Leukemia, Myelodysplasia, Transplantation

Image by Difu Wu

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for dasatinib (Sprycel).

Bristol Myers Squibb is seeking approval for dasatinib as a treatment for children with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML), as well as approval for a powder formulation of dasatinib for oral suspension.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the dasatinib sNDA by November 9, 2017.

The sNDA includes data from CA180-226 (NCT00777036), an ongoing, phase 2 trial of dasatinib in pediatric patients with CP-CML who are resistant to or cannot tolerate imatinib and pediatric patients newly diagnosed with CP-CML.

The trial enrolled patients aged 18 and younger with newly diagnosed CML or Ph+ leukemias resistant to or intolerant of imatinib.

Cohort 1 included 29 CP-CML patients resistant to or intolerant of imatinib. Cohort 2 included patients with accelerated/blast phase CML or Ph+ acute lymphoblastic leukemia. Cohort 3 included 84 patients with newly diagnosed CP-CML.

Data from Cohorts 1 and 3 were recently presented at the 2017 ASCO Annual Meeting.

Three months into treatment with dasatinib, patients with CP-CML who were resistant to or intolerant of imatinib (Cohort 1) had a cumulative major cytogenetic response rate of 55.2%. This response rate increased over time to exceed 90% at 24 months.

Newly diagnosed patients with CP-CML (Cohort 3) received dasatinib orally or as powder for oral suspension once daily. They achieved a cumulative complete cytogenetic response rate of 64% as early as 6 months into treatment. This response rate increased to 94% at 24 months.

The median duration of response was not estimable or not yet reached in each cohort at the time of follow-up.

The estimated progression-free survival at 48 months was greater than 75% for patients in Cohort 1 and greater than 90% for patients in Cohort 3.

The safety profile of dasatinib in this study was deemed comparable to that reported in adults with CP-CML. In this study, there were no reported events of pleural/pericardial effusion, pulmonary edema/hypertension, or pulmonary arterial hypertension related to dasatinib.

Dasatinib first received FDA approval in 2006. The drug is currently approved to treat adults with:

• Newly diagnosed Ph+ CP-CML
• Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
  

Image by Difu Wu

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for dasatinib (Sprycel).

Bristol Myers Squibb is seeking approval for dasatinib as a treatment for children with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML), as well as approval for a powder formulation of dasatinib for oral suspension.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the dasatinib sNDA by November 9, 2017.

The sNDA includes data from CA180-226 (NCT00777036), an ongoing, phase 2 trial of dasatinib in pediatric patients with CP-CML who are resistant to or cannot tolerate imatinib and pediatric patients newly diagnosed with CP-CML.

The trial enrolled patients aged 18 and younger with newly diagnosed CML or Ph+ leukemias resistant to or intolerant of imatinib.

Cohort 1 included 29 CP-CML patients resistant to or intolerant of imatinib. Cohort 2 included patients with accelerated/blast phase CML or Ph+ acute lymphoblastic leukemia. Cohort 3 included 84 patients with newly diagnosed CP-CML.

Data from Cohorts 1 and 3 were recently presented at the 2017 ASCO Annual Meeting.

Three months into treatment with dasatinib, patients with CP-CML who were resistant to or intolerant of imatinib (Cohort 1) had a cumulative major cytogenetic response rate of 55.2%. This response rate increased over time to exceed 90% at 24 months.

Newly diagnosed patients with CP-CML (Cohort 3) received dasatinib orally or as powder for oral suspension once daily. They achieved a cumulative complete cytogenetic response rate of 64% as early as 6 months into treatment. This response rate increased to 94% at 24 months.

The median duration of response was not estimable or not yet reached in each cohort at the time of follow-up.

The estimated progression-free survival at 48 months was greater than 75% for patients in Cohort 1 and greater than 90% for patients in Cohort 3.

The safety profile of dasatinib in this study was deemed comparable to that reported in adults with CP-CML. In this study, there were no reported events of pleural/pericardial effusion, pulmonary edema/hypertension, or pulmonary arterial hypertension related to dasatinib.

Dasatinib first received FDA approval in 2006. The drug is currently approved to treat adults with:

• Newly diagnosed Ph+ CP-CML
• Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
  

Image by Difu Wu

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for dasatinib (Sprycel).

Bristol Myers Squibb is seeking approval for dasatinib as a treatment for children with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML), as well as approval for a powder formulation of dasatinib for oral suspension.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the dasatinib sNDA by November 9, 2017.

The sNDA includes data from CA180-226 (NCT00777036), an ongoing, phase 2 trial of dasatinib in pediatric patients with CP-CML who are resistant to or cannot tolerate imatinib and pediatric patients newly diagnosed with CP-CML.

The trial enrolled patients aged 18 and younger with newly diagnosed CML or Ph+ leukemias resistant to or intolerant of imatinib.

Cohort 1 included 29 CP-CML patients resistant to or intolerant of imatinib. Cohort 2 included patients with accelerated/blast phase CML or Ph+ acute lymphoblastic leukemia. Cohort 3 included 84 patients with newly diagnosed CP-CML.

Data from Cohorts 1 and 3 were recently presented at the 2017 ASCO Annual Meeting.

Three months into treatment with dasatinib, patients with CP-CML who were resistant to or intolerant of imatinib (Cohort 1) had a cumulative major cytogenetic response rate of 55.2%. This response rate increased over time to exceed 90% at 24 months.

Newly diagnosed patients with CP-CML (Cohort 3) received dasatinib orally or as powder for oral suspension once daily. They achieved a cumulative complete cytogenetic response rate of 64% as early as 6 months into treatment. This response rate increased to 94% at 24 months.

The median duration of response was not estimable or not yet reached in each cohort at the time of follow-up.

The estimated progression-free survival at 48 months was greater than 75% for patients in Cohort 1 and greater than 90% for patients in Cohort 3.

The safety profile of dasatinib in this study was deemed comparable to that reported in adults with CP-CML. In this study, there were no reported events of pleural/pericardial effusion, pulmonary edema/hypertension, or pulmonary arterial hypertension related to dasatinib.

Dasatinib first received FDA approval in 2006. The drug is currently approved to treat adults with:

• Newly diagnosed Ph+ CP-CML
• Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
  

Beckman Coulter has been authorized to market its ClearLLab Reagents (T1, T2, B1, B2, M) tests for use with flow cytometry to detect leukemias, lymphomas, and myeloproliferative disorders in blood, bone marrow, and lymph nodes, according to the U.S. Food and Drug Administration.

[email protected]

Beckman Coulter has been authorized to market its ClearLLab Reagents (T1, T2, B1, B2, M) tests for use with flow cytometry to detect leukemias, lymphomas, and myeloproliferative disorders in blood, bone marrow, and lymph nodes, according to the U.S. Food and Drug Administration.

[email protected]

Beckman Coulter has been authorized to market its ClearLLab Reagents (T1, T2, B1, B2, M) tests for use with flow cytometry to detect leukemias, lymphomas, and myeloproliferative disorders in blood, bone marrow, and lymph nodes, according to the U.S. Food and Drug Administration.

[email protected]

MADRID – Monotherapy with the investigational oral agent enasidenib was associated with comparatively high response rates among patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML) and IDH2 mutations in a phase 1/2 study.

Among 214 patients treated at a dose level of 100 mg daily, the overall response rate was 37%, including 20.1% complete responses (CRs) and 7.9% complete responses with incomplete recovery of platelets (CRp) or incomplete hematologic recovery (CRi), reported Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“In patients with relapsed/refractory AML (with IDH2 mutations), most of whom had received multiple prior AML treatments, enasidenib induced durable CRs that were associated with overall survival of greater than 8 months,” he said at the annual congress of the European Hematology Association.

The IDH2 gene encodes for isocitrate dehydrogenase 2, which is an enzyme of the citric acid cycle. An estimated 8%-15% of patients with AML have mutations in IDH2 that cause intracellular accumulation of beta-hydroxyglutarate, which leads to blockage of myeloblast differentiation through a variety of mechanisms. The primary mechanism of action of enasidenib appears to be through its action on differentiation, rather than through cytotoxicity, Dr. Stein said.

He reported updated results from the fully enrolled cohorts of the phase 1/2 study. Earlier data from the study were reported at the 2017 annual meeting of the American Society of Clinical Oncology and in a paper published concurrently in Blood.

In the study, the investigators first enrolled 113 patients with advanced hematologic malignancies with IDH2 mutations and treated them with cumulative daily doses of enasidenib ranging from 50 to 650 mg.

In a phase 1 expansion study at the established dose of 100 mg daily, 126 patients with IDH2 mutations were enrolled in one of four cohorts: patients aged 60 or older with relapsed or refractory AML or AML patients of any age who experienced a relapse after undergoing a bone marrow transplant (BMT); patients under age 60 except those with post-BMT relapses; patients with previously untreated AML who were 60 years or older who declined the standard of care; and patients with other hematologic malignancies who were ineligible for other study arms.

The study also included a phase 2 expansion cohort of 106 patients with relapsed/refractory AML with IDH2 mutations treated with enasidenib 100 mg daily. The data cutoff was Oct. 14, 2016.

Among 214 patients treated at the 100-mg/day dose, the ORR was 37%, including 20.1% with a CR, 7.9% with a CRp or CRi, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state.

The median time to first response was 1.9 months, and the median time to CR was 3.7 months.

Clinicians should wait until patients have received at least four cycles of the drug before determining whether they should be continued on the drug or switched to another therapy, Dr. Stein said.

After 30 months of follow-up, overall survival (OS) among the 281 patients with relapsed/refractory AML with IDH2 mutations who were treated with enasidenib at any dose level was 8.4 months. Among the 214 treated at the 100-mg daily dose level, the median OS was 8.3 months.

When the investigators looked at OS by best response, they saw that patients who had a CR had a median OS of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months.

Patients generally tolerated the drug well. Most adverse events were grade 1 or 2 in severity.

An increase in blood bilirubin was the most frequent grade 3 or 4 adverse event, occurring in 8% of all patients. The effect was caused by an off-target reaction and was not associated with elevations in liver enzymes or evidence of liver damage, Dr. Stein said.

Grade 3 or 4 dyspnea occurred in 6% of patients, and 7% of all patients had serious treatment-related IDH-inhibitor–associated differentiation syndrome (IDH-DS). This syndrome presents with symptoms similar to those of retinoic acid syndrome, which occurs during treatment for acute promyelocytic leukemia.

Enasidenib is being explored in a phase 3 study comparing enasidenib monotherapy with conventional care in patients with late-stage AML and in combination with other agents and regimens in phase 1/2 studies in patients with newly diagnosed AML with IDH2 mutations.

Enasidenib has been granted priority review by the U.S. Food and Drug Administration for relapsed/refractory AML with an IDH2 mutation and has been given a Prescription Drug User Fee Act action date of Aug. 30, 2017, according to Celgene.

The study was funded by Celgene. Dr. Stein disclosed a consulting/advisory role with the company, research funding, and travel expenses.

MADRID – Monotherapy with the investigational oral agent enasidenib was associated with comparatively high response rates among patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML) and IDH2 mutations in a phase 1/2 study.

Among 214 patients treated at a dose level of 100 mg daily, the overall response rate was 37%, including 20.1% complete responses (CRs) and 7.9% complete responses with incomplete recovery of platelets (CRp) or incomplete hematologic recovery (CRi), reported Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“In patients with relapsed/refractory AML (with IDH2 mutations), most of whom had received multiple prior AML treatments, enasidenib induced durable CRs that were associated with overall survival of greater than 8 months,” he said at the annual congress of the European Hematology Association.

The IDH2 gene encodes for isocitrate dehydrogenase 2, which is an enzyme of the citric acid cycle. An estimated 8%-15% of patients with AML have mutations in IDH2 that cause intracellular accumulation of beta-hydroxyglutarate, which leads to blockage of myeloblast differentiation through a variety of mechanisms. The primary mechanism of action of enasidenib appears to be through its action on differentiation, rather than through cytotoxicity, Dr. Stein said.

He reported updated results from the fully enrolled cohorts of the phase 1/2 study. Earlier data from the study were reported at the 2017 annual meeting of the American Society of Clinical Oncology and in a paper published concurrently in Blood.

In the study, the investigators first enrolled 113 patients with advanced hematologic malignancies with IDH2 mutations and treated them with cumulative daily doses of enasidenib ranging from 50 to 650 mg.

In a phase 1 expansion study at the established dose of 100 mg daily, 126 patients with IDH2 mutations were enrolled in one of four cohorts: patients aged 60 or older with relapsed or refractory AML or AML patients of any age who experienced a relapse after undergoing a bone marrow transplant (BMT); patients under age 60 except those with post-BMT relapses; patients with previously untreated AML who were 60 years or older who declined the standard of care; and patients with other hematologic malignancies who were ineligible for other study arms.

The study also included a phase 2 expansion cohort of 106 patients with relapsed/refractory AML with IDH2 mutations treated with enasidenib 100 mg daily. The data cutoff was Oct. 14, 2016.

Among 214 patients treated at the 100-mg/day dose, the ORR was 37%, including 20.1% with a CR, 7.9% with a CRp or CRi, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state.

The median time to first response was 1.9 months, and the median time to CR was 3.7 months.

Clinicians should wait until patients have received at least four cycles of the drug before determining whether they should be continued on the drug or switched to another therapy, Dr. Stein said.

After 30 months of follow-up, overall survival (OS) among the 281 patients with relapsed/refractory AML with IDH2 mutations who were treated with enasidenib at any dose level was 8.4 months. Among the 214 treated at the 100-mg daily dose level, the median OS was 8.3 months.

When the investigators looked at OS by best response, they saw that patients who had a CR had a median OS of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months.

Patients generally tolerated the drug well. Most adverse events were grade 1 or 2 in severity.

An increase in blood bilirubin was the most frequent grade 3 or 4 adverse event, occurring in 8% of all patients. The effect was caused by an off-target reaction and was not associated with elevations in liver enzymes or evidence of liver damage, Dr. Stein said.

Grade 3 or 4 dyspnea occurred in 6% of patients, and 7% of all patients had serious treatment-related IDH-inhibitor–associated differentiation syndrome (IDH-DS). This syndrome presents with symptoms similar to those of retinoic acid syndrome, which occurs during treatment for acute promyelocytic leukemia.

Enasidenib is being explored in a phase 3 study comparing enasidenib monotherapy with conventional care in patients with late-stage AML and in combination with other agents and regimens in phase 1/2 studies in patients with newly diagnosed AML with IDH2 mutations.

Enasidenib has been granted priority review by the U.S. Food and Drug Administration for relapsed/refractory AML with an IDH2 mutation and has been given a Prescription Drug User Fee Act action date of Aug. 30, 2017, according to Celgene.

The study was funded by Celgene. Dr. Stein disclosed a consulting/advisory role with the company, research funding, and travel expenses.

MADRID – Monotherapy with the investigational oral agent enasidenib was associated with comparatively high response rates among patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML) and IDH2 mutations in a phase 1/2 study.

Among 214 patients treated at a dose level of 100 mg daily, the overall response rate was 37%, including 20.1% complete responses (CRs) and 7.9% complete responses with incomplete recovery of platelets (CRp) or incomplete hematologic recovery (CRi), reported Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“In patients with relapsed/refractory AML (with IDH2 mutations), most of whom had received multiple prior AML treatments, enasidenib induced durable CRs that were associated with overall survival of greater than 8 months,” he said at the annual congress of the European Hematology Association.

The IDH2 gene encodes for isocitrate dehydrogenase 2, which is an enzyme of the citric acid cycle. An estimated 8%-15% of patients with AML have mutations in IDH2 that cause intracellular accumulation of beta-hydroxyglutarate, which leads to blockage of myeloblast differentiation through a variety of mechanisms. The primary mechanism of action of enasidenib appears to be through its action on differentiation, rather than through cytotoxicity, Dr. Stein said.

He reported updated results from the fully enrolled cohorts of the phase 1/2 study. Earlier data from the study were reported at the 2017 annual meeting of the American Society of Clinical Oncology and in a paper published concurrently in Blood.

In the study, the investigators first enrolled 113 patients with advanced hematologic malignancies with IDH2 mutations and treated them with cumulative daily doses of enasidenib ranging from 50 to 650 mg.

In a phase 1 expansion study at the established dose of 100 mg daily, 126 patients with IDH2 mutations were enrolled in one of four cohorts: patients aged 60 or older with relapsed or refractory AML or AML patients of any age who experienced a relapse after undergoing a bone marrow transplant (BMT); patients under age 60 except those with post-BMT relapses; patients with previously untreated AML who were 60 years or older who declined the standard of care; and patients with other hematologic malignancies who were ineligible for other study arms.

The study also included a phase 2 expansion cohort of 106 patients with relapsed/refractory AML with IDH2 mutations treated with enasidenib 100 mg daily. The data cutoff was Oct. 14, 2016.

Among 214 patients treated at the 100-mg/day dose, the ORR was 37%, including 20.1% with a CR, 7.9% with a CRp or CRi, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state.

The median time to first response was 1.9 months, and the median time to CR was 3.7 months.

Clinicians should wait until patients have received at least four cycles of the drug before determining whether they should be continued on the drug or switched to another therapy, Dr. Stein said.

After 30 months of follow-up, overall survival (OS) among the 281 patients with relapsed/refractory AML with IDH2 mutations who were treated with enasidenib at any dose level was 8.4 months. Among the 214 treated at the 100-mg daily dose level, the median OS was 8.3 months.

When the investigators looked at OS by best response, they saw that patients who had a CR had a median OS of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months.

Patients generally tolerated the drug well. Most adverse events were grade 1 or 2 in severity.

An increase in blood bilirubin was the most frequent grade 3 or 4 adverse event, occurring in 8% of all patients. The effect was caused by an off-target reaction and was not associated with elevations in liver enzymes or evidence of liver damage, Dr. Stein said.

Grade 3 or 4 dyspnea occurred in 6% of patients, and 7% of all patients had serious treatment-related IDH-inhibitor–associated differentiation syndrome (IDH-DS). This syndrome presents with symptoms similar to those of retinoic acid syndrome, which occurs during treatment for acute promyelocytic leukemia.

Enasidenib is being explored in a phase 3 study comparing enasidenib monotherapy with conventional care in patients with late-stage AML and in combination with other agents and regimens in phase 1/2 studies in patients with newly diagnosed AML with IDH2 mutations.

Enasidenib has been granted priority review by the U.S. Food and Drug Administration for relapsed/refractory AML with an IDH2 mutation and has been given a Prescription Drug User Fee Act action date of Aug. 30, 2017, according to Celgene.

The study was funded by Celgene. Dr. Stein disclosed a consulting/advisory role with the company, research funding, and travel expenses.

Photo by Rhoda Baer

Narrow insurance plan coverage may prevent US cancer patients from receiving care at “high-quality” cancer centers, according to research published in the Journal of Clinical Oncology.

Researchers found that “narrow network” insurance plans—lower-premium plans with reduced access to certain providers—are more likely to exclude doctors associated with National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) cancer centers.

These centers are recognized for their scientific and research leadership, quality and safety initiatives, and access to expert physicians and clinical trials.

NCCN member institutions are particularly recognized for higher-quality care, and treatment at NCI-designated cancer centers is associated with lower mortality than other hospitals, particularly among more severely ill patients and those with more advanced disease.

For this study, researchers examined cancer provider networks offered on the 2014 individual health insurance exchanges and then determined which oncologists were affiliated with NCI-designated and NCCN cancer centers.

The researchers found that narrower networks were less likely to include physicians associated with NCI-designated and NCCN member institutions.

“To see such a robust result was surprising,” said study author Laura Yasaitis, PhD, of the University of Pennsylvania in Philadelphia.

“The finding that narrower networks were more likely to exclude NCI and NCCN oncologists was consistent no matter how we looked at it. This is not just a few networks. It’s a clear trend.”

The researchers said the results point to 2 major problems—transparency and access.

“Patients should be able to easily figure out whether the physicians they might need will be covered under a given plan,” said study author Justin E. Bekelman, MD, of the University of Pennsylvania.

The researchers suggested that insurers report doctor’s affiliations with NCI and NCCN cancer centers so that consumers can make more informed choices.

The team also suggested that insurers offer mechanisms that would allow patients to seek care out of network without incurring penalties in exceptional circumstances.

“If patients have narrow network plans and absolutely need the kind of complex cancer care that they can only receive from one of these providers, there should be a standard exception process to allow patients to access the care they need,” Dr Bekelman said. 

Photo by Rhoda Baer

Narrow insurance plan coverage may prevent US cancer patients from receiving care at “high-quality” cancer centers, according to research published in the Journal of Clinical Oncology.

Researchers found that “narrow network” insurance plans—lower-premium plans with reduced access to certain providers—are more likely to exclude doctors associated with National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) cancer centers.

These centers are recognized for their scientific and research leadership, quality and safety initiatives, and access to expert physicians and clinical trials.

NCCN member institutions are particularly recognized for higher-quality care, and treatment at NCI-designated cancer centers is associated with lower mortality than other hospitals, particularly among more severely ill patients and those with more advanced disease.

For this study, researchers examined cancer provider networks offered on the 2014 individual health insurance exchanges and then determined which oncologists were affiliated with NCI-designated and NCCN cancer centers.

The researchers found that narrower networks were less likely to include physicians associated with NCI-designated and NCCN member institutions.

“To see such a robust result was surprising,” said study author Laura Yasaitis, PhD, of the University of Pennsylvania in Philadelphia.

“The finding that narrower networks were more likely to exclude NCI and NCCN oncologists was consistent no matter how we looked at it. This is not just a few networks. It’s a clear trend.”

The researchers said the results point to 2 major problems—transparency and access.

“Patients should be able to easily figure out whether the physicians they might need will be covered under a given plan,” said study author Justin E. Bekelman, MD, of the University of Pennsylvania.

The researchers suggested that insurers report doctor’s affiliations with NCI and NCCN cancer centers so that consumers can make more informed choices.

The team also suggested that insurers offer mechanisms that would allow patients to seek care out of network without incurring penalties in exceptional circumstances.

“If patients have narrow network plans and absolutely need the kind of complex cancer care that they can only receive from one of these providers, there should be a standard exception process to allow patients to access the care they need,” Dr Bekelman said. 

Photo by Rhoda Baer

Narrow insurance plan coverage may prevent US cancer patients from receiving care at “high-quality” cancer centers, according to research published in the Journal of Clinical Oncology.

Researchers found that “narrow network” insurance plans—lower-premium plans with reduced access to certain providers—are more likely to exclude doctors associated with National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) cancer centers.

These centers are recognized for their scientific and research leadership, quality and safety initiatives, and access to expert physicians and clinical trials.

NCCN member institutions are particularly recognized for higher-quality care, and treatment at NCI-designated cancer centers is associated with lower mortality than other hospitals, particularly among more severely ill patients and those with more advanced disease.

For this study, researchers examined cancer provider networks offered on the 2014 individual health insurance exchanges and then determined which oncologists were affiliated with NCI-designated and NCCN cancer centers.

The researchers found that narrower networks were less likely to include physicians associated with NCI-designated and NCCN member institutions.

“To see such a robust result was surprising,” said study author Laura Yasaitis, PhD, of the University of Pennsylvania in Philadelphia.

“The finding that narrower networks were more likely to exclude NCI and NCCN oncologists was consistent no matter how we looked at it. This is not just a few networks. It’s a clear trend.”

The researchers said the results point to 2 major problems—transparency and access.

“Patients should be able to easily figure out whether the physicians they might need will be covered under a given plan,” said study author Justin E. Bekelman, MD, of the University of Pennsylvania.

The researchers suggested that insurers report doctor’s affiliations with NCI and NCCN cancer centers so that consumers can make more informed choices.

The team also suggested that insurers offer mechanisms that would allow patients to seek care out of network without incurring penalties in exceptional circumstances.

“If patients have narrow network plans and absolutely need the kind of complex cancer care that they can only receive from one of these providers, there should be a standard exception process to allow patients to access the care they need,” Dr Bekelman said. 

Children’s Research Hospital

Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).

The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.

“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.

“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”

The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.

In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.

“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.

He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.

“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.

Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.

Children’s Research Hospital

Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).

The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.

“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.

“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”

The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.

In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.

“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.

He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.

“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.

Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.

Children’s Research Hospital

Researchers say they have uncovered new details of the genomic landscape of T-lineage acute lymphoblastic leukemia (T-ALL).

The team believes their findings will aid the development of drugs to target newly discovered mutations and enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their findings in Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Dr Mullighan said.

“Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

Dr Mullighan and his colleagues sequenced the genomes of 264 children and young adults with T-ALL. This revealed 106 driver genes, half of which had not been identified in childhood T-ALL.

“We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” said Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.

“But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL but not others.”

The researchers’ analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK-STAT, Ras, and PTEN-PI3K. However, the study also revealed new mutations in those known pathways.

In addition, the researchers identified cases in which the same T-ALL subtype had mutations in different pathways triggered by the same founding mutation.

“We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Dr Mullighan said.

He and his colleagues also believe the mutations uncovered in this study will enable researchers to create mouse models that more accurately reflect human T-ALL.

“We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Dr Mullighan said.

Data from this study are available to researchers through the St. Jude PeCan data portal and the TARGET Data Matrix.

NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.

The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.

In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”

That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”

“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”

The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.

Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).

For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.

In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.

Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.

IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.

These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.

The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.

Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.

The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.

Dr. Vaisitti has received research funding from Immune Target.

[email protected]

NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.

The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.

In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”

That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”

“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”

The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.

Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).

For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.

In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.

Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.

IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.

These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.

The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.

Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.

The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.

Dr. Vaisitti has received research funding from Immune Target.

[email protected]

NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.

The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.

In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”

That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”

“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”

The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.

Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).

For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.

In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.

Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.

IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.

These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.

The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.

Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.

The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.

Dr. Vaisitti has received research funding from Immune Target.

[email protected]

NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.

The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.

Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.

The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.

Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.

“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.

Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.

It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide

“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”

Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.

[email protected]

NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.

The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.

Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.

The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.

Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.

“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.

Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.

It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide

“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”

Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.

[email protected]

NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.

The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.

Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.

The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.

Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.

“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.

Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.

It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide

“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”

Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.

[email protected]

BCP-ALL

The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.

The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.

BCP-ALL

The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.

The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.

BCP-ALL

The European Commission (EC) has approved inotuzumab ozogamicin (BESPONSA®) as monotherapy for adults with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Adults with Philadelphia chromosome-positive, relapsed/refractory, CD22-positive BCP-ALL should have failed treatment with at least one tyrosine kinase inhibitor before receiving inotuzumab ozogamicin.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

The EC’s approval of inotuzumab ozogamicin is supported by results from a phase 3 trial, which were published in NEJM in June 2016.

The trial enrolled 326 adult patients with relapsed or refractory BCP-ALL and compared inotuzumab ozogamicin to standard of care chemotherapy.

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab ozogamicin arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab ozogamicin and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab ozogamicin arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab ozogamicin arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab ozogamicin arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab ozogamicin, and 2 were thought to be related to chemotherapy.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”