B Cell Lymphoma

Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.

Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.

“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”

Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.

The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.

Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.

The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).

Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).

Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.

These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.

In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.

“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.

This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.

SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.

Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.

Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.

“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”

Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.

The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.

Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.

The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).

Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).

Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.

These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.

In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.

“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.

This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.

SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.

Checkpoint inhibitors can cause rare, but serious, hematological immune-related adverse events (hem-irAEs), which require early detection and intervention, according to a recent French study.

Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs in the population, reported lead author, Nicolas Delanoy, MD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and his colleagues.

“About 71% of patients treated have any-grade irAEs and 10% have grade 3-4 irAEs after anti-PD-1 immunotherapy,” the investigators wrote. The report is in The Lancet Haematology. “In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints. However, all organs can potentially be affected, including the hemopoietic system.”

Despite this possibility, few reports detail the frequency or character of hematological toxicities from immunotherapy.

The present study involved 948 patients who entered into three French registries between 2014 and 2018. The first registry, consisting of 745 patients, was observed prospectively during checkpoint inhibitor therapy. The other two registries provided retrospective data on confirmed irAEs or hem-irAEs.

Among 745 patients followed during checkpoint inhibitor therapy, four developed hem-irAEs, providing an incidence rate of 0.5%. The other two databases added 31 patients with confirmed hem-irAEs, allowing for characterization of 35 total cases.

The group of 35 patients had a median age of 65 years, with more men (n = 21) than women (n = 14). Melanoma was the most common type of malignancy (43%), followed by non–small-cell lung cancer (34%), lymphoma (11%), and others. The majority of patients received nivolumab (57%), slightly fewer received pembrolizumab (40%), and a small minority received atezolizumab (3%).

Immune thrombocytopenia, hemolytic anemia, and neutropenia were the most common hem-irAEs, each occurring in nine patients (26%). Five patients (14%) had aplastic anemia or pancytopenia, two patients had bicytopenia (6%; neutropenia and anemia or thrombocytopenia and anemia), and one patient had pure red cell aplasia (3%).

Hem-irAEs resolved in 60% of patients, but two patients (6%) died due to febrile neutropenia. Overall, 71% of hem-irAEs were grade 4.

These findings suggest that hem-irAEs are rare, but they are often serious, and potentially life-threatening, the researchers noted.

In 7 of 35 patients (20%) who were rechallenged with checkpoint inhibitor therapy, 3 (43%) had recurrence of hem-irAEs. This finding should elicit caution and close monitoring if rechallenge is elected.

“This observational study encourages further, in-depth investigations of hematological immune toxicities, to search for biomarkers that can be helpful for earlier detection,” the investigators concluded.

This study was funded by Gustave Roussy and the Gustave Roussy Immunotherapy Program. Dr. Delanoy reported nonfinancial support from Sanofi and other authors reported financial relationships with pharmaceutical companies.

SOURCE: Delanoy N et al. Lancet Haematol. 2018 Dec 4. doi: 10.1016/S2352-3026(18)30175-3.

Dual B-cell receptor pathway blockade was tolerable and efficacious for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who participated in a multicenter phase 1-1b clinical study that added umbralisib to ibrutinib.

The study “is the first successful combination for two drugs targeting the B-cell receptor pathway,” Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston and his colleagues wrote in the Lancet Haematology.

Of the 21 patients with CLL, 90% (n = 19) achieved an overall response (OR), 62% (n = 13) achieved partial response (PR) or PR with lymphocytosis, and 29% (n = 6) achieved complete response (CR). All patients in complete response still had minimal residual disease (MRD) in bone marrow. No CLL patients had progressive disease.

Of the 21 patients with MCL, 67% (n = 14) had an OR, with 19% (n = 4) showing CR and 48% (n = 10) achieving partial response. Three MCL patients (14%) had progressive disease.

Umbralisib is a next-generation phosphoinositide-3-kinase-delta inhibitor that, when added to the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, offers once-daily oral dosing. The combination affords the possibility of overcoming the resistance that can come with prolonged ibrutinib monotherapy.

A total of 44 patients were enrolled, and 42 patients (21 with CLL and 21 with MCL) received at least one dose of the study drug and were included in the analysis. At enrollment, patients had received a median of two previous therapies.

Diarrhea was the most frequent adverse event, seen in 22 patients (52%), and half of all patients (n = 21) had infections.

Hematologic toxicities included neutropenia, seen in 9 (43%) of the CLL patients and 8 (38%) of the MCL patients; thrombocytopenia, seen in 6 (29%) of the CLL patients and 10 (48%) of the MCL patients; and anemia, seen in 4 (19%) of the CLL and 9 (43%) of the MCL patients. Grade 3 and 4 hematologic toxicities of any type were less common, occurring in less than 20% of patients. One MCL patient developed febrile neutropenia. According to the study investigators, none of the hematologic toxicities were deemed related to the study drugs.

Adverse events did not appear to be dose-dependent for umbralisib, with the maximum tolerated dose not reached in the study, the investigators wrote. For phase 2 trials, the recommended dose of umbralisib is 800 mg given orally once daily in combination with ibrutinib.

“One unanticipated benefit of doublet B-cell receptor pathway inhibition in this study was the ability to continue one drug when a characteristic toxicity required the other drug to be held,” the investigators wrote.

For MCL patients, 67% achieved OR and 19% achieved CR, figures similar to those reported for ibrutinib monotherapy. However, “the 2-year progression-free survival of 49% and overall survival of 58% suggest that patients who made it to 1 year progression-free had few events during the second year on therapy,” the investigators wrote. They also noted that this MCL population was high risk; more than one-quarter of patients had relapsed after prior autologous stem cell transplantation.

The study was limited by small sample size and a short duration of follow-up, so durability of response can’t yet be assessed. Also, neither pharmacokinetics nor resistance mutations were tracked for participants.

Currently, the doublet regimen is designed to be continuous therapy, and although it’s not known whether this regimen would be effective as time-limited therapy, it’s unlikely because 100% of patients who had CR still had detectable minimal residual disease, the investigators noted.

Umbralisib and ibrutinib are also being explored as part of triplet therapy, with the type 2 CD20 antibody ublituximab, for relapsed or refractory B-cell malignancies (NCT02006485).

“These novel drug-based approaches, along with several others in development, hold promise as highly effective and well-tolerated regimens with the potential to substantially improve outcomes for patients with B-cell malignancies,” the investigators wrote.

The study was supported by TG Therapeutics and the Leukemia and Lymphoma Society Therapy Accelerator Program. The authors reported financial relationships with several pharmaceutical companies, including TG Therapeutics.

[email protected]

SOURCE: Davids MS et al. Lancet Haemtol. 2019;6:e38-47.

Dual B-cell receptor pathway blockade was tolerable and efficacious for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who participated in a multicenter phase 1-1b clinical study that added umbralisib to ibrutinib.

The study “is the first successful combination for two drugs targeting the B-cell receptor pathway,” Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston and his colleagues wrote in the Lancet Haematology.

Of the 21 patients with CLL, 90% (n = 19) achieved an overall response (OR), 62% (n = 13) achieved partial response (PR) or PR with lymphocytosis, and 29% (n = 6) achieved complete response (CR). All patients in complete response still had minimal residual disease (MRD) in bone marrow. No CLL patients had progressive disease.

Of the 21 patients with MCL, 67% (n = 14) had an OR, with 19% (n = 4) showing CR and 48% (n = 10) achieving partial response. Three MCL patients (14%) had progressive disease.

Umbralisib is a next-generation phosphoinositide-3-kinase-delta inhibitor that, when added to the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, offers once-daily oral dosing. The combination affords the possibility of overcoming the resistance that can come with prolonged ibrutinib monotherapy.

A total of 44 patients were enrolled, and 42 patients (21 with CLL and 21 with MCL) received at least one dose of the study drug and were included in the analysis. At enrollment, patients had received a median of two previous therapies.

Diarrhea was the most frequent adverse event, seen in 22 patients (52%), and half of all patients (n = 21) had infections.

Hematologic toxicities included neutropenia, seen in 9 (43%) of the CLL patients and 8 (38%) of the MCL patients; thrombocytopenia, seen in 6 (29%) of the CLL patients and 10 (48%) of the MCL patients; and anemia, seen in 4 (19%) of the CLL and 9 (43%) of the MCL patients. Grade 3 and 4 hematologic toxicities of any type were less common, occurring in less than 20% of patients. One MCL patient developed febrile neutropenia. According to the study investigators, none of the hematologic toxicities were deemed related to the study drugs.

Adverse events did not appear to be dose-dependent for umbralisib, with the maximum tolerated dose not reached in the study, the investigators wrote. For phase 2 trials, the recommended dose of umbralisib is 800 mg given orally once daily in combination with ibrutinib.

“One unanticipated benefit of doublet B-cell receptor pathway inhibition in this study was the ability to continue one drug when a characteristic toxicity required the other drug to be held,” the investigators wrote.

For MCL patients, 67% achieved OR and 19% achieved CR, figures similar to those reported for ibrutinib monotherapy. However, “the 2-year progression-free survival of 49% and overall survival of 58% suggest that patients who made it to 1 year progression-free had few events during the second year on therapy,” the investigators wrote. They also noted that this MCL population was high risk; more than one-quarter of patients had relapsed after prior autologous stem cell transplantation.

The study was limited by small sample size and a short duration of follow-up, so durability of response can’t yet be assessed. Also, neither pharmacokinetics nor resistance mutations were tracked for participants.

Currently, the doublet regimen is designed to be continuous therapy, and although it’s not known whether this regimen would be effective as time-limited therapy, it’s unlikely because 100% of patients who had CR still had detectable minimal residual disease, the investigators noted.

Umbralisib and ibrutinib are also being explored as part of triplet therapy, with the type 2 CD20 antibody ublituximab, for relapsed or refractory B-cell malignancies (NCT02006485).

“These novel drug-based approaches, along with several others in development, hold promise as highly effective and well-tolerated regimens with the potential to substantially improve outcomes for patients with B-cell malignancies,” the investigators wrote.

The study was supported by TG Therapeutics and the Leukemia and Lymphoma Society Therapy Accelerator Program. The authors reported financial relationships with several pharmaceutical companies, including TG Therapeutics.

[email protected]

SOURCE: Davids MS et al. Lancet Haemtol. 2019;6:e38-47.

Dual B-cell receptor pathway blockade was tolerable and efficacious for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who participated in a multicenter phase 1-1b clinical study that added umbralisib to ibrutinib.

The study “is the first successful combination for two drugs targeting the B-cell receptor pathway,” Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston and his colleagues wrote in the Lancet Haematology.

Of the 21 patients with CLL, 90% (n = 19) achieved an overall response (OR), 62% (n = 13) achieved partial response (PR) or PR with lymphocytosis, and 29% (n = 6) achieved complete response (CR). All patients in complete response still had minimal residual disease (MRD) in bone marrow. No CLL patients had progressive disease.

Of the 21 patients with MCL, 67% (n = 14) had an OR, with 19% (n = 4) showing CR and 48% (n = 10) achieving partial response. Three MCL patients (14%) had progressive disease.

Umbralisib is a next-generation phosphoinositide-3-kinase-delta inhibitor that, when added to the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, offers once-daily oral dosing. The combination affords the possibility of overcoming the resistance that can come with prolonged ibrutinib monotherapy.

A total of 44 patients were enrolled, and 42 patients (21 with CLL and 21 with MCL) received at least one dose of the study drug and were included in the analysis. At enrollment, patients had received a median of two previous therapies.

Diarrhea was the most frequent adverse event, seen in 22 patients (52%), and half of all patients (n = 21) had infections.

Hematologic toxicities included neutropenia, seen in 9 (43%) of the CLL patients and 8 (38%) of the MCL patients; thrombocytopenia, seen in 6 (29%) of the CLL patients and 10 (48%) of the MCL patients; and anemia, seen in 4 (19%) of the CLL and 9 (43%) of the MCL patients. Grade 3 and 4 hematologic toxicities of any type were less common, occurring in less than 20% of patients. One MCL patient developed febrile neutropenia. According to the study investigators, none of the hematologic toxicities were deemed related to the study drugs.

Adverse events did not appear to be dose-dependent for umbralisib, with the maximum tolerated dose not reached in the study, the investigators wrote. For phase 2 trials, the recommended dose of umbralisib is 800 mg given orally once daily in combination with ibrutinib.

“One unanticipated benefit of doublet B-cell receptor pathway inhibition in this study was the ability to continue one drug when a characteristic toxicity required the other drug to be held,” the investigators wrote.

For MCL patients, 67% achieved OR and 19% achieved CR, figures similar to those reported for ibrutinib monotherapy. However, “the 2-year progression-free survival of 49% and overall survival of 58% suggest that patients who made it to 1 year progression-free had few events during the second year on therapy,” the investigators wrote. They also noted that this MCL population was high risk; more than one-quarter of patients had relapsed after prior autologous stem cell transplantation.

The study was limited by small sample size and a short duration of follow-up, so durability of response can’t yet be assessed. Also, neither pharmacokinetics nor resistance mutations were tracked for participants.

Currently, the doublet regimen is designed to be continuous therapy, and although it’s not known whether this regimen would be effective as time-limited therapy, it’s unlikely because 100% of patients who had CR still had detectable minimal residual disease, the investigators noted.

Umbralisib and ibrutinib are also being explored as part of triplet therapy, with the type 2 CD20 antibody ublituximab, for relapsed or refractory B-cell malignancies (NCT02006485).

“These novel drug-based approaches, along with several others in development, hold promise as highly effective and well-tolerated regimens with the potential to substantially improve outcomes for patients with B-cell malignancies,” the investigators wrote.

The study was supported by TG Therapeutics and the Leukemia and Lymphoma Society Therapy Accelerator Program. The authors reported financial relationships with several pharmaceutical companies, including TG Therapeutics.

[email protected]

SOURCE: Davids MS et al. Lancet Haemtol. 2019;6:e38-47.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – A second-generation CD19-specific “armored” chimeric antigen receptor (CAR) T-cell construct was associated with high complete remission rates in diffuse large B-cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1 trial.

Neil Osterweil/ MDedge News

The CAR T construct – labeled 1928z-41BBL – also induced “encouraging” complete remission rates in patients with chronic lymphocytic leukemia (CLL) with Richter’s transformation, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, and his colleagues.

“Interestingly and encouragingly, severe [cytokine release syndrome] was not seen and grade 3 neurotoxicity was observed in less than 10%, with no grade 4 neurotoxicity, so there appears to be a favorable side effect profile,” Dr. Park said at the annual meeting of the American Society of Hematology.

Just as armored cars are designed to protect their valuable contents from people with bad intent, armored CAR T cells are engineered to protect the modified T-cells from a hostile tumor microenvironment and simultaneously recruit non-modified T cells to the target to produce a more robust immune response against malignant cells.

MSKCC investigators had previously shown that in contrast to other CAR T-cell constructs, the 1928z-41BBL configuration, which consists of two signaling domains (CD28 and CD3zeta) and the 4-1BB ligand, hit the sweet spot between tumor-killing function and T-cell persistence (Cancer Cell. 2015 Oct 12;28[4]:415-28).

In the current study, they enrolled 35 adults with relapsed or refractory CD19-positive hematologic malignancies, 29 of whom eventually underwent CAR T-cell infusions. The treated population comprised 14 patients with CLL (4 of whom had Richter’s transformation), 9 with DLBCL, 5 with indolent NHL, and 1 with acute lymphoblastic leukemia.

The patients with CLL had received a median of 5.5 prior lines of therapy, including ibrutinib (Imbruvica) and venetoclax (Venclexta).

There were 15 complete remissions (CR), with CR rates of 78% in DLBCL, 20% in CLL, 67% in CLL with Richter’s transformation, 60% in patients with indolent NHL, as well as CR in the single patient with ALL.

There were eight partial remissions. One patient with CLL had stable disease, and four patients had disease progression (one patient each with DLBCL, CLL, CLL with Richter’s, and indolent NHL).

Dr. Park noted that T cells are being detected in peripheral blood more than 6 months after T-cell infusion.

There were no cases of severe cytokine release syndrome, defined as requiring vasopressors and/or mechanical ventilation for hypoxia, and just three cases of grade 3 neurotoxicity. There were no cases of grade 4 neurotoxicity, no deaths related to neurotoxicity, and no cases of cerebral edema – a serious complication that has been seen in earlier CAR T-cell studies.

Split or multiple infusions of CAR T cells or incorporation of the technique into earlier lines of therapy might generate higher response rates, Dr. Park said.

The study was supported by Juno Therapeutics. Dr. Park reported consulting for and research funding from Juno, and financial relationships with other companies.
 

SOURCE: Park JH et al. ASH 2018, Abstract 224.

SAN DIEGO – Longer-term follow-up of patients treated with CD19-targeted chimeric antigen receptor (CAR) T cells for hematologic malignancies indicates that the altered cells are generally safe, with most late events being mild in nature and possibly related to therapies delivered before or after CAR T cells, investigators reported.

Among patients treated with CD19-targeted CAR T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), the most frequent late adverse event was hypogammaglobulinemia, which occurred in 29 of 48 patients evaluated, reported Ana Cordeiro, MD, from the Fred Hutchinson Cancer Research Center in Seattle.

“Our results suggest that CD19 CAR T cells are safe,” Dr. Cordeiro said at the annual meeting of the American Society of Hematology. “However, continuing with prospective systematic and long-term follow-up of these patients is required for better understanding of these late effects.”

Dr. Cordeiro and colleagues studied a total of 60 patients who were enrolled in a phase 1/2 trial at their center of a CD19-targeted CAR T-cell construct and survived for at least 1 year.

The goal of the study was to describe complications that occurred or persisted beyond 90 days after CAR T-cell infusion.

The cohort included 43 patients treated for NHL and 17 treated for CLL. Patients with CLL were followed for a median of 27.5 months, and patients with NHL were followed for a median of 23.8 months.

As of September 2018, 47 patients were still alive, including 15 patients with CLL (88%) and 32 patients with NHL (74%). Of the 17 patients who died, 10 died from progressive disease (2 from CLL and 8 from NHL), and 3 patients died from nonrelapse causes associated with complications from subsequent allogeneic stem cell transplantation (allo-HCT), including 1 patient from graft-versus-host disease (GVHD) and infection, 1 from infection, and 1 from cerberovascular accident/thrombotic microangiopathy.

Of 38 patients who received additional therapies, 17 had subsequent CAR T-cell infusions under the same protocol, and 16 went on to allo-HCT. Treatments for the remaining five patients were not specified.

Of the 22 patients who did not receive additional treatment for their primary malignancies, 21 were in ongoing complete remission following a single CAR T-cell infusion after a median follow-up of 28 months. However, two patients in this group did require treatment for therapy-related myelodysplastic syndrome (t-MDS). The remaining patient had a small CLL clone at last follow-up.

Late adverse events included the following:

• Late significant cytopenias in three of 19 patients evaluated.
• Late hypogammaglobulinemia in 29 of 48 evaluated patients.
• A total of 138 late infections in 31 of the 60 patients.
• Subsequent malignancies in 10 of the 60 patients, including t-MDS, nonmelanoma skin cancer, and noninvasive bladder cancer.
• Late immune-related events in seven patients.
• Late neurogenic/psychiatric events, including one case each of transient ischemic attack at 3.8 months, encephalopathy and myoclonic seizure in the setting of chemotherapy, and a fatal cerebrovascular accident in the setting of allo-HCT and thrombotic microangiopathy. These patients did not have acute neurotoxicity after CAR T-cell therapy, Dr. Cordeiro noted. In addition, three patients experienced exacerbation of depression or anxiety following infusion.
• GVHD in nine patients at a median time from allo-HCT to first CAR T-cell infusion of 46.3 months (range, 6.7 months to 11 years).

Focusing on those patients who achieve complete remissions after CAR T-cell therapy could help investigators isolate late events that are most likely related to CAR T cells, Dr. Cordeiro said.

Dr. Cordeiro reported having no relevant conflicts of interest.

SOURCE: Cordeiro A et al. ASH 2018, Abstract 223.

SAN DIEGO – Longer-term follow-up of patients treated with CD19-targeted chimeric antigen receptor (CAR) T cells for hematologic malignancies indicates that the altered cells are generally safe, with most late events being mild in nature and possibly related to therapies delivered before or after CAR T cells, investigators reported.

Among patients treated with CD19-targeted CAR T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), the most frequent late adverse event was hypogammaglobulinemia, which occurred in 29 of 48 patients evaluated, reported Ana Cordeiro, MD, from the Fred Hutchinson Cancer Research Center in Seattle.

“Our results suggest that CD19 CAR T cells are safe,” Dr. Cordeiro said at the annual meeting of the American Society of Hematology. “However, continuing with prospective systematic and long-term follow-up of these patients is required for better understanding of these late effects.”

Dr. Cordeiro and colleagues studied a total of 60 patients who were enrolled in a phase 1/2 trial at their center of a CD19-targeted CAR T-cell construct and survived for at least 1 year.

The goal of the study was to describe complications that occurred or persisted beyond 90 days after CAR T-cell infusion.

The cohort included 43 patients treated for NHL and 17 treated for CLL. Patients with CLL were followed for a median of 27.5 months, and patients with NHL were followed for a median of 23.8 months.

As of September 2018, 47 patients were still alive, including 15 patients with CLL (88%) and 32 patients with NHL (74%). Of the 17 patients who died, 10 died from progressive disease (2 from CLL and 8 from NHL), and 3 patients died from nonrelapse causes associated with complications from subsequent allogeneic stem cell transplantation (allo-HCT), including 1 patient from graft-versus-host disease (GVHD) and infection, 1 from infection, and 1 from cerberovascular accident/thrombotic microangiopathy.

Of 38 patients who received additional therapies, 17 had subsequent CAR T-cell infusions under the same protocol, and 16 went on to allo-HCT. Treatments for the remaining five patients were not specified.

Of the 22 patients who did not receive additional treatment for their primary malignancies, 21 were in ongoing complete remission following a single CAR T-cell infusion after a median follow-up of 28 months. However, two patients in this group did require treatment for therapy-related myelodysplastic syndrome (t-MDS). The remaining patient had a small CLL clone at last follow-up.

Late adverse events included the following:

• Late significant cytopenias in three of 19 patients evaluated.
• Late hypogammaglobulinemia in 29 of 48 evaluated patients.
• A total of 138 late infections in 31 of the 60 patients.
• Subsequent malignancies in 10 of the 60 patients, including t-MDS, nonmelanoma skin cancer, and noninvasive bladder cancer.
• Late immune-related events in seven patients.
• Late neurogenic/psychiatric events, including one case each of transient ischemic attack at 3.8 months, encephalopathy and myoclonic seizure in the setting of chemotherapy, and a fatal cerebrovascular accident in the setting of allo-HCT and thrombotic microangiopathy. These patients did not have acute neurotoxicity after CAR T-cell therapy, Dr. Cordeiro noted. In addition, three patients experienced exacerbation of depression or anxiety following infusion.
• GVHD in nine patients at a median time from allo-HCT to first CAR T-cell infusion of 46.3 months (range, 6.7 months to 11 years).

Focusing on those patients who achieve complete remissions after CAR T-cell therapy could help investigators isolate late events that are most likely related to CAR T cells, Dr. Cordeiro said.

Dr. Cordeiro reported having no relevant conflicts of interest.

SOURCE: Cordeiro A et al. ASH 2018, Abstract 223.

SAN DIEGO – Longer-term follow-up of patients treated with CD19-targeted chimeric antigen receptor (CAR) T cells for hematologic malignancies indicates that the altered cells are generally safe, with most late events being mild in nature and possibly related to therapies delivered before or after CAR T cells, investigators reported.

Among patients treated with CD19-targeted CAR T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), the most frequent late adverse event was hypogammaglobulinemia, which occurred in 29 of 48 patients evaluated, reported Ana Cordeiro, MD, from the Fred Hutchinson Cancer Research Center in Seattle.

“Our results suggest that CD19 CAR T cells are safe,” Dr. Cordeiro said at the annual meeting of the American Society of Hematology. “However, continuing with prospective systematic and long-term follow-up of these patients is required for better understanding of these late effects.”

Dr. Cordeiro and colleagues studied a total of 60 patients who were enrolled in a phase 1/2 trial at their center of a CD19-targeted CAR T-cell construct and survived for at least 1 year.

The goal of the study was to describe complications that occurred or persisted beyond 90 days after CAR T-cell infusion.

The cohort included 43 patients treated for NHL and 17 treated for CLL. Patients with CLL were followed for a median of 27.5 months, and patients with NHL were followed for a median of 23.8 months.

As of September 2018, 47 patients were still alive, including 15 patients with CLL (88%) and 32 patients with NHL (74%). Of the 17 patients who died, 10 died from progressive disease (2 from CLL and 8 from NHL), and 3 patients died from nonrelapse causes associated with complications from subsequent allogeneic stem cell transplantation (allo-HCT), including 1 patient from graft-versus-host disease (GVHD) and infection, 1 from infection, and 1 from cerberovascular accident/thrombotic microangiopathy.

Of 38 patients who received additional therapies, 17 had subsequent CAR T-cell infusions under the same protocol, and 16 went on to allo-HCT. Treatments for the remaining five patients were not specified.

Of the 22 patients who did not receive additional treatment for their primary malignancies, 21 were in ongoing complete remission following a single CAR T-cell infusion after a median follow-up of 28 months. However, two patients in this group did require treatment for therapy-related myelodysplastic syndrome (t-MDS). The remaining patient had a small CLL clone at last follow-up.

Late adverse events included the following:

• Late significant cytopenias in three of 19 patients evaluated.
• Late hypogammaglobulinemia in 29 of 48 evaluated patients.
• A total of 138 late infections in 31 of the 60 patients.
• Subsequent malignancies in 10 of the 60 patients, including t-MDS, nonmelanoma skin cancer, and noninvasive bladder cancer.
• Late immune-related events in seven patients.
• Late neurogenic/psychiatric events, including one case each of transient ischemic attack at 3.8 months, encephalopathy and myoclonic seizure in the setting of chemotherapy, and a fatal cerebrovascular accident in the setting of allo-HCT and thrombotic microangiopathy. These patients did not have acute neurotoxicity after CAR T-cell therapy, Dr. Cordeiro noted. In addition, three patients experienced exacerbation of depression or anxiety following infusion.
• GVHD in nine patients at a median time from allo-HCT to first CAR T-cell infusion of 46.3 months (range, 6.7 months to 11 years).

Focusing on those patients who achieve complete remissions after CAR T-cell therapy could help investigators isolate late events that are most likely related to CAR T cells, Dr. Cordeiro said.

Dr. Cordeiro reported having no relevant conflicts of interest.

SOURCE: Cordeiro A et al. ASH 2018, Abstract 223.

SAN DIEGO – For patients 65 years or younger with mantle cell lymphoma (MCL) who have undergone autologous stem cell transplantation (ASCT), maintenance therapy with lenalidomide (Revlimid) can significantly improve progression-free survival (PFS), suggest results of the phase, 3 randomized MCL0208 trial.

Neil Osterweil/MDedge News

After a median follow-up of 39 months, the 3-year PFS in an intention-to-treat analysis was 80% for patients treated with ASCT and lenalidomide maintenance, compared with 64% for patients treated with ASCT alone, reported Marco Ladetto, MD, of Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo in Alessandria, Italy.

“Lenalidomide maintenance after autologous stem cell transplant has substantial clinical activity in mantle cell lymphoma in terms of progression-free survival,” he said at the annual meeting of the American Society of Hematology. “Follow-up is still too short for meaningful overall survival considerations.”

Dr. Ladetto and his colleagues at centers in Italy and Portugal enrolled patients aged 18-65 years with previously untreated MCL stage III or IV, or stage II with bulky disease (5 cm or greater), and good performance status.

The patients first underwent induction with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone), which was followed by treatment with rituximab plus high-dose cyclophosphamide and two cycles of rituximab with high-dose cytarabine. Stem cells were collected after the first course of the latter regimen.

The patients then underwent conditioning with BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT.

Following ASCT, patients with complete or partial remissions were randomized either to maintenance therapy with lenalidomide 15 mg for 21 of 28 days for each cycle or to observation.

Of the 303 patients initially enrolled, 248 went on to ASCT, and 205 went on to randomization – 104 assigned to maintenance and 101 assigned to observation.

A total of 52 patients completed 2 years of maintenance: Of the rest, 2 patients died from toxicities (thrombotic thrombocytopenic purpura and pneumonia), 7 had disease progression, 41 dropped out for nonprogression reasons, and 2 patients were still in maintenance at the time of the data cutoff. In this arm, 6 of 8 patients with partial responses converted to complete responses by the end of maintenance. More than a quarter of patients (28%) received less than 25% of the planned lenalidomide dose.

In the observation arm, 1 patient died from pneumonia, 20 had disease progression, 3 were lost to follow-up, 6 were still under observation, and 71 completed observation. In this arm, 1 of 4 patients with a partial response converted to a complete response at the end of the observation period.

Despite suboptimal dosing in a large proportion of patients, the PFS primary endpoint showed significant benefit for lenalidomide, with an unstratified hazard ratio of 0.52 (P = .015) and a stratified HR of 0.51 (P = .013).

At a median follow-up of 39 months from randomization, 3-year overall survival (OS) rates were 93% with lenalidomide and 86% with observation, a difference that was not statistically significant.

Grade 3 or 4 hematologic toxicities occurred in 63% of patients in the lenalidomide arm, compared with 11% in the observation arm. The respective rates of granulocytopenia were 59% vs. 10%. Nonhematological grade 3 toxicity was comparable in the two arms except for grade 3 or 4 infections, which were more common with lenalidomide. Seven patients in the lenalidomide arm and three patients in the observation arm developed second cancers.

Dr. Ladetto noted that difficulties in delivering the planned dose of lenalidomide may have been caused by an already-stressed hematopoietic compartment; he commented that the question of the relative benefit of a fixed lenalidomide schedule or an until-progression approach still needs to be answered.

Additionally, the induction schedule used in the trial, while feasible, is not superior to “less cumbersome and possibly less toxic regimens,” he said.

The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.

SOURCE: Ladetto M et al. ASH 2018, Abstract 401.

SAN DIEGO – For patients 65 years or younger with mantle cell lymphoma (MCL) who have undergone autologous stem cell transplantation (ASCT), maintenance therapy with lenalidomide (Revlimid) can significantly improve progression-free survival (PFS), suggest results of the phase, 3 randomized MCL0208 trial.

Neil Osterweil/MDedge News

After a median follow-up of 39 months, the 3-year PFS in an intention-to-treat analysis was 80% for patients treated with ASCT and lenalidomide maintenance, compared with 64% for patients treated with ASCT alone, reported Marco Ladetto, MD, of Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo in Alessandria, Italy.

“Lenalidomide maintenance after autologous stem cell transplant has substantial clinical activity in mantle cell lymphoma in terms of progression-free survival,” he said at the annual meeting of the American Society of Hematology. “Follow-up is still too short for meaningful overall survival considerations.”

Dr. Ladetto and his colleagues at centers in Italy and Portugal enrolled patients aged 18-65 years with previously untreated MCL stage III or IV, or stage II with bulky disease (5 cm or greater), and good performance status.

The patients first underwent induction with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone), which was followed by treatment with rituximab plus high-dose cyclophosphamide and two cycles of rituximab with high-dose cytarabine. Stem cells were collected after the first course of the latter regimen.

The patients then underwent conditioning with BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT.

Following ASCT, patients with complete or partial remissions were randomized either to maintenance therapy with lenalidomide 15 mg for 21 of 28 days for each cycle or to observation.

Of the 303 patients initially enrolled, 248 went on to ASCT, and 205 went on to randomization – 104 assigned to maintenance and 101 assigned to observation.

A total of 52 patients completed 2 years of maintenance: Of the rest, 2 patients died from toxicities (thrombotic thrombocytopenic purpura and pneumonia), 7 had disease progression, 41 dropped out for nonprogression reasons, and 2 patients were still in maintenance at the time of the data cutoff. In this arm, 6 of 8 patients with partial responses converted to complete responses by the end of maintenance. More than a quarter of patients (28%) received less than 25% of the planned lenalidomide dose.

In the observation arm, 1 patient died from pneumonia, 20 had disease progression, 3 were lost to follow-up, 6 were still under observation, and 71 completed observation. In this arm, 1 of 4 patients with a partial response converted to a complete response at the end of the observation period.

Despite suboptimal dosing in a large proportion of patients, the PFS primary endpoint showed significant benefit for lenalidomide, with an unstratified hazard ratio of 0.52 (P = .015) and a stratified HR of 0.51 (P = .013).

At a median follow-up of 39 months from randomization, 3-year overall survival (OS) rates were 93% with lenalidomide and 86% with observation, a difference that was not statistically significant.

Grade 3 or 4 hematologic toxicities occurred in 63% of patients in the lenalidomide arm, compared with 11% in the observation arm. The respective rates of granulocytopenia were 59% vs. 10%. Nonhematological grade 3 toxicity was comparable in the two arms except for grade 3 or 4 infections, which were more common with lenalidomide. Seven patients in the lenalidomide arm and three patients in the observation arm developed second cancers.

Dr. Ladetto noted that difficulties in delivering the planned dose of lenalidomide may have been caused by an already-stressed hematopoietic compartment; he commented that the question of the relative benefit of a fixed lenalidomide schedule or an until-progression approach still needs to be answered.

Additionally, the induction schedule used in the trial, while feasible, is not superior to “less cumbersome and possibly less toxic regimens,” he said.

The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.

SOURCE: Ladetto M et al. ASH 2018, Abstract 401.

SAN DIEGO – For patients 65 years or younger with mantle cell lymphoma (MCL) who have undergone autologous stem cell transplantation (ASCT), maintenance therapy with lenalidomide (Revlimid) can significantly improve progression-free survival (PFS), suggest results of the phase, 3 randomized MCL0208 trial.

Neil Osterweil/MDedge News

After a median follow-up of 39 months, the 3-year PFS in an intention-to-treat analysis was 80% for patients treated with ASCT and lenalidomide maintenance, compared with 64% for patients treated with ASCT alone, reported Marco Ladetto, MD, of Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo in Alessandria, Italy.

“Lenalidomide maintenance after autologous stem cell transplant has substantial clinical activity in mantle cell lymphoma in terms of progression-free survival,” he said at the annual meeting of the American Society of Hematology. “Follow-up is still too short for meaningful overall survival considerations.”

Dr. Ladetto and his colleagues at centers in Italy and Portugal enrolled patients aged 18-65 years with previously untreated MCL stage III or IV, or stage II with bulky disease (5 cm or greater), and good performance status.

The patients first underwent induction with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone), which was followed by treatment with rituximab plus high-dose cyclophosphamide and two cycles of rituximab with high-dose cytarabine. Stem cells were collected after the first course of the latter regimen.

The patients then underwent conditioning with BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT.

Following ASCT, patients with complete or partial remissions were randomized either to maintenance therapy with lenalidomide 15 mg for 21 of 28 days for each cycle or to observation.

Of the 303 patients initially enrolled, 248 went on to ASCT, and 205 went on to randomization – 104 assigned to maintenance and 101 assigned to observation.

A total of 52 patients completed 2 years of maintenance: Of the rest, 2 patients died from toxicities (thrombotic thrombocytopenic purpura and pneumonia), 7 had disease progression, 41 dropped out for nonprogression reasons, and 2 patients were still in maintenance at the time of the data cutoff. In this arm, 6 of 8 patients with partial responses converted to complete responses by the end of maintenance. More than a quarter of patients (28%) received less than 25% of the planned lenalidomide dose.

In the observation arm, 1 patient died from pneumonia, 20 had disease progression, 3 were lost to follow-up, 6 were still under observation, and 71 completed observation. In this arm, 1 of 4 patients with a partial response converted to a complete response at the end of the observation period.

Despite suboptimal dosing in a large proportion of patients, the PFS primary endpoint showed significant benefit for lenalidomide, with an unstratified hazard ratio of 0.52 (P = .015) and a stratified HR of 0.51 (P = .013).

At a median follow-up of 39 months from randomization, 3-year overall survival (OS) rates were 93% with lenalidomide and 86% with observation, a difference that was not statistically significant.

Grade 3 or 4 hematologic toxicities occurred in 63% of patients in the lenalidomide arm, compared with 11% in the observation arm. The respective rates of granulocytopenia were 59% vs. 10%. Nonhematological grade 3 toxicity was comparable in the two arms except for grade 3 or 4 infections, which were more common with lenalidomide. Seven patients in the lenalidomide arm and three patients in the observation arm developed second cancers.

Dr. Ladetto noted that difficulties in delivering the planned dose of lenalidomide may have been caused by an already-stressed hematopoietic compartment; he commented that the question of the relative benefit of a fixed lenalidomide schedule or an until-progression approach still needs to be answered.

Additionally, the induction schedule used in the trial, while feasible, is not superior to “less cumbersome and possibly less toxic regimens,” he said.

The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.

SOURCE: Ladetto M et al. ASH 2018, Abstract 401.

SAN DIEGO – Nivolumab plus brentuximab vedotin may be a new treatment option for patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to investigators from the CheckMate 436 trial.

Interim results from this phase 1/2 trial revealed an overall response rate of 70%, including a complete response rate of 27%.

“It’s very promising ... to see this level of activity in this advanced, relapsed/refractory population,” said Joseph E. Eid, MD, senior vice president of Bristol-Myers Squibb, which is sponsoring CheckMate 436 in collaboration with Seattle Genetics.

Dr. Eid noted that adverse events (AEs) observed with this regimen were consistent with the safety profiles of nivolumab and brentuximab vedotin alone.

These results were presented as a poster at the annual meeting of the American Society of Hematology.

Dr. Eid noted that patients with relapsed or refractory PMBCL have limited treatment options.

“The initial therapy works well in 70% to 80% of patients but the patients who fail don’t have good options,” he said.

Prior research has shown that PMBCL is often characterized by overexpression of the PD-1 ligands PD-L1 and PD-L2, and most PMBCL expresses CD30.

Dr. Eid said CheckMate 436 (NCT02581631) was designed to “take advantage” of these characteristics by employing the anti-PD-1 checkpoint inhibitor nivolumab and the anti-CD30 antibody-drug conjugate brentuximab vedotin.

The interim analysis of this trial included 30 patients with relapsed/refractory PMBCL. Their median age at enrollment was 35.5 and 57% of patients were female. More than half of the patients (60%) had refractory disease, 23% had relapsed disease, and 17% had both.

The median number of prior therapies was two and 13% of patients had prior autologous stem cell transplant.

The patients received nivolumab at 240 mg and brentuximab vedotin at 1.8 mg/kg every 3 weeks until progression or unacceptable toxicity.

At a median follow-up of 6.1 months, 10 patients were still on treatment. Reasons for discontinuation included maximum clinical benefit, disease progression, AEs unrelated to treatment, patient request, and other concerns.

The rate of treatment-related AEs was 83%. The most common of these were neutropenia (27%), peripheral neuropathy (20%), hyperthyroidism (13%), rash (10%), and thrombocytopenia (10%).

Grade 3-4 treatment-related AEs included neutropenia (27%), thrombocytopenia (7%), decreased neutrophil count (7%), hypersensitivity (3%), diarrhea (3%), and maculopapular rash (3%).

The rate of serious treatment-related AEs was 10%. This included grade 3-4 diarrhea and maculopapular rash and grade 5 acute kidney injury.

The acute kidney injury was the only fatal AE considered treatment related. There were three other deaths in the trial, but they were considered unrelated to treatment.

The complete response rate was 27% (n = 8), and the partial response rate was 43% (n = 13), for an overall response rate of 70% (n = 21).

“The early indication is that 70% response is a pretty good outcome in a relapsed/refractory population that, otherwise, their outcome is pretty dismal,” Dr. Eid said.

Ten percent of patients (n = 3) had stable disease, 13% (n = 4) progressed, and investigators were unable to determine the status for 7% of patients (n = 2).

The median time to response was 1.3 months, and the median time to complete response was 3.0 months. The median duration of response and complete response were not reached.

Overall and progression-free survival data are not yet mature.

Still, the investigators concluded that nivolumab and brentuximab vedotin “may provide a new treatment option” for patients with relapsed/refractory PMBCL.

This trial is supported by Bristol-Myers Squibb in collaboration with Seattle Genetics. Investigators reported relationships with Bristol-Myers Squibb, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Moskowitz AJ et al. ASH 2018. Abstract 1691.

SAN DIEGO – Nivolumab plus brentuximab vedotin may be a new treatment option for patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to investigators from the CheckMate 436 trial.

Interim results from this phase 1/2 trial revealed an overall response rate of 70%, including a complete response rate of 27%.

“It’s very promising ... to see this level of activity in this advanced, relapsed/refractory population,” said Joseph E. Eid, MD, senior vice president of Bristol-Myers Squibb, which is sponsoring CheckMate 436 in collaboration with Seattle Genetics.

Dr. Eid noted that adverse events (AEs) observed with this regimen were consistent with the safety profiles of nivolumab and brentuximab vedotin alone.

These results were presented as a poster at the annual meeting of the American Society of Hematology.

Dr. Eid noted that patients with relapsed or refractory PMBCL have limited treatment options.

“The initial therapy works well in 70% to 80% of patients but the patients who fail don’t have good options,” he said.

Prior research has shown that PMBCL is often characterized by overexpression of the PD-1 ligands PD-L1 and PD-L2, and most PMBCL expresses CD30.

Dr. Eid said CheckMate 436 (NCT02581631) was designed to “take advantage” of these characteristics by employing the anti-PD-1 checkpoint inhibitor nivolumab and the anti-CD30 antibody-drug conjugate brentuximab vedotin.

The interim analysis of this trial included 30 patients with relapsed/refractory PMBCL. Their median age at enrollment was 35.5 and 57% of patients were female. More than half of the patients (60%) had refractory disease, 23% had relapsed disease, and 17% had both.

The median number of prior therapies was two and 13% of patients had prior autologous stem cell transplant.

The patients received nivolumab at 240 mg and brentuximab vedotin at 1.8 mg/kg every 3 weeks until progression or unacceptable toxicity.

At a median follow-up of 6.1 months, 10 patients were still on treatment. Reasons for discontinuation included maximum clinical benefit, disease progression, AEs unrelated to treatment, patient request, and other concerns.

The rate of treatment-related AEs was 83%. The most common of these were neutropenia (27%), peripheral neuropathy (20%), hyperthyroidism (13%), rash (10%), and thrombocytopenia (10%).

Grade 3-4 treatment-related AEs included neutropenia (27%), thrombocytopenia (7%), decreased neutrophil count (7%), hypersensitivity (3%), diarrhea (3%), and maculopapular rash (3%).

The rate of serious treatment-related AEs was 10%. This included grade 3-4 diarrhea and maculopapular rash and grade 5 acute kidney injury.

The acute kidney injury was the only fatal AE considered treatment related. There were three other deaths in the trial, but they were considered unrelated to treatment.

The complete response rate was 27% (n = 8), and the partial response rate was 43% (n = 13), for an overall response rate of 70% (n = 21).

“The early indication is that 70% response is a pretty good outcome in a relapsed/refractory population that, otherwise, their outcome is pretty dismal,” Dr. Eid said.

Ten percent of patients (n = 3) had stable disease, 13% (n = 4) progressed, and investigators were unable to determine the status for 7% of patients (n = 2).

The median time to response was 1.3 months, and the median time to complete response was 3.0 months. The median duration of response and complete response were not reached.

Overall and progression-free survival data are not yet mature.

Still, the investigators concluded that nivolumab and brentuximab vedotin “may provide a new treatment option” for patients with relapsed/refractory PMBCL.

This trial is supported by Bristol-Myers Squibb in collaboration with Seattle Genetics. Investigators reported relationships with Bristol-Myers Squibb, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Moskowitz AJ et al. ASH 2018. Abstract 1691.

SAN DIEGO – Nivolumab plus brentuximab vedotin may be a new treatment option for patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to investigators from the CheckMate 436 trial.

Interim results from this phase 1/2 trial revealed an overall response rate of 70%, including a complete response rate of 27%.

“It’s very promising ... to see this level of activity in this advanced, relapsed/refractory population,” said Joseph E. Eid, MD, senior vice president of Bristol-Myers Squibb, which is sponsoring CheckMate 436 in collaboration with Seattle Genetics.

Dr. Eid noted that adverse events (AEs) observed with this regimen were consistent with the safety profiles of nivolumab and brentuximab vedotin alone.

These results were presented as a poster at the annual meeting of the American Society of Hematology.

Dr. Eid noted that patients with relapsed or refractory PMBCL have limited treatment options.

“The initial therapy works well in 70% to 80% of patients but the patients who fail don’t have good options,” he said.

Prior research has shown that PMBCL is often characterized by overexpression of the PD-1 ligands PD-L1 and PD-L2, and most PMBCL expresses CD30.

Dr. Eid said CheckMate 436 (NCT02581631) was designed to “take advantage” of these characteristics by employing the anti-PD-1 checkpoint inhibitor nivolumab and the anti-CD30 antibody-drug conjugate brentuximab vedotin.

The interim analysis of this trial included 30 patients with relapsed/refractory PMBCL. Their median age at enrollment was 35.5 and 57% of patients were female. More than half of the patients (60%) had refractory disease, 23% had relapsed disease, and 17% had both.

The median number of prior therapies was two and 13% of patients had prior autologous stem cell transplant.

The patients received nivolumab at 240 mg and brentuximab vedotin at 1.8 mg/kg every 3 weeks until progression or unacceptable toxicity.

At a median follow-up of 6.1 months, 10 patients were still on treatment. Reasons for discontinuation included maximum clinical benefit, disease progression, AEs unrelated to treatment, patient request, and other concerns.

The rate of treatment-related AEs was 83%. The most common of these were neutropenia (27%), peripheral neuropathy (20%), hyperthyroidism (13%), rash (10%), and thrombocytopenia (10%).

Grade 3-4 treatment-related AEs included neutropenia (27%), thrombocytopenia (7%), decreased neutrophil count (7%), hypersensitivity (3%), diarrhea (3%), and maculopapular rash (3%).

The rate of serious treatment-related AEs was 10%. This included grade 3-4 diarrhea and maculopapular rash and grade 5 acute kidney injury.

The acute kidney injury was the only fatal AE considered treatment related. There were three other deaths in the trial, but they were considered unrelated to treatment.

The complete response rate was 27% (n = 8), and the partial response rate was 43% (n = 13), for an overall response rate of 70% (n = 21).

“The early indication is that 70% response is a pretty good outcome in a relapsed/refractory population that, otherwise, their outcome is pretty dismal,” Dr. Eid said.

Ten percent of patients (n = 3) had stable disease, 13% (n = 4) progressed, and investigators were unable to determine the status for 7% of patients (n = 2).

The median time to response was 1.3 months, and the median time to complete response was 3.0 months. The median duration of response and complete response were not reached.

Overall and progression-free survival data are not yet mature.

Still, the investigators concluded that nivolumab and brentuximab vedotin “may provide a new treatment option” for patients with relapsed/refractory PMBCL.

This trial is supported by Bristol-Myers Squibb in collaboration with Seattle Genetics. Investigators reported relationships with Bristol-Myers Squibb, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Moskowitz AJ et al. ASH 2018. Abstract 1691.

Survivors of childhood Hodgkin lymphoma have a 14-fold greater risk for second cancers, compared with the general population, according to newly published data.

The subsequent malignant neoplasms (SMNs) tend to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and body region treated.

And although the risk of SMNs appears to be somewhat lower for patients treated in more recent decades, it is still significantly elevated, compared with that of the general population, according to Anna S. Holmqvist, MD, PhD, from Lund University (Sweden), and her colleagues.

“A major goal of the current study was to develop evidence with which to guide the screening of survivors of HL for the development of [solid] SMNs,” the investigators wrote in Cancer.

They examined at data from the Late Effects Study Group, a multinational cohort of patients aged 16 years or younger who were treated for Hodgkin lymphoma and other cancers from 1955 to 1986.

The current report is the third update from an expanded cohort, including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years and the patients were followed for 23,212 person-years following the Hodgkin lymphoma diagnosis.

In all, 162 patients developed a total of 196 solid SMNs, including breast cancer in 54 patients, basal cell carcinoma in 34 patients, thyroid cancer in 30, colorectal cancer in 15, lung cancer in 11, other malignancies in 40, and disease site not available in 12 patients.

The cumulative incidence of any solid SMN 40 years after a diagnosis of Hodgkin lymphoma was 26.4%. The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.

Predisposing factors for breast cancer in females included a Hodgkin lymphoma diagnosis from the ages of 10-16 years, and treatment with radiotherapy to the chest.

The patients at highest risk for subsequent development of lung cancer were males treated with chest radiotherapy before age 10 years. Those at highest risk for colorectal cancer were males and females who had received abdominal/pelvic radiotherapy and high-dose alkylating agents. Patients at highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10.

The cumulative incidence for breast cancer by age 50 years for those at highest risk was 45.3%. The respective cumulative incidences for lung, colorectal, and thyroid cancers by age 50 were 4.2%, 9.5%, and 17.3%.

The investigators noted that patients treated more recently are likely to have received lower doses and volumes of radiotherapy, compared with patients treated in 1970s and earlier. “However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for [solid] SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life.”

No specific funding source for the study was reported. The authors made no financial disclosures.
 

SOURCE: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.

Survivors of childhood Hodgkin lymphoma have a 14-fold greater risk for second cancers, compared with the general population, according to newly published data.

The subsequent malignant neoplasms (SMNs) tend to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and body region treated.

And although the risk of SMNs appears to be somewhat lower for patients treated in more recent decades, it is still significantly elevated, compared with that of the general population, according to Anna S. Holmqvist, MD, PhD, from Lund University (Sweden), and her colleagues.

“A major goal of the current study was to develop evidence with which to guide the screening of survivors of HL for the development of [solid] SMNs,” the investigators wrote in Cancer.

They examined at data from the Late Effects Study Group, a multinational cohort of patients aged 16 years or younger who were treated for Hodgkin lymphoma and other cancers from 1955 to 1986.

The current report is the third update from an expanded cohort, including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years and the patients were followed for 23,212 person-years following the Hodgkin lymphoma diagnosis.

In all, 162 patients developed a total of 196 solid SMNs, including breast cancer in 54 patients, basal cell carcinoma in 34 patients, thyroid cancer in 30, colorectal cancer in 15, lung cancer in 11, other malignancies in 40, and disease site not available in 12 patients.

The cumulative incidence of any solid SMN 40 years after a diagnosis of Hodgkin lymphoma was 26.4%. The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.

Predisposing factors for breast cancer in females included a Hodgkin lymphoma diagnosis from the ages of 10-16 years, and treatment with radiotherapy to the chest.

The patients at highest risk for subsequent development of lung cancer were males treated with chest radiotherapy before age 10 years. Those at highest risk for colorectal cancer were males and females who had received abdominal/pelvic radiotherapy and high-dose alkylating agents. Patients at highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10.

The cumulative incidence for breast cancer by age 50 years for those at highest risk was 45.3%. The respective cumulative incidences for lung, colorectal, and thyroid cancers by age 50 were 4.2%, 9.5%, and 17.3%.

The investigators noted that patients treated more recently are likely to have received lower doses and volumes of radiotherapy, compared with patients treated in 1970s and earlier. “However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for [solid] SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life.”

No specific funding source for the study was reported. The authors made no financial disclosures.
 

SOURCE: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.

Survivors of childhood Hodgkin lymphoma have a 14-fold greater risk for second cancers, compared with the general population, according to newly published data.

The subsequent malignant neoplasms (SMNs) tend to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and body region treated.

And although the risk of SMNs appears to be somewhat lower for patients treated in more recent decades, it is still significantly elevated, compared with that of the general population, according to Anna S. Holmqvist, MD, PhD, from Lund University (Sweden), and her colleagues.

“A major goal of the current study was to develop evidence with which to guide the screening of survivors of HL for the development of [solid] SMNs,” the investigators wrote in Cancer.

They examined at data from the Late Effects Study Group, a multinational cohort of patients aged 16 years or younger who were treated for Hodgkin lymphoma and other cancers from 1955 to 1986.

The current report is the third update from an expanded cohort, including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years and the patients were followed for 23,212 person-years following the Hodgkin lymphoma diagnosis.

In all, 162 patients developed a total of 196 solid SMNs, including breast cancer in 54 patients, basal cell carcinoma in 34 patients, thyroid cancer in 30, colorectal cancer in 15, lung cancer in 11, other malignancies in 40, and disease site not available in 12 patients.

The cumulative incidence of any solid SMN 40 years after a diagnosis of Hodgkin lymphoma was 26.4%. The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.

Predisposing factors for breast cancer in females included a Hodgkin lymphoma diagnosis from the ages of 10-16 years, and treatment with radiotherapy to the chest.

The patients at highest risk for subsequent development of lung cancer were males treated with chest radiotherapy before age 10 years. Those at highest risk for colorectal cancer were males and females who had received abdominal/pelvic radiotherapy and high-dose alkylating agents. Patients at highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10.

The cumulative incidence for breast cancer by age 50 years for those at highest risk was 45.3%. The respective cumulative incidences for lung, colorectal, and thyroid cancers by age 50 were 4.2%, 9.5%, and 17.3%.

The investigators noted that patients treated more recently are likely to have received lower doses and volumes of radiotherapy, compared with patients treated in 1970s and earlier. “However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for [solid] SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life.”

No specific funding source for the study was reported. The authors made no financial disclosures.
 

SOURCE: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.

SAN DIEGO – A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to new research presented at the annual meeting of the American Society of Hematology.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS), compared with patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large cell lymphoma or other CD30-expressing PTCLs.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, with locations in New York and New Jersey.

Dr. Horwitz presented data from this trial at the ASH meeting. Results were simultaneously published in the Lancet (2018 Dec 3. doi: 10.1016/S0140-6736[18]32984-2).

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive or ALK-negative systemic anaplastic large-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and adult T-cell leukemia/lymphoma.

Patients were randomized to receive BV-CHP plus placebo (n = 226) or CHOP plus placebo (n = 226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in the BV-CHP arm and the CHOP arm. The majority of patients were male – 59% in the BV-CHP arm and 67% in the CHOP arm – and most patients had stage III/IV disease, 81% and 80%, respectively.

In all, 89% of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P = .0032). The complete response rates were 68% and 56%, respectively (P = .0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio = 0.71, P = .011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (HR = 0.66, P = .0244).

Dr. Horwitz noted that this study was not powered to determine differences in PFS or OS by PTCL subtypes.

BV-CHP had a safety profile comparable with that of CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The study was funded by Seattle Genetics, Millennium Pharmaceuticals, and the National Institutes of Health. Dr. Horwitz reported relationships with Seattle Genetics, Millennium Pharmaceuticals, and other companies.

[email protected]

SOURCE: Horwitz S et al. ASH 2018, Abstract 997.

SAN DIEGO – A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to new research presented at the annual meeting of the American Society of Hematology.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS), compared with patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large cell lymphoma or other CD30-expressing PTCLs.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, with locations in New York and New Jersey.

Dr. Horwitz presented data from this trial at the ASH meeting. Results were simultaneously published in the Lancet (2018 Dec 3. doi: 10.1016/S0140-6736[18]32984-2).

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive or ALK-negative systemic anaplastic large-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and adult T-cell leukemia/lymphoma.

Patients were randomized to receive BV-CHP plus placebo (n = 226) or CHOP plus placebo (n = 226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in the BV-CHP arm and the CHOP arm. The majority of patients were male – 59% in the BV-CHP arm and 67% in the CHOP arm – and most patients had stage III/IV disease, 81% and 80%, respectively.

In all, 89% of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P = .0032). The complete response rates were 68% and 56%, respectively (P = .0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio = 0.71, P = .011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (HR = 0.66, P = .0244).

Dr. Horwitz noted that this study was not powered to determine differences in PFS or OS by PTCL subtypes.

BV-CHP had a safety profile comparable with that of CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The study was funded by Seattle Genetics, Millennium Pharmaceuticals, and the National Institutes of Health. Dr. Horwitz reported relationships with Seattle Genetics, Millennium Pharmaceuticals, and other companies.

[email protected]

SOURCE: Horwitz S et al. ASH 2018, Abstract 997.

SAN DIEGO – A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to new research presented at the annual meeting of the American Society of Hematology.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS), compared with patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large cell lymphoma or other CD30-expressing PTCLs.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, with locations in New York and New Jersey.

Dr. Horwitz presented data from this trial at the ASH meeting. Results were simultaneously published in the Lancet (2018 Dec 3. doi: 10.1016/S0140-6736[18]32984-2).

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive or ALK-negative systemic anaplastic large-cell lymphoma, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and adult T-cell leukemia/lymphoma.

Patients were randomized to receive BV-CHP plus placebo (n = 226) or CHOP plus placebo (n = 226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in the BV-CHP arm and the CHOP arm. The majority of patients were male – 59% in the BV-CHP arm and 67% in the CHOP arm – and most patients had stage III/IV disease, 81% and 80%, respectively.

In all, 89% of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P = .0032). The complete response rates were 68% and 56%, respectively (P = .0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio = 0.71, P = .011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (HR = 0.66, P = .0244).

Dr. Horwitz noted that this study was not powered to determine differences in PFS or OS by PTCL subtypes.

BV-CHP had a safety profile comparable with that of CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The study was funded by Seattle Genetics, Millennium Pharmaceuticals, and the National Institutes of Health. Dr. Horwitz reported relationships with Seattle Genetics, Millennium Pharmaceuticals, and other companies.

[email protected]

SOURCE: Horwitz S et al. ASH 2018, Abstract 997.

Photo from Business Wire

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).

The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

BV is already EC-approved to treat adults with:

• CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Relapsed or refractory systemic anaplastic large-cell lymphoma
• CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

Phase 3 trial

The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.

Photo from Business Wire

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).

The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

BV is already EC-approved to treat adults with:

• CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Relapsed or refractory systemic anaplastic large-cell lymphoma
• CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

Phase 3 trial

The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.

Photo from Business Wire

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).

The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of a CHMP recommendation.

BV is already EC-approved to treat adults with:

• CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Relapsed or refractory systemic anaplastic large-cell lymphoma
• CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

Phase 3 trial

The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.