration of response was 8.8 months.
Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.
The median overall survival was 10.7 months.
“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”
Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.
*Data in the presentation differ from the abstract.
Combo shows promise for elderly/unfit ALL patients
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
EC approves new formulation of pegaspargase
The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).
The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.
The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.
Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.
The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.
Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.
“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.
“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”
The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).
The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.
The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.
Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.
The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.
Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.
“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.
“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”
The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).
The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.
The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.
Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.
The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.
Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.
“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.
“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”
Flu vaccine did not protect children with acute leukemia
said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.
Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.
Also, whether the children and youth received one or two doses of flu vaccine made no difference in the rates of influenza (0.60 vs. 1.02; P = .107), the investigators reported.
These data suggest “that influenza vaccine may be ineffective in children receiving therapy for acute leukemia and that routine administration of TIV may not reflect high-value care,” the researchers said. “Until more immunogenic and protective vaccines are developed, efforts to prevent influenza in high-risk populations should focus on more general strategies, such as avoiding ill persons and practicing good respiratory hygiene in households and health care facilities.”
Read more in the Journal of Pediatrics (2017 Nov 21. doi: 10.1016/j.jpeds.2017.08.071).
said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.
Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.
Also, whether the children and youth received one or two doses of flu vaccine made no difference in the rates of influenza (0.60 vs. 1.02; P = .107), the investigators reported.
These data suggest “that influenza vaccine may be ineffective in children receiving therapy for acute leukemia and that routine administration of TIV may not reflect high-value care,” the researchers said. “Until more immunogenic and protective vaccines are developed, efforts to prevent influenza in high-risk populations should focus on more general strategies, such as avoiding ill persons and practicing good respiratory hygiene in households and health care facilities.”
Read more in the Journal of Pediatrics (2017 Nov 21. doi: 10.1016/j.jpeds.2017.08.071).
said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.
Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.
Also, whether the children and youth received one or two doses of flu vaccine made no difference in the rates of influenza (0.60 vs. 1.02; P = .107), the investigators reported.
These data suggest “that influenza vaccine may be ineffective in children receiving therapy for acute leukemia and that routine administration of TIV may not reflect high-value care,” the researchers said. “Until more immunogenic and protective vaccines are developed, efforts to prevent influenza in high-risk populations should focus on more general strategies, such as avoiding ill persons and practicing good respiratory hygiene in households and health care facilities.”
Read more in the Journal of Pediatrics (2017 Nov 21. doi: 10.1016/j.jpeds.2017.08.071).
FROM THE JOURNAL OF PEDIATRICS
System helps predict RFS, OS in BCP-ALL
Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.
The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.
The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.
On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).
Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.
The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.
Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.
“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”
“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”
The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”
And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.
The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.
The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.
Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.
“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”
Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.
The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.
The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.
On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).
Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.
The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.
Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.
“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”
“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”
The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”
And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.
The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.
The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.
Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.
“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”
Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.
The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.
The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.
On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).
Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.
The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.
Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.
“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”
“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”
The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”
And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.
The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.
The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.
Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.
“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”
Antimalarial could aid treatment of ALL
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
Method identifies effective treatments for leukemias, lymphomas
An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.
Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.
The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).
“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.
With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.
In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.
Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.
There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).
The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.
The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).
None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.
At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.
In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).
“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.
“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”
An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.
Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.
The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).
“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.
With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.
In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.
Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.
There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).
The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.
The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).
None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.
At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.
In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).
“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.
“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”
An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.
Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.
The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).
“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.
With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.
In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.
Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.
There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).
The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.
The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).
None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.
At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.
In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).
“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.
“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”
CD22 CAR activity in B-ALL highlights promise of multispecific CARs
NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.
In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).
This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.
The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.
“All in all, once we got to the dose that was appropriate ... this CAR had really impressive activity,” said Dr. Mackall, director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”
Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.
“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”
Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.
“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”
“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.
Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.
Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.
“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”
Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.
In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).
This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.
The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.
“All in all, once we got to the dose that was appropriate ... this CAR had really impressive activity,” said Dr. Mackall, director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”
Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.
“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”
Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.
“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”
“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.
Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.
Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.
“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”
Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
NATIONAL HARBOR, MD. – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.
In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD, of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine (2017 Nov 20. doi: 10.1038.nm.4441).
This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.
The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.
“All in all, once we got to the dose that was appropriate ... this CAR had really impressive activity,” said Dr. Mackall, director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”
Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.
“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”
Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.
“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”
“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.
Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.
Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.
“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”
Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
AT SITC 2017
Key clinical point:
Major finding: Complete remission occurred in 73% of patients who received bioactive doses of the CD22 CAR.
Data source: A phase 1 study of 21 patients.
Disclosures: Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.
CAR T-cell therapy: Moving from cost to value
Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.
“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.
In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
Price tag pressure
During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.
The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.
The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.
At the heart of the issue of cost is the matter of value, he said.
“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.
Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.
“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.
The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.
Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD, the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.
Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.
Groups like the United Kingdom’s National Institute for Health and Care Excellence (NICE) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.
“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.
When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.
Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.
Preliminary results from phase I studies (CALM and PALL) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.
Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.
Cost-saving proposals
Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.
Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.
In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.
“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.
In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.
In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.
“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.
The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.
Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).
“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.
The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.
Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.
“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”
Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.
Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.
“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.
In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
Price tag pressure
During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.
The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.
The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.
At the heart of the issue of cost is the matter of value, he said.
“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.
Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.
“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.
The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.
Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD, the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.
Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.
Groups like the United Kingdom’s National Institute for Health and Care Excellence (NICE) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.
“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.
When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.
Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.
Preliminary results from phase I studies (CALM and PALL) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.
Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.
Cost-saving proposals
Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.
Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.
In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.
“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.
In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.
In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.
“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.
The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.
Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).
“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.
The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.
Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.
“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”
Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.
Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.
“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.
In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
Price tag pressure
During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.
The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.
The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.
At the heart of the issue of cost is the matter of value, he said.
“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.
Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.
“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.
The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.
Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD, the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.
Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.
Groups like the United Kingdom’s National Institute for Health and Care Excellence (NICE) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.
“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.
When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.
Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.
Preliminary results from phase I studies (CALM and PALL) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.
Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.
Cost-saving proposals
Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.
Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.
In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.
“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.
In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.
In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.
“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.
The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.
Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).
“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.
The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.
Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.
“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”
Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.