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Brentuximab changes landscape for post-transplant Hodgkin’s lymphoma patients
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
AT ASH 2014
Key clinical point: Brentuximab vedotin given immediately post-transplant significantly improves progression-free survival in patients with Hodgkin’s lymphoma at high risk for progression.
Major finding: Median progression-free survival per independent review was 24 months with placebo vs. 43 months with brentuximab (HR, 0.57; P = .001).
Data source: Randomized, double-blind, phase III study in 329 patients with Hodgkin’s lymphoma.
Disclosures: Seattle Genetics sponsored the study. Dr. Moskowitz reported research funding from Genentech and Merck, and research funding from and consultancy for Seattle Genetics. Several co-authors reported financial ties with industry, including employment with or equity ownership in Seattle Genetics.
PD-1 checkpoint inhibitors show mettle against relapsed Hodgkin’s lymphoma
SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.
In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.
The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.
“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.
Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.
“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.
Genetic Achilles heel
Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.
To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.
The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.
The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.
Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.
In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).
Pembrolizumab trial
Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).
In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.
Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.
The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.
Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.
The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.
SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.
In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.
The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.
“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.
Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.
“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.
Genetic Achilles heel
Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.
To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.
The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.
The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.
Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.
In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).
Pembrolizumab trial
Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).
In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.
Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.
The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.
Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.
The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.
SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.
In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.
The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.
“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.
Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.
“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.
Genetic Achilles heel
Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.
To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.
The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.
The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.
Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.
In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).
Pembrolizumab trial
Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).
In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.
Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.
The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.
Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.
The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.
Key clinical point: PD-1 checkpoint inhibition appears to be an effective strategy against treatment-refractory Hodgkin’s lymphoma.
Major finding: Nivolumab produced an 87% objective response rate and pembrolizumab a 66% response rate in patients with heavily pre-treated Hodgkin’s lymphoma.
Data source: A phase I study with 23 patients and a phase Ib study with 29 patients with relapsed or refractory Hodgkin’s lymphoma.
Disclosures: Dr. Armand’s study is supported by Bristol-Myers Squibb. He reported grant support from Bristol-Myers Squibb during the conduct of the study and personal fees from Merck outside the study. Dr. Moskowitz’ study is supported by Merck. He reported receiving research funding from the company. Dr. Sznol reported personal fees from Bristol-Myers Squibb, Dr. Longo reported no relevant disclosures.
Brentuximab tops chemo in HL, doc says
NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.
She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.
“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”
She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.
After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.
“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”
She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.
The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.
“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”
On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.
“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”
Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.
Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.
Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.
In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”
For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.” 
NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.
She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.
“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”
She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.
After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.
“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”
She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.
The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.
“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”
On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.
“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”
Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.
Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.
Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.
In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”
For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”
NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.
She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.
“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”
She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.
After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.
“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”
She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.
The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.
“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”
On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.
“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”
Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.
Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.
Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.
In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”
For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”
Speaker advocates chemo-based salvage in HL
Credit: Rhoda Baer
NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent
Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.
First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.
“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.
She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.
“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”
Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.
Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.
In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.
Dr Wagner-Johnston expressed other concerns about brentuximab as well.
“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”
There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.
“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”
She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.
Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”
Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.
In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.
In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”
For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”
Credit: Rhoda Baer
NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent
Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.
First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.
“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.
She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.
“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”
Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.
Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.
In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.
Dr Wagner-Johnston expressed other concerns about brentuximab as well.
“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”
There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.
“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”
She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.
Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”
Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.
In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.
In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”
For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”
Credit: Rhoda Baer
NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent
Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.
Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.
First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.
“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.
She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.
“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”
Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.
Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.
In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.
Dr Wagner-Johnston expressed other concerns about brentuximab as well.
“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”
There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.
“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”
She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.
Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”
Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.
In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.
In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”
For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”
Risk factors for premature menopause in HL survivors
Credit: NCI
The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.
The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.
And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.
The findings appear in the Journal of the National Cancer Institute.
Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.
To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.
All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.
Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.
The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.
The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.
However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).
Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.
The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.
“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.
“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”
Credit: NCI
The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.
The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.
And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.
The findings appear in the Journal of the National Cancer Institute.
Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.
To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.
All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.
Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.
The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.
The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.
However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).
Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.
The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.
“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.
“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”
Credit: NCI
The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.
The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.
And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.
The findings appear in the Journal of the National Cancer Institute.
Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.
To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.
All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.
Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.
The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.
The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.
However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).
Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.
The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.
“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.
“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”
Repeat biopsy and long-term surveillance key for rare Hodgkin’s lymphoma subtype
Time to progression was inferior in patients with advanced-stage nodular lymphocyte-predominant Hodgkin’s lymphoma, compared with patients with classical Hodgkin’s lymphoma, in a study that compared outcomes between the two groups of Hodgkin’s lymphoma patients enrolled in the British Columbia Cancer Agency database.
Over 10 years, time to progression was 63% in the nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL) group, vs. 73% in the classical Hodgkin’s lymphoma (CHL) group (P =.040), reported Dr. Katharine Xing of the Centre for Lymphoid Cancer at the BCCA and the University of British Columbia, Vancouver, and her associates.
Transformation to an aggressive non–Hodgkin’s lymphoma (NHL) over 15 years occurred in 24% of those with NLPHL, but in none of those with CHL (P = .00018), and the median time to transformation among those with NLPHL was 5.45 years (Blood 2014;123:3567-73).
The study compared 42 patients with advanced-stage NLPHL to 84 controls with advanced CHL, matched for age, sex, decade of diagnosis, stage, and chemotherapy type; all had been diagnosed between 1970 and 2011. Their mean age was 37 years, about two-thirds were men, most in both groups had stage III disease, and they were followed up for a median of about 11 years. Treatments included standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and most received standard ABVD or ABVD-equivalent chemotherapy. The study was conducted to "highlight the distinct natural history of this rare HL subtype," which accounts for 5% of HL cases, the authors noted.
Over 10 years, "HL freedom from treatment failure," which reflects only relapses from HL, was 75% among those with NLPHL and 73% among those with CHL. Overall survival was also similar between the two groups (83.5% among those with NLPHL and 81% among those with CHL at 10 years).
Among their other findings was a significantly higher incidence of transformation over 10 years among those who had splenic involvement at the time of NLPHL diagnosis, compared with those who did not have splenic involvement (29% vs. 7.8%). When they looked at only those NLPHL patients who had received ABVD-like treatment, the incidence of transformation over 10 years was 34% among those with splenic involvement at diagnosis, vs. 9% among those who did not have splenic involvement (P = .014).
Since NLPHL is rare, information on the optimal treatment is limited, particularly for those with advanced disease, the authors pointed out. The analysis "highlights the distinct disease behavior of NLPHL, compared with CHL, and the need for repeat biopsy at relapse as well as long-term surveillance," the authors concluded. "Given the strong expression of CD20" on the lymphocyte predominant cells that distinguishes NLPHL from CHL, the results also provide "a rationale for further evaluation" of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with rituximab, they added.
Time to progression was inferior in patients with advanced-stage nodular lymphocyte-predominant Hodgkin’s lymphoma, compared with patients with classical Hodgkin’s lymphoma, in a study that compared outcomes between the two groups of Hodgkin’s lymphoma patients enrolled in the British Columbia Cancer Agency database.
Over 10 years, time to progression was 63% in the nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL) group, vs. 73% in the classical Hodgkin’s lymphoma (CHL) group (P =.040), reported Dr. Katharine Xing of the Centre for Lymphoid Cancer at the BCCA and the University of British Columbia, Vancouver, and her associates.
Transformation to an aggressive non–Hodgkin’s lymphoma (NHL) over 15 years occurred in 24% of those with NLPHL, but in none of those with CHL (P = .00018), and the median time to transformation among those with NLPHL was 5.45 years (Blood 2014;123:3567-73).
The study compared 42 patients with advanced-stage NLPHL to 84 controls with advanced CHL, matched for age, sex, decade of diagnosis, stage, and chemotherapy type; all had been diagnosed between 1970 and 2011. Their mean age was 37 years, about two-thirds were men, most in both groups had stage III disease, and they were followed up for a median of about 11 years. Treatments included standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and most received standard ABVD or ABVD-equivalent chemotherapy. The study was conducted to "highlight the distinct natural history of this rare HL subtype," which accounts for 5% of HL cases, the authors noted.
Over 10 years, "HL freedom from treatment failure," which reflects only relapses from HL, was 75% among those with NLPHL and 73% among those with CHL. Overall survival was also similar between the two groups (83.5% among those with NLPHL and 81% among those with CHL at 10 years).
Among their other findings was a significantly higher incidence of transformation over 10 years among those who had splenic involvement at the time of NLPHL diagnosis, compared with those who did not have splenic involvement (29% vs. 7.8%). When they looked at only those NLPHL patients who had received ABVD-like treatment, the incidence of transformation over 10 years was 34% among those with splenic involvement at diagnosis, vs. 9% among those who did not have splenic involvement (P = .014).
Since NLPHL is rare, information on the optimal treatment is limited, particularly for those with advanced disease, the authors pointed out. The analysis "highlights the distinct disease behavior of NLPHL, compared with CHL, and the need for repeat biopsy at relapse as well as long-term surveillance," the authors concluded. "Given the strong expression of CD20" on the lymphocyte predominant cells that distinguishes NLPHL from CHL, the results also provide "a rationale for further evaluation" of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with rituximab, they added.
Time to progression was inferior in patients with advanced-stage nodular lymphocyte-predominant Hodgkin’s lymphoma, compared with patients with classical Hodgkin’s lymphoma, in a study that compared outcomes between the two groups of Hodgkin’s lymphoma patients enrolled in the British Columbia Cancer Agency database.
Over 10 years, time to progression was 63% in the nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL) group, vs. 73% in the classical Hodgkin’s lymphoma (CHL) group (P =.040), reported Dr. Katharine Xing of the Centre for Lymphoid Cancer at the BCCA and the University of British Columbia, Vancouver, and her associates.
Transformation to an aggressive non–Hodgkin’s lymphoma (NHL) over 15 years occurred in 24% of those with NLPHL, but in none of those with CHL (P = .00018), and the median time to transformation among those with NLPHL was 5.45 years (Blood 2014;123:3567-73).
The study compared 42 patients with advanced-stage NLPHL to 84 controls with advanced CHL, matched for age, sex, decade of diagnosis, stage, and chemotherapy type; all had been diagnosed between 1970 and 2011. Their mean age was 37 years, about two-thirds were men, most in both groups had stage III disease, and they were followed up for a median of about 11 years. Treatments included standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and most received standard ABVD or ABVD-equivalent chemotherapy. The study was conducted to "highlight the distinct natural history of this rare HL subtype," which accounts for 5% of HL cases, the authors noted.
Over 10 years, "HL freedom from treatment failure," which reflects only relapses from HL, was 75% among those with NLPHL and 73% among those with CHL. Overall survival was also similar between the two groups (83.5% among those with NLPHL and 81% among those with CHL at 10 years).
Among their other findings was a significantly higher incidence of transformation over 10 years among those who had splenic involvement at the time of NLPHL diagnosis, compared with those who did not have splenic involvement (29% vs. 7.8%). When they looked at only those NLPHL patients who had received ABVD-like treatment, the incidence of transformation over 10 years was 34% among those with splenic involvement at diagnosis, vs. 9% among those who did not have splenic involvement (P = .014).
Since NLPHL is rare, information on the optimal treatment is limited, particularly for those with advanced disease, the authors pointed out. The analysis "highlights the distinct disease behavior of NLPHL, compared with CHL, and the need for repeat biopsy at relapse as well as long-term surveillance," the authors concluded. "Given the strong expression of CD20" on the lymphocyte predominant cells that distinguishes NLPHL from CHL, the results also provide "a rationale for further evaluation" of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with rituximab, they added.
FROM BLOOD
Key clinical point: Repeat biopsy and long-term surveillance are necessary in nodular lymphocyte-predominant Hodgkin’s lymphoma.
Major finding: Overall survival was similar between patients with advanced-stage NLPHL and those with advanced-stage CHL, but differences between the two groups included an inferior time to progression among those with NLPHL over 10 years (63% vs 73%).
Data source: The study compared outcomes in 42 patients with advanced-stage NLPHL and 84 matched controls with advanced CHL, who were diagnosed between 1970 and 2011 and were enrolled in a Canadian cancer database.
Disclosures: Fourauthors received research funding from Roche; the remaining seven authors, including the lead author, had no relevant disclosures.
Screening catches breast cancer early in HL survivors
Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).
Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.
The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.
“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.
“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”
Dr Hodgson and his colleagues reported this evidence in Cancer.
The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.
The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.
The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).
“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”
MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.
In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.
The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.
Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.
Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).
Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.
The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.
“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.
“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”
Dr Hodgson and his colleagues reported this evidence in Cancer.
The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.
The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.
The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).
“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”
MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.
In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.
The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.
Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.
Results of a new study indicate that MRI and mammography can detect invasive breast tumors at very early stages in female survivors of Hodgkin lymphoma (HL).
Researchers said the findings underscore the need for at-risk childhood HL survivors and their physicians to be aware of screening guidelines.
The guidelines recommend survivors undergo breast MRI screening beginning at age 25 or 8 years after they received chest radiation, whichever is later.
“Female survivors of childhood HL who had chest radiation should speak with their family doctor about after-care assessment and breast cancer screening,” said David Hodgson, MD, of Princess Margaret Cancer Centre in Toronto, Canada.
“We estimate that 75% of women who are at high risk because of prior radiotherapy to the chest are not being screened. So my hope is that this new evidence will encourage these survivors to discuss early screening with their doctors.”
Dr Hodgson and his colleagues reported this evidence in Cancer.
The researchers evaluated the results of breast MRI and mammography screening among 96 female survivors of childhood HL who had been treated with chest radiotherapy.
The median patient age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers—half of them invasive tumors—were diagnosed in 9 women during 363 person-years follow up.
The median age at breast cancer diagnosis was 39 years (range, 24 to 43 years), and the median latency period between HL diagnosis and age at breast cancer diagnoses was 21 years (range, 12 to 27 years).
“This illustrates the young age at which these cancers can occur,” Dr Hodgson said. “For some of these women, if they had been screened starting at age 40 or 50, like average-risk women, it would have been too late.”
MRI alone detected tumors with 80% sensitivity and 93.5% specificity. Mammography alone detected tumors with 70% sensitivity and 95% specificity. And both modalities combined detected tumors with 100% sensitivity and 88.6% specificity. All invasive tumors were detected by MRI.
In other words, of the 10 breast tumors, 5 were visible on both MRI and mammogram, 3 were visible only on MRI, and 2 were detected via mammogram alone (but were non-invasive). The median size of invasive tumors size was 8 mm (range, 3-15 mm), and none had spread to the lymph nodes.
The researchers noted that these results are substantially better than prior studies using only mammographic screening in young patients.
Dr Hodgson also pointed out that, because MRI screening is so much more sensitive to small changes in the appearance of the breast tissue than mammography, up to a third of patients may be called back for further testing of suspicious findings. But many of these are benign or not clinically significant and, therefore, require no treatment.
Inhibitor gets breakthrough designation for HL
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.
The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.
Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.
Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.
The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.
The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.
Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.
Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.
These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.
A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.
The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.
Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.
Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.
The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.
The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.
Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.
Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.
These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.
A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational PD-1 immune checkpoint inhibitor nivolumab to treat Hodgkin lymphoma (HL) in patients who have failed autologous stem cell transplant and treatment with brentuximab vedotin.
The FDA’s decision is based on data from a cohort of HL patients in an ongoing phase 1b study of patients with relapsed or refractory hematologic malignancies.
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence that demonstrates the drug may offer substantial improvement over currently available therapy on at least 1 clinically significant endpoint.
Nivolumab is an investigational agent that binds to the checkpoint receptor PD-1 expressed on activated T cells. Researchers are investigating whether, by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack, and destroy cancer cells.
Nivolumab is under investigation in multiple tumor types as monotherapy or in combination with other therapies. There are 35 trials of the agent underway, in which more than 7000 patients have been enrolled.
The breakthrough designation for nivolumab in HL is based on results of a 2-part phase 1 study, which have not been made public.
The researchers planned to enroll 100 patients with relapsed or refractory hematologic malignancies on this study. For the dose-escalation portion, the team planned to treat successive cohorts of patients using a 6+3 escalation design.
Patients would receive 1 mg/kg or 3 mg/kg of intravenous nivolumab every 2 weeks (although the first dose would be followed by a 3-week evaluation period) for 2 years, with the potential for an additional year of therapy for patients who progress.
Then, the researchers would enroll 5 cohorts of 16 patients representing the following tumor sites: HL/primary mediastinal B-cell lymphoma, multiple myeloma, B-cell lymphoma, T-cell lymphoma, and chronic myelogenous leukemia.
These patients would receive nivolumab at the maximum-tolerated dose identified in the first part of the study.
A poster describing the study plan was presented at the 2013 ASCO Annual Meeting (abstract TPS3113). The study is funded by Bristol-Myers Squibb, the company developing nivolumab.
Omitting RT can increase risk of relapse in HL
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Mutations appear to drive lymphoma development
Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.
Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.
Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.