User login
Follicular lymphoma treatment can benefit patients 80 years and older
Follicular lymphoma (FL) treatment was associated with improved survival among patients diagnosed with FL at aged 80 years and older, according to the results of a large, retrospective database cohort study.
Researchers used the linked Surveillance, Epidemiology, and End Results–Medicare dataset to identify patients 80 years of age and older, diagnosed with FL between 2000 and 2013, identifying FL-directed treatments based on published guidelines. They used a propensity-score matched sample to compare treated and untreated patient cohorts who had similar observed characteristics.
They assessed 3,705 older patients with FL and a mean age of 84 years). Over a median follow-up of 2.9 years, 68% of the sample received FL-directed therapy and the most common regimen was rituximab monotherapy, which 21% (768 patients) received.
The median overall survival for the treated group was 4.31 years (95% confidence interval [CI], 4.00-4.61) vs. 2.86 years (95% CI, 2.59-3.16) for the untreated group, according to the report, published in the Journal of Geriatric Oncology.
The 3-year restricted mean survival time for the treated group was 2.36 years (95% CI, 2.30-2.41), vs. 2.05 years (95% CI, 1.98-2.11) for the untreated group. Treatment was associated with a 23% reduction in the hazard of death (HR: 0.77; P < .001).
Multivariable analysis showed that older age and a Charlson Comorbidity Index score of two or higher, and a proxy indicator for poor performance status, were inversely associated with receiving treatment. “These factors are expected to discourage physicians from providing FL-directed therapy,” the researchers suggested.
“We observed that, in a cohort of FL patients aged 80 years or older, FL-directed therapy was associated with an overall survival benefit, which persisted in important subgroups,” the researchers concluded.
Financial support for this study was provided by Bayer. One of the authors is employed by Bayer.
SOURCE: Albarmawi H et al. J Geriatric Oncol. 2020;11:55-61.
Follicular lymphoma (FL) treatment was associated with improved survival among patients diagnosed with FL at aged 80 years and older, according to the results of a large, retrospective database cohort study.
Researchers used the linked Surveillance, Epidemiology, and End Results–Medicare dataset to identify patients 80 years of age and older, diagnosed with FL between 2000 and 2013, identifying FL-directed treatments based on published guidelines. They used a propensity-score matched sample to compare treated and untreated patient cohorts who had similar observed characteristics.
They assessed 3,705 older patients with FL and a mean age of 84 years). Over a median follow-up of 2.9 years, 68% of the sample received FL-directed therapy and the most common regimen was rituximab monotherapy, which 21% (768 patients) received.
The median overall survival for the treated group was 4.31 years (95% confidence interval [CI], 4.00-4.61) vs. 2.86 years (95% CI, 2.59-3.16) for the untreated group, according to the report, published in the Journal of Geriatric Oncology.
The 3-year restricted mean survival time for the treated group was 2.36 years (95% CI, 2.30-2.41), vs. 2.05 years (95% CI, 1.98-2.11) for the untreated group. Treatment was associated with a 23% reduction in the hazard of death (HR: 0.77; P < .001).
Multivariable analysis showed that older age and a Charlson Comorbidity Index score of two or higher, and a proxy indicator for poor performance status, were inversely associated with receiving treatment. “These factors are expected to discourage physicians from providing FL-directed therapy,” the researchers suggested.
“We observed that, in a cohort of FL patients aged 80 years or older, FL-directed therapy was associated with an overall survival benefit, which persisted in important subgroups,” the researchers concluded.
Financial support for this study was provided by Bayer. One of the authors is employed by Bayer.
SOURCE: Albarmawi H et al. J Geriatric Oncol. 2020;11:55-61.
Follicular lymphoma (FL) treatment was associated with improved survival among patients diagnosed with FL at aged 80 years and older, according to the results of a large, retrospective database cohort study.
Researchers used the linked Surveillance, Epidemiology, and End Results–Medicare dataset to identify patients 80 years of age and older, diagnosed with FL between 2000 and 2013, identifying FL-directed treatments based on published guidelines. They used a propensity-score matched sample to compare treated and untreated patient cohorts who had similar observed characteristics.
They assessed 3,705 older patients with FL and a mean age of 84 years). Over a median follow-up of 2.9 years, 68% of the sample received FL-directed therapy and the most common regimen was rituximab monotherapy, which 21% (768 patients) received.
The median overall survival for the treated group was 4.31 years (95% confidence interval [CI], 4.00-4.61) vs. 2.86 years (95% CI, 2.59-3.16) for the untreated group, according to the report, published in the Journal of Geriatric Oncology.
The 3-year restricted mean survival time for the treated group was 2.36 years (95% CI, 2.30-2.41), vs. 2.05 years (95% CI, 1.98-2.11) for the untreated group. Treatment was associated with a 23% reduction in the hazard of death (HR: 0.77; P < .001).
Multivariable analysis showed that older age and a Charlson Comorbidity Index score of two or higher, and a proxy indicator for poor performance status, were inversely associated with receiving treatment. “These factors are expected to discourage physicians from providing FL-directed therapy,” the researchers suggested.
“We observed that, in a cohort of FL patients aged 80 years or older, FL-directed therapy was associated with an overall survival benefit, which persisted in important subgroups,” the researchers concluded.
Financial support for this study was provided by Bayer. One of the authors is employed by Bayer.
SOURCE: Albarmawi H et al. J Geriatric Oncol. 2020;11:55-61.
FROM THE JOURNAL OF GERIATRIC ONCOLOGY
Survival data reported from largest CAR T trial in B-cell lymphoma
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
REPORTING FROM ASH 2019
5F9 plus rituximab take a bite out of drug-resistant NHL
AMSTERDAM – The novel monoclonal antibody , thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.
Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.
5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.
5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.
In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.
“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.
In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.
Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.
In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.
Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.
The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.
Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.
Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.
The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.
Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.
For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).
Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.
Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.
Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.
Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.
Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.
The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.
SOURCE: Roschewski M et al. EHA Congress, Abstract S867.
AMSTERDAM – The novel monoclonal antibody , thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.
Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.
5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.
5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.
In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.
“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.
In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.
Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.
In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.
Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.
The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.
Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.
Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.
The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.
Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.
For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).
Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.
Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.
Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.
Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.
Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.
The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.
SOURCE: Roschewski M et al. EHA Congress, Abstract S867.
AMSTERDAM – The novel monoclonal antibody , thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.
Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.
5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.
5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.
In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.
“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.
In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.
Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.
In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.
Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.
The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.
Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.
Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.
The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.
Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.
For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).
Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.
Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.
Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.
Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.
Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.
The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.
SOURCE: Roschewski M et al. EHA Congress, Abstract S867.
REPORTING FROM EHA CONGRESS
Key clinical point: The combination of Hu5F9 and rituximab shows activity in heavily pretreated, relapsed/refractory lymphomas.
Major finding: Among all evaluable patients, the objective response rate was 45%. The objective response rate for patients with diffuse large B-cell lymphoma was 35%.
Study details: A pooled analysis of data from phase 1b/2 studies in patients with aggressive and indolent lymphomas. Among 97 patients evaluable for response, there were 59 patients with diffuse large B-cell lymphoma, 35 with follicular lymphoma, and 3 with marginal zone lymphoma.
Disclosures: The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.
Source: Roschewski M et al. EHA Congress, Abstract S867.
R2 appears active in high-risk FL and MZL
CHICAGO – Lenalidomide plus rituximab (R2) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.
R2 produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.
David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.
The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.
For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m2 per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R2 induction are randomized to maintenance with R2 or rituximab alone.
Dr. Andorsky and colleagues presented results of R2 induction in 310 evaluable patients – 247 with FL and 63 with MZL.
The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.
Results
At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.
The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.
The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.
“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R2] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.
The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).
The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.
SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.
CHICAGO – Lenalidomide plus rituximab (R2) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.
R2 produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.
David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.
The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.
For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m2 per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R2 induction are randomized to maintenance with R2 or rituximab alone.
Dr. Andorsky and colleagues presented results of R2 induction in 310 evaluable patients – 247 with FL and 63 with MZL.
The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.
Results
At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.
The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.
The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.
“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R2] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.
The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).
The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.
SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.
CHICAGO – Lenalidomide plus rituximab (R2) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.
R2 produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.
David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.
The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.
For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m2 per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R2 induction are randomized to maintenance with R2 or rituximab alone.
Dr. Andorsky and colleagues presented results of R2 induction in 310 evaluable patients – 247 with FL and 63 with MZL.
The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.
Results
At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.
The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.
The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.
“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R2] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.
The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).
The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.
SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.
REPORTING FROM ASCO 2019
FDA approves lenalidomide/rituximab for previously treated FL, MZL
The Food and Drug Administration has approved lenalidomide (Revlimid), in combination with rituximab, for the treatment of adult patients with previously treated follicular or marginal zone lymphoma.
FDA approval is based on results from the randomized, double-blind, phase 3 AUGMENT trial, which evaluated lenalidomide/rituximab versus rituximab and placebo in patients with previously treated follicular or marginal zone lymphoma. The median progression-free survival in those receiving lenalidomide/rituximab was 39.4 months, compared with 14.1 months for those receiving rituximab/placebo (odds ratio, 0.46; 95% confidence interval, 0.34-0.62; P less than .0001).
A numeric trend was seen in overall survival over the follow-up period of 28.3 months (16 vs. 26 deaths; hazard ratio, 0.61; 95% CI, 0.33-1.13).
The most common adverse events associated with lenalidomide/rituximab are neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia. Lenalidomide also contains a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
“Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment. This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to initial treatment,” Meghan Gutierrez, CEO of the Lymphoma Research Foundation, said in a statement.
The Food and Drug Administration has approved lenalidomide (Revlimid), in combination with rituximab, for the treatment of adult patients with previously treated follicular or marginal zone lymphoma.
FDA approval is based on results from the randomized, double-blind, phase 3 AUGMENT trial, which evaluated lenalidomide/rituximab versus rituximab and placebo in patients with previously treated follicular or marginal zone lymphoma. The median progression-free survival in those receiving lenalidomide/rituximab was 39.4 months, compared with 14.1 months for those receiving rituximab/placebo (odds ratio, 0.46; 95% confidence interval, 0.34-0.62; P less than .0001).
A numeric trend was seen in overall survival over the follow-up period of 28.3 months (16 vs. 26 deaths; hazard ratio, 0.61; 95% CI, 0.33-1.13).
The most common adverse events associated with lenalidomide/rituximab are neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia. Lenalidomide also contains a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
“Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment. This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to initial treatment,” Meghan Gutierrez, CEO of the Lymphoma Research Foundation, said in a statement.
The Food and Drug Administration has approved lenalidomide (Revlimid), in combination with rituximab, for the treatment of adult patients with previously treated follicular or marginal zone lymphoma.
FDA approval is based on results from the randomized, double-blind, phase 3 AUGMENT trial, which evaluated lenalidomide/rituximab versus rituximab and placebo in patients with previously treated follicular or marginal zone lymphoma. The median progression-free survival in those receiving lenalidomide/rituximab was 39.4 months, compared with 14.1 months for those receiving rituximab/placebo (odds ratio, 0.46; 95% confidence interval, 0.34-0.62; P less than .0001).
A numeric trend was seen in overall survival over the follow-up period of 28.3 months (16 vs. 26 deaths; hazard ratio, 0.61; 95% CI, 0.33-1.13).
The most common adverse events associated with lenalidomide/rituximab are neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia. Lenalidomide also contains a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
“Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment. This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to initial treatment,” Meghan Gutierrez, CEO of the Lymphoma Research Foundation, said in a statement.
In situ vaccination produced responses in indolent NHL
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
FROM NATURE MEDICINE
High survival in relapsed FL after primary radiotherapy
The prognosis post relapse following primary radiotherapy was found to be excellent for patients with localized follicular lymphoma (FL), according to a retrospective analysis.
But patients who experienced early relapse – at 1 year or less after diagnosis – had significantly worse survival.
While primary radiotherapy may be curative for localized FL, about 30%-50% of patients will relapse and optimal salvage therapy is not well defined, Michael S. Binkley, MD, of Stanford (Calif.) University, and his colleagues wrote in the International Journal of Radiation Oncology, Biology, Physics.
The researchers retrospectively studied 512 patients with localized FL using data from multiple centers under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Clinical information was collected, including method of detection, age at relapse, location of recurrence, and response to salvage therapy.
The team defined disease recurrence as lymphoma nonresponsive to primary radiotherapy inside of the prescribed dose volume, which included having no radiographic or clinical response within 6 months of initial radiotherapy treatment.
With a median follow-up of 52 months, Dr. Binkley and his colleagues found that 29.1% of patients developed relapsed lymphoma at a median 23 months (range, 1-143 months) following primary radiotherapy.
The team reported that the 3-year overall survival rate was 91.4% for patients with lymphoma recurrence after primary radiotherapy. In total, 16 deaths occurred during follow-up: eight were lymphoma specific deaths, three were from other causes, and in five patients the cause was unknown.
Of the 149 cases of relapsed lymphoma, 93 were indolent. There were also three cases of FL grade 3B/not otherwise specified and 18 cases of diffuse large B-cell lymphoma. In 35 patients who relapsed, biopsies were not performed.
“The excellent prognosis observed for this relapse cohort emphasizes that primary radiation for localized follicular lymphoma is an excellent treatment option,” the researchers wrote.
When the researchers examined survival based on the time of relapse, they found that overall survival was “significantly worse” for patients who had relapsed 12 months or less after the date of diagnosis, at 88.7%, compared with all others at 95.8% (P = .01).
They found no difference in overall survival between patients who received immediate salvage treatment, compared with observation after relapse (P = .28). There was also no significant difference in survival between patients who relapsed in 1 year or less but underwent immediate treatment, compared to early relapsed patients who were observed (log-rank P = .34).
“[A]ny decision to offer treatment at time of relapse must be weighed with the risk of acute and late adverse effects. Greater than 60% of patients in our cohort with indolent recurrence who underwent salvage treatment received rituximab, likely contributing to the excellent outcomes,” the researchers wrote. “However, nearly 60% of patients with indolent recurrence who were observed did not have disease progression nor [did they] receive treatment within 3 years.”
The researchers reported having no conflicts of interest.
SOURCE: Binkley MS et al. Int J Radiat Oncol Biol Phys. 2019 Mar 8. doi: 10.1016/j.ijrobp.2019.03.004.
The prognosis post relapse following primary radiotherapy was found to be excellent for patients with localized follicular lymphoma (FL), according to a retrospective analysis.
But patients who experienced early relapse – at 1 year or less after diagnosis – had significantly worse survival.
While primary radiotherapy may be curative for localized FL, about 30%-50% of patients will relapse and optimal salvage therapy is not well defined, Michael S. Binkley, MD, of Stanford (Calif.) University, and his colleagues wrote in the International Journal of Radiation Oncology, Biology, Physics.
The researchers retrospectively studied 512 patients with localized FL using data from multiple centers under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Clinical information was collected, including method of detection, age at relapse, location of recurrence, and response to salvage therapy.
The team defined disease recurrence as lymphoma nonresponsive to primary radiotherapy inside of the prescribed dose volume, which included having no radiographic or clinical response within 6 months of initial radiotherapy treatment.
With a median follow-up of 52 months, Dr. Binkley and his colleagues found that 29.1% of patients developed relapsed lymphoma at a median 23 months (range, 1-143 months) following primary radiotherapy.
The team reported that the 3-year overall survival rate was 91.4% for patients with lymphoma recurrence after primary radiotherapy. In total, 16 deaths occurred during follow-up: eight were lymphoma specific deaths, three were from other causes, and in five patients the cause was unknown.
Of the 149 cases of relapsed lymphoma, 93 were indolent. There were also three cases of FL grade 3B/not otherwise specified and 18 cases of diffuse large B-cell lymphoma. In 35 patients who relapsed, biopsies were not performed.
“The excellent prognosis observed for this relapse cohort emphasizes that primary radiation for localized follicular lymphoma is an excellent treatment option,” the researchers wrote.
When the researchers examined survival based on the time of relapse, they found that overall survival was “significantly worse” for patients who had relapsed 12 months or less after the date of diagnosis, at 88.7%, compared with all others at 95.8% (P = .01).
They found no difference in overall survival between patients who received immediate salvage treatment, compared with observation after relapse (P = .28). There was also no significant difference in survival between patients who relapsed in 1 year or less but underwent immediate treatment, compared to early relapsed patients who were observed (log-rank P = .34).
“[A]ny decision to offer treatment at time of relapse must be weighed with the risk of acute and late adverse effects. Greater than 60% of patients in our cohort with indolent recurrence who underwent salvage treatment received rituximab, likely contributing to the excellent outcomes,” the researchers wrote. “However, nearly 60% of patients with indolent recurrence who were observed did not have disease progression nor [did they] receive treatment within 3 years.”
The researchers reported having no conflicts of interest.
SOURCE: Binkley MS et al. Int J Radiat Oncol Biol Phys. 2019 Mar 8. doi: 10.1016/j.ijrobp.2019.03.004.
The prognosis post relapse following primary radiotherapy was found to be excellent for patients with localized follicular lymphoma (FL), according to a retrospective analysis.
But patients who experienced early relapse – at 1 year or less after diagnosis – had significantly worse survival.
While primary radiotherapy may be curative for localized FL, about 30%-50% of patients will relapse and optimal salvage therapy is not well defined, Michael S. Binkley, MD, of Stanford (Calif.) University, and his colleagues wrote in the International Journal of Radiation Oncology, Biology, Physics.
The researchers retrospectively studied 512 patients with localized FL using data from multiple centers under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Clinical information was collected, including method of detection, age at relapse, location of recurrence, and response to salvage therapy.
The team defined disease recurrence as lymphoma nonresponsive to primary radiotherapy inside of the prescribed dose volume, which included having no radiographic or clinical response within 6 months of initial radiotherapy treatment.
With a median follow-up of 52 months, Dr. Binkley and his colleagues found that 29.1% of patients developed relapsed lymphoma at a median 23 months (range, 1-143 months) following primary radiotherapy.
The team reported that the 3-year overall survival rate was 91.4% for patients with lymphoma recurrence after primary radiotherapy. In total, 16 deaths occurred during follow-up: eight were lymphoma specific deaths, three were from other causes, and in five patients the cause was unknown.
Of the 149 cases of relapsed lymphoma, 93 were indolent. There were also three cases of FL grade 3B/not otherwise specified and 18 cases of diffuse large B-cell lymphoma. In 35 patients who relapsed, biopsies were not performed.
“The excellent prognosis observed for this relapse cohort emphasizes that primary radiation for localized follicular lymphoma is an excellent treatment option,” the researchers wrote.
When the researchers examined survival based on the time of relapse, they found that overall survival was “significantly worse” for patients who had relapsed 12 months or less after the date of diagnosis, at 88.7%, compared with all others at 95.8% (P = .01).
They found no difference in overall survival between patients who received immediate salvage treatment, compared with observation after relapse (P = .28). There was also no significant difference in survival between patients who relapsed in 1 year or less but underwent immediate treatment, compared to early relapsed patients who were observed (log-rank P = .34).
“[A]ny decision to offer treatment at time of relapse must be weighed with the risk of acute and late adverse effects. Greater than 60% of patients in our cohort with indolent recurrence who underwent salvage treatment received rituximab, likely contributing to the excellent outcomes,” the researchers wrote. “However, nearly 60% of patients with indolent recurrence who were observed did not have disease progression nor [did they] receive treatment within 3 years.”
The researchers reported having no conflicts of interest.
SOURCE: Binkley MS et al. Int J Radiat Oncol Biol Phys. 2019 Mar 8. doi: 10.1016/j.ijrobp.2019.03.004.
FROM THE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY, BIOLOGY, PHYSICS
BCL expression intensity key in distinguishing FL lesions
Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.
Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.
The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.
“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.
One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.
Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.
While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.
Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.
Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).
The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).
Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.
“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.
The investigators did not report disclosures related to the research.
SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.
Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.
Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.
The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.
“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.
One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.
Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.
While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.
Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.
Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).
The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).
Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.
“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.
The investigators did not report disclosures related to the research.
SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.
Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.
Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.
The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.
“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.
One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.
Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.
While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.
Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.
Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).
The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).
Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.
“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.
The investigators did not report disclosures related to the research.
SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.
FROM THE JOURNAL OF CUTANEOUS PATHOLOGY
Key clinical point:
Major finding: Strong BCL2 expression was seen in 46% of secondary lymphomas, versus just 4% of primary cutaneous follicular center-cell lymphomas (P = .001).
Study details: A comparative study evaluating clinicopathologic and genetic features in a series of patients, including 59 with PCFCL and 22 with SCFL.
Disclosures: Investigators did not report disclosures related to the research.
Source: Servitje O et al. J Cutan Pathol. 2019;46:182-9.
GALLIUM: MRD response correlates with outcomes in follicular lymphoma
SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.
After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.
GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m2 on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.
Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.
The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.
The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.
Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.
Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.
“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”
Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.
“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.
The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.
For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.
“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.
“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.
The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
SOURCE: Pott C et al. ASH 2018, Abstract 396.
SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.
After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.
GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m2 on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.
Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.
The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.
The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.
Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.
Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.
“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”
Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.
“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.
The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.
For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.
“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.
“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.
The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
SOURCE: Pott C et al. ASH 2018, Abstract 396.
SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.
After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.
GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m2 on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.
Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.
The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.
The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.
Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.
Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.
“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”
Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.
“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.
The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.
For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.
“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.
“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.
The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
SOURCE: Pott C et al. ASH 2018, Abstract 396.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Progression-free survival (PFS) probability was about 80% in patients who were MRD negative at the end of induction, compared with about 50% in patients who were MRD positive (hazard ratio, 0.38).
Study details: An analysis of data from 634 patients in the phase 3 GALLIUM study.
Disclosures: The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.
Source: Pott C et al. ASH 2018, Abstract 396.
Umbralisib gains FDA breakthrough designation for MZL
The who have received at least one prior anti-CD20 regimen.
Umbralisib (formerly TGR-1202) is a PI3K-delta inhibitor being developed by TG Therapeutics.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance and other actions that may expedite FDA review. For a treatment to earn breakthrough designation, early clinical results must show that it provides improvement over available therapies or fulfills an unmet need.
The breakthrough designation for umbralisib was based on interim data from the MZL cohort in the ongoing, phase 2b UNITY-NHL trial (NCT02793583).
In this trial, researchers are testing umbralisib alone or in combination with ublituximab, with or without bendamustine, in patients with previously treated non-Hodgkin lymphoma.
“The MZL single-agent umbralisib cohort of the UNITY-NHL study is fully enrolled, and we look forward to reporting topline results from this cohort by mid-year and presenting the data at a major medical meeting in 2019,” Michael S. Weiss, chief executive officer of TG Therapeutics, said in a statement.
Umbralisib monotherapy was previously evaluated in a phase 1 trial (NCT01767766) of patients with relapsed or refractory B-cell malignancies (Lancet Oncol. 2018 Apr;19[4]:486-96).
The trial enrolled 90 patients, and five of them had MZL. A total of 33 patients achieved a response to umbralisib. This includes one MZL patient who achieved a partial response.
The most common treatment-emergent adverse events (AEs) in this trial were diarrhea, nausea, and fatigue. The most common grade 3/4 AEs were neutropenia, anemia, and thrombocytopenia.
Serious AEs considered at least possibly related to umbralisib were pneumonia, lung infection, febrile neutropenia, and colitis. There were no treatment-related deaths.
The who have received at least one prior anti-CD20 regimen.
Umbralisib (formerly TGR-1202) is a PI3K-delta inhibitor being developed by TG Therapeutics.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance and other actions that may expedite FDA review. For a treatment to earn breakthrough designation, early clinical results must show that it provides improvement over available therapies or fulfills an unmet need.
The breakthrough designation for umbralisib was based on interim data from the MZL cohort in the ongoing, phase 2b UNITY-NHL trial (NCT02793583).
In this trial, researchers are testing umbralisib alone or in combination with ublituximab, with or without bendamustine, in patients with previously treated non-Hodgkin lymphoma.
“The MZL single-agent umbralisib cohort of the UNITY-NHL study is fully enrolled, and we look forward to reporting topline results from this cohort by mid-year and presenting the data at a major medical meeting in 2019,” Michael S. Weiss, chief executive officer of TG Therapeutics, said in a statement.
Umbralisib monotherapy was previously evaluated in a phase 1 trial (NCT01767766) of patients with relapsed or refractory B-cell malignancies (Lancet Oncol. 2018 Apr;19[4]:486-96).
The trial enrolled 90 patients, and five of them had MZL. A total of 33 patients achieved a response to umbralisib. This includes one MZL patient who achieved a partial response.
The most common treatment-emergent adverse events (AEs) in this trial were diarrhea, nausea, and fatigue. The most common grade 3/4 AEs were neutropenia, anemia, and thrombocytopenia.
Serious AEs considered at least possibly related to umbralisib were pneumonia, lung infection, febrile neutropenia, and colitis. There were no treatment-related deaths.
The who have received at least one prior anti-CD20 regimen.
Umbralisib (formerly TGR-1202) is a PI3K-delta inhibitor being developed by TG Therapeutics.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance and other actions that may expedite FDA review. For a treatment to earn breakthrough designation, early clinical results must show that it provides improvement over available therapies or fulfills an unmet need.
The breakthrough designation for umbralisib was based on interim data from the MZL cohort in the ongoing, phase 2b UNITY-NHL trial (NCT02793583).
In this trial, researchers are testing umbralisib alone or in combination with ublituximab, with or without bendamustine, in patients with previously treated non-Hodgkin lymphoma.
“The MZL single-agent umbralisib cohort of the UNITY-NHL study is fully enrolled, and we look forward to reporting topline results from this cohort by mid-year and presenting the data at a major medical meeting in 2019,” Michael S. Weiss, chief executive officer of TG Therapeutics, said in a statement.
Umbralisib monotherapy was previously evaluated in a phase 1 trial (NCT01767766) of patients with relapsed or refractory B-cell malignancies (Lancet Oncol. 2018 Apr;19[4]:486-96).
The trial enrolled 90 patients, and five of them had MZL. A total of 33 patients achieved a response to umbralisib. This includes one MZL patient who achieved a partial response.
The most common treatment-emergent adverse events (AEs) in this trial were diarrhea, nausea, and fatigue. The most common grade 3/4 AEs were neutropenia, anemia, and thrombocytopenia.
Serious AEs considered at least possibly related to umbralisib were pneumonia, lung infection, febrile neutropenia, and colitis. There were no treatment-related deaths.