Lymphoma & Plasma Cell Disorders

In frail elderly patients with multiple myeloma, starting lenalidomide at low doses was associated with fewer adverse events and less treatment discontinuation, and did not compromise overall response rates, in a single-center, retrospective study conducted in Japan.

Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73% (complete response in 17% of patients, very good partial response in 19%, and partial response in 37%), Aya Nakaya, MD, PhD, of Kansai Medical University, Hirakata, and colleagues wrote (Acta Haematol. 2017;138:55-60). In addition, 23% of patients had stable disease and 4% had disease progression. Nine patients developed other types of malignancies during treatment with lenalidomide.

Starting patients on a reduced dose and increasing it gradually while monitoring carefully for adverse events meant that patients did not have to stop treatment, the researchers said. Continuous treatment may improve survival, and “treatment with lenalidomide for long periods of time, even in small doses, may yield favorable outcomes.”

The 30 men and 26 women, mean age 76.5 years, were consecutively diagnosed as transplant-ineligible patients with relapsed/refractory multiple myeloma; 34%, 32%, and 34% had stages I-III disease, respectively. The M-protein consisted of IgG in 52% of patients and IgA in 30%, with Bence-Jones protein detected in 14%.

They were treated with lenalidomide plus dexamethasone at a starting dose determined by the treating physician; 73% were treated with lenalidomide as a second-line regimen and 14% as a third-line regimen. During each 28-day treatment cycle, patients received lenalidomide on days 1-21 and dexamethasone (20 or 40 mg) on days 1, 8, 15, and 22.

The most common starting lenalidomide dose was 10 mg/day (45%), followed by 5 mg/day (21%), 15 mg/day (20%), 20 mg/day (4%), and 25 mg/day (10%). The treatment dose used for the longest period was 10 mg/day (46% of patients), followed by 5 mg/day (25%), 15 mg/day (16%), 20 mg/day (4%), and 25 mg/day (9%).

The most frequent reasons for dose reduction were renal dysfunction (54%), fatigue (20%), hematologic disorder (14%), and rash (9%).

The median treatment period was 9 months (range 1-60 months) and the median follow-up period was 16 months.

The median time to disease progression was 11.8 months (range 8.4-21.9), and the median overall survival was 39.2 months. For those who took 5-10 mg of lenalidomide, the median time to progression was 14.5 months; for those who took lenalidomide at a dose of more than 10 mg, the median time to progression was 8.9 months. The median overall survival of the patients who received a 5- to 10-mg dose of lenalidomide was 38.9 months; the median overall survival of the patients given a dose of more than 10 mg was not available.

The authors declared no competing financial interests in relation to this work.

mdales@frontlinemedcom.com

On Twitter @maryjodales

In frail elderly patients with multiple myeloma, starting lenalidomide at low doses was associated with fewer adverse events and less treatment discontinuation, and did not compromise overall response rates, in a single-center, retrospective study conducted in Japan.

Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73% (complete response in 17% of patients, very good partial response in 19%, and partial response in 37%), Aya Nakaya, MD, PhD, of Kansai Medical University, Hirakata, and colleagues wrote (Acta Haematol. 2017;138:55-60). In addition, 23% of patients had stable disease and 4% had disease progression. Nine patients developed other types of malignancies during treatment with lenalidomide.

Starting patients on a reduced dose and increasing it gradually while monitoring carefully for adverse events meant that patients did not have to stop treatment, the researchers said. Continuous treatment may improve survival, and “treatment with lenalidomide for long periods of time, even in small doses, may yield favorable outcomes.”

The 30 men and 26 women, mean age 76.5 years, were consecutively diagnosed as transplant-ineligible patients with relapsed/refractory multiple myeloma; 34%, 32%, and 34% had stages I-III disease, respectively. The M-protein consisted of IgG in 52% of patients and IgA in 30%, with Bence-Jones protein detected in 14%.

They were treated with lenalidomide plus dexamethasone at a starting dose determined by the treating physician; 73% were treated with lenalidomide as a second-line regimen and 14% as a third-line regimen. During each 28-day treatment cycle, patients received lenalidomide on days 1-21 and dexamethasone (20 or 40 mg) on days 1, 8, 15, and 22.

The most common starting lenalidomide dose was 10 mg/day (45%), followed by 5 mg/day (21%), 15 mg/day (20%), 20 mg/day (4%), and 25 mg/day (10%). The treatment dose used for the longest period was 10 mg/day (46% of patients), followed by 5 mg/day (25%), 15 mg/day (16%), 20 mg/day (4%), and 25 mg/day (9%).

The most frequent reasons for dose reduction were renal dysfunction (54%), fatigue (20%), hematologic disorder (14%), and rash (9%).

The median treatment period was 9 months (range 1-60 months) and the median follow-up period was 16 months.

The median time to disease progression was 11.8 months (range 8.4-21.9), and the median overall survival was 39.2 months. For those who took 5-10 mg of lenalidomide, the median time to progression was 14.5 months; for those who took lenalidomide at a dose of more than 10 mg, the median time to progression was 8.9 months. The median overall survival of the patients who received a 5- to 10-mg dose of lenalidomide was 38.9 months; the median overall survival of the patients given a dose of more than 10 mg was not available.

The authors declared no competing financial interests in relation to this work.

mdales@frontlinemedcom.com

On Twitter @maryjodales

In frail elderly patients with multiple myeloma, starting lenalidomide at low doses was associated with fewer adverse events and less treatment discontinuation, and did not compromise overall response rates, in a single-center, retrospective study conducted in Japan.

Although most of the 56 study patients received 5-10 mg/day of lenalidomide, not the recommended 25-mg/day dose, their overall response rate was 73% (complete response in 17% of patients, very good partial response in 19%, and partial response in 37%), Aya Nakaya, MD, PhD, of Kansai Medical University, Hirakata, and colleagues wrote (Acta Haematol. 2017;138:55-60). In addition, 23% of patients had stable disease and 4% had disease progression. Nine patients developed other types of malignancies during treatment with lenalidomide.

Starting patients on a reduced dose and increasing it gradually while monitoring carefully for adverse events meant that patients did not have to stop treatment, the researchers said. Continuous treatment may improve survival, and “treatment with lenalidomide for long periods of time, even in small doses, may yield favorable outcomes.”

The 30 men and 26 women, mean age 76.5 years, were consecutively diagnosed as transplant-ineligible patients with relapsed/refractory multiple myeloma; 34%, 32%, and 34% had stages I-III disease, respectively. The M-protein consisted of IgG in 52% of patients and IgA in 30%, with Bence-Jones protein detected in 14%.

They were treated with lenalidomide plus dexamethasone at a starting dose determined by the treating physician; 73% were treated with lenalidomide as a second-line regimen and 14% as a third-line regimen. During each 28-day treatment cycle, patients received lenalidomide on days 1-21 and dexamethasone (20 or 40 mg) on days 1, 8, 15, and 22.

The most common starting lenalidomide dose was 10 mg/day (45%), followed by 5 mg/day (21%), 15 mg/day (20%), 20 mg/day (4%), and 25 mg/day (10%). The treatment dose used for the longest period was 10 mg/day (46% of patients), followed by 5 mg/day (25%), 15 mg/day (16%), 20 mg/day (4%), and 25 mg/day (9%).

The most frequent reasons for dose reduction were renal dysfunction (54%), fatigue (20%), hematologic disorder (14%), and rash (9%).

The median treatment period was 9 months (range 1-60 months) and the median follow-up period was 16 months.

The median time to disease progression was 11.8 months (range 8.4-21.9), and the median overall survival was 39.2 months. For those who took 5-10 mg of lenalidomide, the median time to progression was 14.5 months; for those who took lenalidomide at a dose of more than 10 mg, the median time to progression was 8.9 months. The median overall survival of the patients who received a 5- to 10-mg dose of lenalidomide was 38.9 months; the median overall survival of the patients given a dose of more than 10 mg was not available.

The authors declared no competing financial interests in relation to this work.

mdales@frontlinemedcom.com

On Twitter @maryjodales

FLT3-ligand (FLT3-L) levels exceeding 92 pg/mL in bone marrow and 121 pg/mL in peripheral blood are associated with relapsed and refractory disease in patients with multiple myeloma, Normann Steiner, MD, and his colleagues report in a study published in PLoS ONE.

In the study of 14 patients with monoclonal gamm opathy of undetermined significance (MGUS), 42 patients with newly diagnosed myeloma, and 27 patients with relapsed/refractory myeloma, there was a 61% probability that patients with FLT3-L levels above 92 pg/mL in bone marrow had relapsed or refractory multiple myeloma and a 79% probability that those with FLT3-L levels of 92 pg/mL or less had not relapsed and were not refractory. Based on FLT3-L levels in peripheral blood, values of 121 pg/mL or more were associated with a 71% probability of relapsed or refractory disease. The likelihood of not having relapses or refractory disease was 87% for patients with values less than 121 pg/mL.

“FLT3-L could be useful as a marker to identify (relapsed or refractory multiple myeloma) patients and should be evaluated as a potential target for future therapy strategies,” Dr. Steiner of Innsbruck (Austria) Medical University, and his fellow researchers wrote in PLoS ONE.

The researchers obtained bone marrow aspirates from all patients. Peripheral blood was examined from 4 MGUS patients, 31 patients with newly diagnosed myeloma, and 16 patients with relapsed or refractory myeloma. Peripheral blood was also obtained from 16 control subjects.

The levels of four potential risk factors were measured – soluble TIE2, FLT3-L, endostatin, and osteoactivin. The most significant association with risk was seen with FLT3-L levels.

Expression of soluble TIE2 in bone marrow differed significantly among the three patient cohorts and may be driven by the same factors that influence FLT3-L levels. However, soluble TIE2 levels were not as effective at differentiating patients at risk for disease progression, the researchers wrote.

Soluble TIE2 expression in bone marrow was highest in MGUS patients (median 4003.97 pg/mL) in comparison to relapsed or refractory disease (median 2223.26 pg/mL; P = .03) and to newly diagnosed patients with myeloma (median 861.98 pg/mL; P less than .001). A statistically significant difference among bone marrow levels of soluble TIE2 was observed for newly diagnosed patients and those with relapsed or refractory disease (P = .03).

However, soluble TIE2 in peripheral blood plasma did not differ significantly in the three cohorts nor did it differ between patients and controls.

In contrast to TIE2 and FLT3-L, levels of endostatin were lowest (median 146.50 ng/mL) in bone marrow plasma samples of patients with relapsed or refractory disease. Levels were higher in MGUS patients (median 190.37 mg/dL) than in newly diagnosed myeloma patients (median 170.15 mg/mL; P = .5).

Similar to soluble TIE2, plasma levels of endostatin in peripheral blood did not differ significantly in the three patient cohorts. Measurements of endostatin in bone marrow and peripheral blood correlated significantly (P less than .001), and peripheral blood levels differed significantly (P less than .001) for patients and control persons.

Osteoactivin expression was highest in the MGUS cohort, with median bone marrow plasma levels of 36 ng/mL as compared with median levels of 24.92 ng/mL in newly diagnosed myeloma patients and 22.30 ng/mL in patients with relapsed or refractory myeloma. Osteoactivin levels in peripheral blood did not differ significantly in the three cohorts, but differed between patients and control subjects. Osteoactivin measures in bone marrow and peripheral blood correlated significantly.

Citation: Steiner N, et al. High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma. PLoS ONE 2017 Jul 20;12:e0181487. doi. org/10.1371/journal.pone.0181487.

mdales@frontlinemedcom.com

On Twitter @maryjodales

FLT3-ligand (FLT3-L) levels exceeding 92 pg/mL in bone marrow and 121 pg/mL in peripheral blood are associated with relapsed and refractory disease in patients with multiple myeloma, Normann Steiner, MD, and his colleagues report in a study published in PLoS ONE.

In the study of 14 patients with monoclonal gamm opathy of undetermined significance (MGUS), 42 patients with newly diagnosed myeloma, and 27 patients with relapsed/refractory myeloma, there was a 61% probability that patients with FLT3-L levels above 92 pg/mL in bone marrow had relapsed or refractory multiple myeloma and a 79% probability that those with FLT3-L levels of 92 pg/mL or less had not relapsed and were not refractory. Based on FLT3-L levels in peripheral blood, values of 121 pg/mL or more were associated with a 71% probability of relapsed or refractory disease. The likelihood of not having relapses or refractory disease was 87% for patients with values less than 121 pg/mL.

“FLT3-L could be useful as a marker to identify (relapsed or refractory multiple myeloma) patients and should be evaluated as a potential target for future therapy strategies,” Dr. Steiner of Innsbruck (Austria) Medical University, and his fellow researchers wrote in PLoS ONE.

The researchers obtained bone marrow aspirates from all patients. Peripheral blood was examined from 4 MGUS patients, 31 patients with newly diagnosed myeloma, and 16 patients with relapsed or refractory myeloma. Peripheral blood was also obtained from 16 control subjects.

The levels of four potential risk factors were measured – soluble TIE2, FLT3-L, endostatin, and osteoactivin. The most significant association with risk was seen with FLT3-L levels.

Expression of soluble TIE2 in bone marrow differed significantly among the three patient cohorts and may be driven by the same factors that influence FLT3-L levels. However, soluble TIE2 levels were not as effective at differentiating patients at risk for disease progression, the researchers wrote.

Soluble TIE2 expression in bone marrow was highest in MGUS patients (median 4003.97 pg/mL) in comparison to relapsed or refractory disease (median 2223.26 pg/mL; P = .03) and to newly diagnosed patients with myeloma (median 861.98 pg/mL; P less than .001). A statistically significant difference among bone marrow levels of soluble TIE2 was observed for newly diagnosed patients and those with relapsed or refractory disease (P = .03).

However, soluble TIE2 in peripheral blood plasma did not differ significantly in the three cohorts nor did it differ between patients and controls.

In contrast to TIE2 and FLT3-L, levels of endostatin were lowest (median 146.50 ng/mL) in bone marrow plasma samples of patients with relapsed or refractory disease. Levels were higher in MGUS patients (median 190.37 mg/dL) than in newly diagnosed myeloma patients (median 170.15 mg/mL; P = .5).

Similar to soluble TIE2, plasma levels of endostatin in peripheral blood did not differ significantly in the three patient cohorts. Measurements of endostatin in bone marrow and peripheral blood correlated significantly (P less than .001), and peripheral blood levels differed significantly (P less than .001) for patients and control persons.

Osteoactivin expression was highest in the MGUS cohort, with median bone marrow plasma levels of 36 ng/mL as compared with median levels of 24.92 ng/mL in newly diagnosed myeloma patients and 22.30 ng/mL in patients with relapsed or refractory myeloma. Osteoactivin levels in peripheral blood did not differ significantly in the three cohorts, but differed between patients and control subjects. Osteoactivin measures in bone marrow and peripheral blood correlated significantly.

Citation: Steiner N, et al. High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma. PLoS ONE 2017 Jul 20;12:e0181487. doi. org/10.1371/journal.pone.0181487.

mdales@frontlinemedcom.com

On Twitter @maryjodales

FLT3-ligand (FLT3-L) levels exceeding 92 pg/mL in bone marrow and 121 pg/mL in peripheral blood are associated with relapsed and refractory disease in patients with multiple myeloma, Normann Steiner, MD, and his colleagues report in a study published in PLoS ONE.

In the study of 14 patients with monoclonal gamm opathy of undetermined significance (MGUS), 42 patients with newly diagnosed myeloma, and 27 patients with relapsed/refractory myeloma, there was a 61% probability that patients with FLT3-L levels above 92 pg/mL in bone marrow had relapsed or refractory multiple myeloma and a 79% probability that those with FLT3-L levels of 92 pg/mL or less had not relapsed and were not refractory. Based on FLT3-L levels in peripheral blood, values of 121 pg/mL or more were associated with a 71% probability of relapsed or refractory disease. The likelihood of not having relapses or refractory disease was 87% for patients with values less than 121 pg/mL.

“FLT3-L could be useful as a marker to identify (relapsed or refractory multiple myeloma) patients and should be evaluated as a potential target for future therapy strategies,” Dr. Steiner of Innsbruck (Austria) Medical University, and his fellow researchers wrote in PLoS ONE.

The researchers obtained bone marrow aspirates from all patients. Peripheral blood was examined from 4 MGUS patients, 31 patients with newly diagnosed myeloma, and 16 patients with relapsed or refractory myeloma. Peripheral blood was also obtained from 16 control subjects.

The levels of four potential risk factors were measured – soluble TIE2, FLT3-L, endostatin, and osteoactivin. The most significant association with risk was seen with FLT3-L levels.

Expression of soluble TIE2 in bone marrow differed significantly among the three patient cohorts and may be driven by the same factors that influence FLT3-L levels. However, soluble TIE2 levels were not as effective at differentiating patients at risk for disease progression, the researchers wrote.

Soluble TIE2 expression in bone marrow was highest in MGUS patients (median 4003.97 pg/mL) in comparison to relapsed or refractory disease (median 2223.26 pg/mL; P = .03) and to newly diagnosed patients with myeloma (median 861.98 pg/mL; P less than .001). A statistically significant difference among bone marrow levels of soluble TIE2 was observed for newly diagnosed patients and those with relapsed or refractory disease (P = .03).

However, soluble TIE2 in peripheral blood plasma did not differ significantly in the three cohorts nor did it differ between patients and controls.

In contrast to TIE2 and FLT3-L, levels of endostatin were lowest (median 146.50 ng/mL) in bone marrow plasma samples of patients with relapsed or refractory disease. Levels were higher in MGUS patients (median 190.37 mg/dL) than in newly diagnosed myeloma patients (median 170.15 mg/mL; P = .5).

Similar to soluble TIE2, plasma levels of endostatin in peripheral blood did not differ significantly in the three patient cohorts. Measurements of endostatin in bone marrow and peripheral blood correlated significantly (P less than .001), and peripheral blood levels differed significantly (P less than .001) for patients and control persons.

Osteoactivin expression was highest in the MGUS cohort, with median bone marrow plasma levels of 36 ng/mL as compared with median levels of 24.92 ng/mL in newly diagnosed myeloma patients and 22.30 ng/mL in patients with relapsed or refractory myeloma. Osteoactivin levels in peripheral blood did not differ significantly in the three cohorts, but differed between patients and control subjects. Osteoactivin measures in bone marrow and peripheral blood correlated significantly.

Citation: Steiner N, et al. High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma. PLoS ONE 2017 Jul 20;12:e0181487. doi. org/10.1371/journal.pone.0181487.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Photo from Business Wire

Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).

This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.

Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.

Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.

AETHERA trial

Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.

The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Photo from Business Wire

Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).

This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.

Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.

Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.

AETHERA trial

Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.

The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Photo from Business Wire

Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).

This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.

Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.

Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.

AETHERA trial

Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.

The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.

In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.

In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.

“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.

Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.

For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.

Nancy B. Baron

hematologynews@frontlinemedcom.com

MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.

In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.

In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.

“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.

Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.

For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.

Nancy B. Baron

hematologynews@frontlinemedcom.com

MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.

In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.

In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.

“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.

Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.

For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.

Nancy B. Baron

hematologynews@frontlinemedcom.com

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing FL

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

The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.

The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:

• In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
• In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
• In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.

GALLIUM trial

The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.

The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Micrograph showing FL

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

The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.

The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:

• In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
• In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
• In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.

GALLIUM trial

The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.

The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Micrograph showing FL

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

The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.

The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:

• In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
• In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
• In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.

GALLIUM trial

The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.

The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.

Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Image by Joshua Stokes

Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.

Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.

The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”

Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.

Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.

Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.

When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.

Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).

To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.

The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.

Next steps

A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.

Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.

The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.

Photo by Rhoda Baer

New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.

The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.

These findings were published in Cancer.

“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.

He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.

The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.

Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:

• Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
• At 12 months—73.1 vs 85.1 (P<0.001)
• At 24 months—69.2 vs 85.1 (P<0.001).

Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.

The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.

“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.

“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”

Photo by Rhoda Baer

New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.

The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.

These findings were published in Cancer.

“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.

He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.

The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.

Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:

• Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
• At 12 months—73.1 vs 85.1 (P<0.001)
• At 24 months—69.2 vs 85.1 (P<0.001).

Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.

The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.

“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.

“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”

Photo by Rhoda Baer

New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.

The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.

These findings were published in Cancer.

“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.

He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.

The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.

Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:

• Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
• At 12 months—73.1 vs 85.1 (P<0.001)
• At 24 months—69.2 vs 85.1 (P<0.001).

Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.

The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.

“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.

“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”

LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.

Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.

“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.

Neil Osterweil/Frontline Medical News

LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.

Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.

“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.

Neil Osterweil/Frontline Medical News

LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.

Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.

“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.

Neil Osterweil/Frontline Medical News

LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.

Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.

“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.

Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.

Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.

“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.

Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.

In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).

A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).

The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.

The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.

The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.

In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.

In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.

In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.

Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.

“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.

The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.

LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.

Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.

“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.

Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.

Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.

“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.

Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.

In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).

A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).

The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.

The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.

The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.

In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.

In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.

In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.

Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.

“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.

The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.

LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.

Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.

“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.

Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.

Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.

“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.

Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.

In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).

A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).

The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.

The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.

The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.

In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.

In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.

In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.

Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.

“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.

The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.