Mantle Cell Lymphoma

SAN DIEGO – A “mechanism-based” combination of ibrutinib and palbociclib was reasonably well tolerated and induced complete responses in 44% of patients with previously treated mantle cell lymphoma, Peter Martin, MD, reported at the annual meeting of the American Society of Hematology.

Fully 67% of patients remained alive and progression-free after a median of 11 months of follow-up, and no responders progressed during this phase I trial, added Dr. Martin of Weill Cornell Medical College in New York. These rates “appear better than those reported in studies of single-agent ibrutinib, although the number of patients was very small,” he acknowledged. Most patients tolerated therapy, although 25% developed dose-limiting toxicities or stopped treatment because of adverse effects. Based on these results, the investigators are studying biomarkers for resistance and are planning a phase II, multicenter trial to evaluate time to progression.

Single-agent ibrutinib (Imbruvica) has shown promise in mantle cell lymphoma, but treatment failure affects about half of patients within 1 year, Dr. Martin noted. The CDK4/6 inhibitor palbociclib (Ibrance) induces prolonged arrest early in the G1 phase of the cell cycle, which overcame ibrutinib resistance in mantle cell lymphoma cell lines in a prior study (Cancer Discov. 2014;4[9]:1022-35).

To test the maximum tolerated dose of combination therapy, Dr. Martin and his associates enrolled 20 adults with previously treated mantle cell lymphoma who were naive to ibrutinib and CD4/6 inhibitors. The patients had received a median of one and up to five prior lines of therapy, and six (30%) were refractory to their most recent therapy. They received ibrutinib daily and palbociclib on the first 21 days of each 28-day treatment cycle. Dosing began at one of five levels, ranging from 280 mg ibrutinib/75 mg palbociclib to 560 mg ibrutinib/125 mg palbociclib. Doses were escalated based on a standard phase I 3+3 design.

Among 18 patients evaluated, 12 (67%) responded to treatment, and 8 (44%) had a complete response. Median time to complete response was three cycles. The most common grade 1-2 adverse events were diarrhea, fatigue, rash, and bruising. Three patients (15%) developed dose-limiting toxicities. These included one case of grade 4 thrombocytopenia at 420 mg ibrutinib/100 mg palbociclib and two cases of grade 3 rash at 560 mg ibrutinib/125 mg palbociclib. The grade 3 rashes led to dose reductions, and six patients needed dose interruptions. Also, four patients stopped treatment because of disease progression, two did so because of elevated liver enzymes or prolonged cytopenia, and one did so to undergo allogeneic stem cell transplantation.

The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.

SAN DIEGO – A “mechanism-based” combination of ibrutinib and palbociclib was reasonably well tolerated and induced complete responses in 44% of patients with previously treated mantle cell lymphoma, Peter Martin, MD, reported at the annual meeting of the American Society of Hematology.

Fully 67% of patients remained alive and progression-free after a median of 11 months of follow-up, and no responders progressed during this phase I trial, added Dr. Martin of Weill Cornell Medical College in New York. These rates “appear better than those reported in studies of single-agent ibrutinib, although the number of patients was very small,” he acknowledged. Most patients tolerated therapy, although 25% developed dose-limiting toxicities or stopped treatment because of adverse effects. Based on these results, the investigators are studying biomarkers for resistance and are planning a phase II, multicenter trial to evaluate time to progression.

Single-agent ibrutinib (Imbruvica) has shown promise in mantle cell lymphoma, but treatment failure affects about half of patients within 1 year, Dr. Martin noted. The CDK4/6 inhibitor palbociclib (Ibrance) induces prolonged arrest early in the G1 phase of the cell cycle, which overcame ibrutinib resistance in mantle cell lymphoma cell lines in a prior study (Cancer Discov. 2014;4[9]:1022-35).

To test the maximum tolerated dose of combination therapy, Dr. Martin and his associates enrolled 20 adults with previously treated mantle cell lymphoma who were naive to ibrutinib and CD4/6 inhibitors. The patients had received a median of one and up to five prior lines of therapy, and six (30%) were refractory to their most recent therapy. They received ibrutinib daily and palbociclib on the first 21 days of each 28-day treatment cycle. Dosing began at one of five levels, ranging from 280 mg ibrutinib/75 mg palbociclib to 560 mg ibrutinib/125 mg palbociclib. Doses were escalated based on a standard phase I 3+3 design.

Among 18 patients evaluated, 12 (67%) responded to treatment, and 8 (44%) had a complete response. Median time to complete response was three cycles. The most common grade 1-2 adverse events were diarrhea, fatigue, rash, and bruising. Three patients (15%) developed dose-limiting toxicities. These included one case of grade 4 thrombocytopenia at 420 mg ibrutinib/100 mg palbociclib and two cases of grade 3 rash at 560 mg ibrutinib/125 mg palbociclib. The grade 3 rashes led to dose reductions, and six patients needed dose interruptions. Also, four patients stopped treatment because of disease progression, two did so because of elevated liver enzymes or prolonged cytopenia, and one did so to undergo allogeneic stem cell transplantation.

The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.

SAN DIEGO – A “mechanism-based” combination of ibrutinib and palbociclib was reasonably well tolerated and induced complete responses in 44% of patients with previously treated mantle cell lymphoma, Peter Martin, MD, reported at the annual meeting of the American Society of Hematology.

Fully 67% of patients remained alive and progression-free after a median of 11 months of follow-up, and no responders progressed during this phase I trial, added Dr. Martin of Weill Cornell Medical College in New York. These rates “appear better than those reported in studies of single-agent ibrutinib, although the number of patients was very small,” he acknowledged. Most patients tolerated therapy, although 25% developed dose-limiting toxicities or stopped treatment because of adverse effects. Based on these results, the investigators are studying biomarkers for resistance and are planning a phase II, multicenter trial to evaluate time to progression.

Single-agent ibrutinib (Imbruvica) has shown promise in mantle cell lymphoma, but treatment failure affects about half of patients within 1 year, Dr. Martin noted. The CDK4/6 inhibitor palbociclib (Ibrance) induces prolonged arrest early in the G1 phase of the cell cycle, which overcame ibrutinib resistance in mantle cell lymphoma cell lines in a prior study (Cancer Discov. 2014;4[9]:1022-35).

To test the maximum tolerated dose of combination therapy, Dr. Martin and his associates enrolled 20 adults with previously treated mantle cell lymphoma who were naive to ibrutinib and CD4/6 inhibitors. The patients had received a median of one and up to five prior lines of therapy, and six (30%) were refractory to their most recent therapy. They received ibrutinib daily and palbociclib on the first 21 days of each 28-day treatment cycle. Dosing began at one of five levels, ranging from 280 mg ibrutinib/75 mg palbociclib to 560 mg ibrutinib/125 mg palbociclib. Doses were escalated based on a standard phase I 3+3 design.

Among 18 patients evaluated, 12 (67%) responded to treatment, and 8 (44%) had a complete response. Median time to complete response was three cycles. The most common grade 1-2 adverse events were diarrhea, fatigue, rash, and bruising. Three patients (15%) developed dose-limiting toxicities. These included one case of grade 4 thrombocytopenia at 420 mg ibrutinib/100 mg palbociclib and two cases of grade 3 rash at 560 mg ibrutinib/125 mg palbociclib. The grade 3 rashes led to dose reductions, and six patients needed dose interruptions. Also, four patients stopped treatment because of disease progression, two did so because of elevated liver enzymes or prolonged cytopenia, and one did so to undergo allogeneic stem cell transplantation.

The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.

SAN DIEGO – For adults with mantle cell lymphoma, adding bortezomib to a modified hyper-CVAD (VcR-CVAD) regimen followed by rituximab maintenance induced durable remissions at rates resembling those seen with more intensive chemotherapy followed by autologous hematopoietic stem cell transplantation, according to long-term results from a multicenter phase II trial.

Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years, said Julie E. Chang, MD, who reported the results of the study at the annual meeting of the American Society of Hematology. “VcR-CVAD is a moderate-intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of mantle cell lymphoma,” she emphasized.

Mantle cell lymphoma lacks a clear standard first-line therapy, noted Dr. Chang of the University of Wisconsin in Madison. “We hypothesized that the addition of bortezomib would improve the complete response rate, and maintenance rituximab would improve the remission duration,” she said.

To test that idea, she and her associates enrolled 30 adults with histologically confirmed mantle cell lymphoma who had received either no treatment or just one cycle of CHOP or CHOP-like chemotherapy.

Patients received six 21-day cycles of VcR-CVAD induction chemotherapy. This regimen consisted of rituximab (375 mg/m² IV) on day 1; bortezomib (1.3 mg/m² IV) on days 1 and 4; cyclophosphamide (300 mg/m² IV every 12 hours) on days 1 through 3; doxorubicin (50 mg/m² IV given as a continuous infusion) on days 1 and 2; vincristine (1 mg IV) on day 3; and dexamethasone (40 mg orally) on days 1 through 4.

Patients were permitted all supportive care measures, including prophylaxis for tumor lysis syndrome, transfusions, and antibiotics. Those with at least a partial response received rituximab consolidation (375 mg/m² IV per week for 4 weeks) followed by rituximab maintenance (375 mg/m² IV every 12 weeks for 5 years).

Median age was 61 years (range, 48-74 years), 80% of patients were male, all had advanced-stage disease, 60% were mantle cell lymphoma international prognostic index (MIPI) medium or high risk, and six had blastic morphology, the researchers noted.

Estimated 6-year rates of progression-free and overall survival were 53% (95% confidence interval, 38%-75%) and 70% (95% CI, 55%-84%), respectively. Neither age nor MIPI score significantly affected the chances of progression-free or overall survival, but there was a trend toward worse survival among MIPI high-risk patients.

The 10 deaths included 5 from progressive disease, 3 from complications after allogeneic transplant, and 2 from unrelated causes. No patients who remained progression free for 5 years subsequently relapsed, nor were there late toxicities related to treatment.

A recent phase III trial (N Engl J Med. 2015 Mar 5;372[10]:944-53) confirmed the benefits of adding bortezomib to standard immunochemotherapy in mantle cell lymphoma, Dr. Chang noted. “VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations,” she concluded.

Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.

hematologynews@frontlinemedcom.com

SAN DIEGO – For adults with mantle cell lymphoma, adding bortezomib to a modified hyper-CVAD (VcR-CVAD) regimen followed by rituximab maintenance induced durable remissions at rates resembling those seen with more intensive chemotherapy followed by autologous hematopoietic stem cell transplantation, according to long-term results from a multicenter phase II trial.

Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years, said Julie E. Chang, MD, who reported the results of the study at the annual meeting of the American Society of Hematology. “VcR-CVAD is a moderate-intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of mantle cell lymphoma,” she emphasized.

Mantle cell lymphoma lacks a clear standard first-line therapy, noted Dr. Chang of the University of Wisconsin in Madison. “We hypothesized that the addition of bortezomib would improve the complete response rate, and maintenance rituximab would improve the remission duration,” she said.

To test that idea, she and her associates enrolled 30 adults with histologically confirmed mantle cell lymphoma who had received either no treatment or just one cycle of CHOP or CHOP-like chemotherapy.

Patients received six 21-day cycles of VcR-CVAD induction chemotherapy. This regimen consisted of rituximab (375 mg/m² IV) on day 1; bortezomib (1.3 mg/m² IV) on days 1 and 4; cyclophosphamide (300 mg/m² IV every 12 hours) on days 1 through 3; doxorubicin (50 mg/m² IV given as a continuous infusion) on days 1 and 2; vincristine (1 mg IV) on day 3; and dexamethasone (40 mg orally) on days 1 through 4.

Patients were permitted all supportive care measures, including prophylaxis for tumor lysis syndrome, transfusions, and antibiotics. Those with at least a partial response received rituximab consolidation (375 mg/m² IV per week for 4 weeks) followed by rituximab maintenance (375 mg/m² IV every 12 weeks for 5 years).

Median age was 61 years (range, 48-74 years), 80% of patients were male, all had advanced-stage disease, 60% were mantle cell lymphoma international prognostic index (MIPI) medium or high risk, and six had blastic morphology, the researchers noted.

Estimated 6-year rates of progression-free and overall survival were 53% (95% confidence interval, 38%-75%) and 70% (95% CI, 55%-84%), respectively. Neither age nor MIPI score significantly affected the chances of progression-free or overall survival, but there was a trend toward worse survival among MIPI high-risk patients.

The 10 deaths included 5 from progressive disease, 3 from complications after allogeneic transplant, and 2 from unrelated causes. No patients who remained progression free for 5 years subsequently relapsed, nor were there late toxicities related to treatment.

A recent phase III trial (N Engl J Med. 2015 Mar 5;372[10]:944-53) confirmed the benefits of adding bortezomib to standard immunochemotherapy in mantle cell lymphoma, Dr. Chang noted. “VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations,” she concluded.

Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.

hematologynews@frontlinemedcom.com

SAN DIEGO – For adults with mantle cell lymphoma, adding bortezomib to a modified hyper-CVAD (VcR-CVAD) regimen followed by rituximab maintenance induced durable remissions at rates resembling those seen with more intensive chemotherapy followed by autologous hematopoietic stem cell transplantation, according to long-term results from a multicenter phase II trial.

Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years, said Julie E. Chang, MD, who reported the results of the study at the annual meeting of the American Society of Hematology. “VcR-CVAD is a moderate-intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of mantle cell lymphoma,” she emphasized.

Mantle cell lymphoma lacks a clear standard first-line therapy, noted Dr. Chang of the University of Wisconsin in Madison. “We hypothesized that the addition of bortezomib would improve the complete response rate, and maintenance rituximab would improve the remission duration,” she said.

To test that idea, she and her associates enrolled 30 adults with histologically confirmed mantle cell lymphoma who had received either no treatment or just one cycle of CHOP or CHOP-like chemotherapy.

Patients received six 21-day cycles of VcR-CVAD induction chemotherapy. This regimen consisted of rituximab (375 mg/m² IV) on day 1; bortezomib (1.3 mg/m² IV) on days 1 and 4; cyclophosphamide (300 mg/m² IV every 12 hours) on days 1 through 3; doxorubicin (50 mg/m² IV given as a continuous infusion) on days 1 and 2; vincristine (1 mg IV) on day 3; and dexamethasone (40 mg orally) on days 1 through 4.

Patients were permitted all supportive care measures, including prophylaxis for tumor lysis syndrome, transfusions, and antibiotics. Those with at least a partial response received rituximab consolidation (375 mg/m² IV per week for 4 weeks) followed by rituximab maintenance (375 mg/m² IV every 12 weeks for 5 years).

Median age was 61 years (range, 48-74 years), 80% of patients were male, all had advanced-stage disease, 60% were mantle cell lymphoma international prognostic index (MIPI) medium or high risk, and six had blastic morphology, the researchers noted.

Estimated 6-year rates of progression-free and overall survival were 53% (95% confidence interval, 38%-75%) and 70% (95% CI, 55%-84%), respectively. Neither age nor MIPI score significantly affected the chances of progression-free or overall survival, but there was a trend toward worse survival among MIPI high-risk patients.

The 10 deaths included 5 from progressive disease, 3 from complications after allogeneic transplant, and 2 from unrelated causes. No patients who remained progression free for 5 years subsequently relapsed, nor were there late toxicities related to treatment.

A recent phase III trial (N Engl J Med. 2015 Mar 5;372[10]:944-53) confirmed the benefits of adding bortezomib to standard immunochemotherapy in mantle cell lymphoma, Dr. Chang noted. “VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations,” she concluded.

Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.

hematologynews@frontlinemedcom.com

SAN DIEGO – Maintenance therapy every other month with rituximab significantly prolonged event-free and overall survival after autologous stem cell transplantation among younger patients with mantle cell lymphoma, based on results from a multicenter, randomized, phase 3 trial.

After a median follow-up period of 50 months, 79% of the rituximab maintenance arm remained alive and free of progression, relapse, and severe infection, compared with 61% of the no-maintenance arm (P = .001), said Steven Le Gouill, MD, PhD, at the 2016 meeting of the American Society of Hematology.

Courtesy Wikimedia Commons/Nephron/Creative Commons

SAN DIEGO – Maintenance therapy every other month with rituximab significantly prolonged event-free and overall survival after autologous stem cell transplantation among younger patients with mantle cell lymphoma, based on results from a multicenter, randomized, phase 3 trial.

After a median follow-up period of 50 months, 79% of the rituximab maintenance arm remained alive and free of progression, relapse, and severe infection, compared with 61% of the no-maintenance arm (P = .001), said Steven Le Gouill, MD, PhD, at the 2016 meeting of the American Society of Hematology.

Courtesy Wikimedia Commons/Nephron/Creative Commons

SAN DIEGO – Maintenance therapy every other month with rituximab significantly prolonged event-free and overall survival after autologous stem cell transplantation among younger patients with mantle cell lymphoma, based on results from a multicenter, randomized, phase 3 trial.

After a median follow-up period of 50 months, 79% of the rituximab maintenance arm remained alive and free of progression, relapse, and severe infection, compared with 61% of the no-maintenance arm (P = .001), said Steven Le Gouill, MD, PhD, at the 2016 meeting of the American Society of Hematology.

Courtesy Wikimedia Commons/Nephron/Creative Commons

SAN DIEGO – Aggressive, refractory non-Hodgkin lymphomas responded to anti-CD19 chimeric antigen receptor T cells in ZUMA-1, the first multicenter trial of the cellular immunotherapy, based on early data reported at the annual meeting of the American Society of Hematology.

In an interim analysis of 51 patients with diffuse large B-cell lymphomas, 47% had complete remissions and 29% had partial remissions. But the remission rate declined to 33% complete remissions and 6% partial remissions after 3 months.

There have really been no new treatments in the last 20 years for patients with non-Hodgkin lymphoma that does not respond to chemotherapy or recurs after autologous stem cell transplant. With median overall survival of 6 months, and about 8% complete remissions with existing therapies, CAR T cells might be a solution for these patients, said ZUMA-1 investigator Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In our video interview at the meeting, Dr. Neelapu discussed initial results in the real-world setting of 22 participating centers, most of which had no previous experience with CAR T-cell therapy. With an efficient production and logistics plan, 91% of 110 patients were able to receive the investigational product, known as KTE-C19.

ZUMA-1 is funded by Kite, which makes KTE-C19, and the Leukemia & Lymphoma Society Therapy Acceleration Program. Dr. Neelapu receives research support from and is an advisor to Kite.

mdales@frontlinemedcom.com

On Twitter @maryjodales

SAN DIEGO – Aggressive, refractory non-Hodgkin lymphomas responded to anti-CD19 chimeric antigen receptor T cells in ZUMA-1, the first multicenter trial of the cellular immunotherapy, based on early data reported at the annual meeting of the American Society of Hematology.

In an interim analysis of 51 patients with diffuse large B-cell lymphomas, 47% had complete remissions and 29% had partial remissions. But the remission rate declined to 33% complete remissions and 6% partial remissions after 3 months.

There have really been no new treatments in the last 20 years for patients with non-Hodgkin lymphoma that does not respond to chemotherapy or recurs after autologous stem cell transplant. With median overall survival of 6 months, and about 8% complete remissions with existing therapies, CAR T cells might be a solution for these patients, said ZUMA-1 investigator Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In our video interview at the meeting, Dr. Neelapu discussed initial results in the real-world setting of 22 participating centers, most of which had no previous experience with CAR T-cell therapy. With an efficient production and logistics plan, 91% of 110 patients were able to receive the investigational product, known as KTE-C19.

ZUMA-1 is funded by Kite, which makes KTE-C19, and the Leukemia & Lymphoma Society Therapy Acceleration Program. Dr. Neelapu receives research support from and is an advisor to Kite.

mdales@frontlinemedcom.com

On Twitter @maryjodales

SAN DIEGO – Aggressive, refractory non-Hodgkin lymphomas responded to anti-CD19 chimeric antigen receptor T cells in ZUMA-1, the first multicenter trial of the cellular immunotherapy, based on early data reported at the annual meeting of the American Society of Hematology.

In an interim analysis of 51 patients with diffuse large B-cell lymphomas, 47% had complete remissions and 29% had partial remissions. But the remission rate declined to 33% complete remissions and 6% partial remissions after 3 months.

There have really been no new treatments in the last 20 years for patients with non-Hodgkin lymphoma that does not respond to chemotherapy or recurs after autologous stem cell transplant. With median overall survival of 6 months, and about 8% complete remissions with existing therapies, CAR T cells might be a solution for these patients, said ZUMA-1 investigator Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In our video interview at the meeting, Dr. Neelapu discussed initial results in the real-world setting of 22 participating centers, most of which had no previous experience with CAR T-cell therapy. With an efficient production and logistics plan, 91% of 110 patients were able to receive the investigational product, known as KTE-C19.

ZUMA-1 is funded by Kite, which makes KTE-C19, and the Leukemia & Lymphoma Society Therapy Acceleration Program. Dr. Neelapu receives research support from and is an advisor to Kite.

mdales@frontlinemedcom.com

On Twitter @maryjodales

SAN DIEGO – A chemotherapy-free induction regimen of ibrutinib and rituximab was well tolerated and achieved an overall response rate of 100% among patients with newly diagnosed mantle cell lymphoma (MCL), according to results of a small single-center phase II trial.

A total of 72% of patients had complete responses to induction, while 28% had partial responses, and 100% had complete responses to consolidation, reported Michael Wang, MD, at the annual meeting of the American Society of Hematology. The findings highlight a “window of opportunity” to effectively treat de novo MCL in young, fit patients while potentially sparing them from repeated cycles of intensive chemoimmunotherapy, the investigators noted.

Established treatments for MCL include eight cycles of rituximab–hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab–methotrexate–Ara-C (cytarabine). Median overall survival with this regimen exceeds 10 years, but during that decade, more than 6% of patients will develop myeloid neoplasms related to treatment, noted Dr. Wang of the University of Texas MD Anderson Cancer Center in Houston.

For the study, patients up to 65 years old with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib (560 mg), plus rituximab (375 mg/m²) administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD, alternating every 28 days with rituximab plus high-dose methotrexate–Ara-C. Complete responders to induction received four cycles of chemoimmunotherapy, while progressors and partial responders received chemoimmunotherapy for two cycles beyond the point of complete remission.

Among 36 evaluable patients, 28% had a partial response and the rest had complete responses to induction. Moreover, all 19 patients who completed consolidation had a complete response. During induction, the most common toxicities were fatigue, diarrhea, rash, and myalgia, nearly all of which were mild or moderate in severity. During consolidation, two patients developed severe neutropenia, one patient developed severe febrile neutropenia, and one developed a severe increase in liver enzymes. There were no treatment-related deaths.

“The toxicity after intensive immune-chemotherapy in shortened cycles [is] much improved compared to historical controls, but longer follow-up is needed,” the researchers wrote. “This unprecedented efficacy and safety may provide a window of opportunity for less chemoimmunotherapy needed for consolidation.”

Dr. Wang disclosed ties to Janssen, Onyx, BeiGene, Kite Pharma, Asana Biosciences, Juno Therapeutics, Acerta Pharma, and Celgene.

SAN DIEGO – A chemotherapy-free induction regimen of ibrutinib and rituximab was well tolerated and achieved an overall response rate of 100% among patients with newly diagnosed mantle cell lymphoma (MCL), according to results of a small single-center phase II trial.

A total of 72% of patients had complete responses to induction, while 28% had partial responses, and 100% had complete responses to consolidation, reported Michael Wang, MD, at the annual meeting of the American Society of Hematology. The findings highlight a “window of opportunity” to effectively treat de novo MCL in young, fit patients while potentially sparing them from repeated cycles of intensive chemoimmunotherapy, the investigators noted.

Established treatments for MCL include eight cycles of rituximab–hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab–methotrexate–Ara-C (cytarabine). Median overall survival with this regimen exceeds 10 years, but during that decade, more than 6% of patients will develop myeloid neoplasms related to treatment, noted Dr. Wang of the University of Texas MD Anderson Cancer Center in Houston.

For the study, patients up to 65 years old with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib (560 mg), plus rituximab (375 mg/m²) administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD, alternating every 28 days with rituximab plus high-dose methotrexate–Ara-C. Complete responders to induction received four cycles of chemoimmunotherapy, while progressors and partial responders received chemoimmunotherapy for two cycles beyond the point of complete remission.

Among 36 evaluable patients, 28% had a partial response and the rest had complete responses to induction. Moreover, all 19 patients who completed consolidation had a complete response. During induction, the most common toxicities were fatigue, diarrhea, rash, and myalgia, nearly all of which were mild or moderate in severity. During consolidation, two patients developed severe neutropenia, one patient developed severe febrile neutropenia, and one developed a severe increase in liver enzymes. There were no treatment-related deaths.

“The toxicity after intensive immune-chemotherapy in shortened cycles [is] much improved compared to historical controls, but longer follow-up is needed,” the researchers wrote. “This unprecedented efficacy and safety may provide a window of opportunity for less chemoimmunotherapy needed for consolidation.”

Dr. Wang disclosed ties to Janssen, Onyx, BeiGene, Kite Pharma, Asana Biosciences, Juno Therapeutics, Acerta Pharma, and Celgene.

SAN DIEGO – A chemotherapy-free induction regimen of ibrutinib and rituximab was well tolerated and achieved an overall response rate of 100% among patients with newly diagnosed mantle cell lymphoma (MCL), according to results of a small single-center phase II trial.

A total of 72% of patients had complete responses to induction, while 28% had partial responses, and 100% had complete responses to consolidation, reported Michael Wang, MD, at the annual meeting of the American Society of Hematology. The findings highlight a “window of opportunity” to effectively treat de novo MCL in young, fit patients while potentially sparing them from repeated cycles of intensive chemoimmunotherapy, the investigators noted.

Established treatments for MCL include eight cycles of rituximab–hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab–methotrexate–Ara-C (cytarabine). Median overall survival with this regimen exceeds 10 years, but during that decade, more than 6% of patients will develop myeloid neoplasms related to treatment, noted Dr. Wang of the University of Texas MD Anderson Cancer Center in Houston.

For the study, patients up to 65 years old with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib (560 mg), plus rituximab (375 mg/m²) administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD, alternating every 28 days with rituximab plus high-dose methotrexate–Ara-C. Complete responders to induction received four cycles of chemoimmunotherapy, while progressors and partial responders received chemoimmunotherapy for two cycles beyond the point of complete remission.

Among 36 evaluable patients, 28% had a partial response and the rest had complete responses to induction. Moreover, all 19 patients who completed consolidation had a complete response. During induction, the most common toxicities were fatigue, diarrhea, rash, and myalgia, nearly all of which were mild or moderate in severity. During consolidation, two patients developed severe neutropenia, one patient developed severe febrile neutropenia, and one developed a severe increase in liver enzymes. There were no treatment-related deaths.

“The toxicity after intensive immune-chemotherapy in shortened cycles [is] much improved compared to historical controls, but longer follow-up is needed,” the researchers wrote. “This unprecedented efficacy and safety may provide a window of opportunity for less chemoimmunotherapy needed for consolidation.”

Dr. Wang disclosed ties to Janssen, Onyx, BeiGene, Kite Pharma, Asana Biosciences, Juno Therapeutics, Acerta Pharma, and Celgene.

SAN DIEGO – Rituximab can at least temporarily vanquish minimal residual disease (MRD) in mantle cell lymphoma (MCL) patients who relapse after induction therapy and autologous stem cell transplantation (ASCT), researchers reported at the annual meeting of the American Society of Hematology.

Of 58 patients whose MCL relapsed after induction therapy and ASCT, 82% converted back to an MRD-negative state after receiving 4 weekly doses of rituximab (375 mg/m²), Arne Kolstad, MD, PhD, and his associates. The data “strongly suggest that preemptive rituximab treatment delayed clinical relapse in MCL,” they wrote in their abstract. They recommended molecular and clinical monitoring after ASCT, not only “as an alternative to maintenance therapy for all MCL patients” but to identify MRD-positive candidates for clinical trials.

The study was an analysis of the Nordic Lymphoma Group phase II MCL2 and MCL3 trials (NTC 00514475), in which patients received six alternating cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and R-Ara-C (rituximab-cytarabine). followed by high-dose ASCT. In MCL3, responders who fell short of complete remission also received intensification with yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) 1 week before treatment with BEAM/C (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide). Patients were evaluated 2-3 months after completing ASCT, and then every 6 months for 5 years or until relapse. Survivors were followed for a median of 8.5 years, noted Dr. Kolstad, who is with Oslo University Hospital in Norway.

Among 183 patients who underwent polymerase chain reaction–based testing for markers of MRD, median time to molecular relapse was 55 months. However, the relapse-free survival curve did not plateau – patients in all risk groups continued to relapse 5-10 years after undergoing ASCT, the researchers said. “Hence, it is fair to consider MCL as a chronic incurable lymphoma entity, and novel approaches will be necessary to change the natural course of this disease,” they wrote.

After controlling for potential confounders, significant predictors of molecular relapse included high MCL international prognostic index at diagnosis (hazard ratio, 1.9; 95% confidence interval 1.4-2.7; P = .0001) and detection of MRD before patients underwent ASCT (HR, 2.5; 95% CI, 1.5-4.1; P = .0005). Minimal residual disease predicted clinical relapse and shorter survival (P less than .001 for both associations). In contrast, the 86 patients who remained in continuous molecular remission had a 76% chance of having at least a 10-year clinical remission, the investigators said.

Minimal residual disease was assessed by testing bone marrow and blood samples with combined standard nested and quantitative real-time polymerase chain reaction (PCR) for Bcl-1 or IgH rearrangement. They defined molecular relapse as conversion from a negative to a positive result on standard nested PCR, or, for patients who were MRD positive after ASCT, as a more than fivefold rise in real-time quantitative PCR levels in two consecutive bone marrow samples.

Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.

SAN DIEGO – Rituximab can at least temporarily vanquish minimal residual disease (MRD) in mantle cell lymphoma (MCL) patients who relapse after induction therapy and autologous stem cell transplantation (ASCT), researchers reported at the annual meeting of the American Society of Hematology.

Of 58 patients whose MCL relapsed after induction therapy and ASCT, 82% converted back to an MRD-negative state after receiving 4 weekly doses of rituximab (375 mg/m²), Arne Kolstad, MD, PhD, and his associates. The data “strongly suggest that preemptive rituximab treatment delayed clinical relapse in MCL,” they wrote in their abstract. They recommended molecular and clinical monitoring after ASCT, not only “as an alternative to maintenance therapy for all MCL patients” but to identify MRD-positive candidates for clinical trials.

The study was an analysis of the Nordic Lymphoma Group phase II MCL2 and MCL3 trials (NTC 00514475), in which patients received six alternating cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and R-Ara-C (rituximab-cytarabine). followed by high-dose ASCT. In MCL3, responders who fell short of complete remission also received intensification with yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) 1 week before treatment with BEAM/C (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide). Patients were evaluated 2-3 months after completing ASCT, and then every 6 months for 5 years or until relapse. Survivors were followed for a median of 8.5 years, noted Dr. Kolstad, who is with Oslo University Hospital in Norway.

Among 183 patients who underwent polymerase chain reaction–based testing for markers of MRD, median time to molecular relapse was 55 months. However, the relapse-free survival curve did not plateau – patients in all risk groups continued to relapse 5-10 years after undergoing ASCT, the researchers said. “Hence, it is fair to consider MCL as a chronic incurable lymphoma entity, and novel approaches will be necessary to change the natural course of this disease,” they wrote.

After controlling for potential confounders, significant predictors of molecular relapse included high MCL international prognostic index at diagnosis (hazard ratio, 1.9; 95% confidence interval 1.4-2.7; P = .0001) and detection of MRD before patients underwent ASCT (HR, 2.5; 95% CI, 1.5-4.1; P = .0005). Minimal residual disease predicted clinical relapse and shorter survival (P less than .001 for both associations). In contrast, the 86 patients who remained in continuous molecular remission had a 76% chance of having at least a 10-year clinical remission, the investigators said.

Minimal residual disease was assessed by testing bone marrow and blood samples with combined standard nested and quantitative real-time polymerase chain reaction (PCR) for Bcl-1 or IgH rearrangement. They defined molecular relapse as conversion from a negative to a positive result on standard nested PCR, or, for patients who were MRD positive after ASCT, as a more than fivefold rise in real-time quantitative PCR levels in two consecutive bone marrow samples.

Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.

SAN DIEGO – Rituximab can at least temporarily vanquish minimal residual disease (MRD) in mantle cell lymphoma (MCL) patients who relapse after induction therapy and autologous stem cell transplantation (ASCT), researchers reported at the annual meeting of the American Society of Hematology.

Of 58 patients whose MCL relapsed after induction therapy and ASCT, 82% converted back to an MRD-negative state after receiving 4 weekly doses of rituximab (375 mg/m²), Arne Kolstad, MD, PhD, and his associates. The data “strongly suggest that preemptive rituximab treatment delayed clinical relapse in MCL,” they wrote in their abstract. They recommended molecular and clinical monitoring after ASCT, not only “as an alternative to maintenance therapy for all MCL patients” but to identify MRD-positive candidates for clinical trials.

The study was an analysis of the Nordic Lymphoma Group phase II MCL2 and MCL3 trials (NTC 00514475), in which patients received six alternating cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and R-Ara-C (rituximab-cytarabine). followed by high-dose ASCT. In MCL3, responders who fell short of complete remission also received intensification with yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) 1 week before treatment with BEAM/C (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide). Patients were evaluated 2-3 months after completing ASCT, and then every 6 months for 5 years or until relapse. Survivors were followed for a median of 8.5 years, noted Dr. Kolstad, who is with Oslo University Hospital in Norway.

Among 183 patients who underwent polymerase chain reaction–based testing for markers of MRD, median time to molecular relapse was 55 months. However, the relapse-free survival curve did not plateau – patients in all risk groups continued to relapse 5-10 years after undergoing ASCT, the researchers said. “Hence, it is fair to consider MCL as a chronic incurable lymphoma entity, and novel approaches will be necessary to change the natural course of this disease,” they wrote.

After controlling for potential confounders, significant predictors of molecular relapse included high MCL international prognostic index at diagnosis (hazard ratio, 1.9; 95% confidence interval 1.4-2.7; P = .0001) and detection of MRD before patients underwent ASCT (HR, 2.5; 95% CI, 1.5-4.1; P = .0005). Minimal residual disease predicted clinical relapse and shorter survival (P less than .001 for both associations). In contrast, the 86 patients who remained in continuous molecular remission had a 76% chance of having at least a 10-year clinical remission, the investigators said.

Minimal residual disease was assessed by testing bone marrow and blood samples with combined standard nested and quantitative real-time polymerase chain reaction (PCR) for Bcl-1 or IgH rearrangement. They defined molecular relapse as conversion from a negative to a positive result on standard nested PCR, or, for patients who were MRD positive after ASCT, as a more than fivefold rise in real-time quantitative PCR levels in two consecutive bone marrow samples.

Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

Progression-free survival was significantly better when patients with relapsed or refractory mantle-cell lymphoma were treated with oral ibrutinib than with intravenous temsirolimus, based on results from 280 patients in an international, randomized, open-label phase III trial.

Study subjects had undergone one or more previous rituximab-containing chemotherapy regimens to receive intravenous temsirolimus or oral ibrutinib at a daily dose of 560 mg.

Compared with temsirolimus, ibrutinib resulted in a 57% reduction in the risk of disease progression or death at a median follow-up of 20 months. Median progression-free survival – the trial’s primary endpoint – was 14.6 months for the ibrutinib group and 6.2 months for the temsirolimus group.

Ibrutinib was also better tolerated, with 68% of patients having grade 3 or higher treatment-emergent adverse events as compared to 87% of patients in the temsirolimus group, despite a median 4-fold longer treatment duration for the ibrutinib group than the temsirolimus group. Additionally, 6% of patients discontinued ibrutinib because of adverse events versus 26% in the temsirolimus group, reported Dr. Martin Dreyling of Klinikum der Universität in Munich, Germany, and his associates.

Courtesy Wikimedia Commons/Nephron/Creative Commons

Based on results of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire, ibrutinib was associated with greater and more rapid improvements, and also with less worsening in lymphoma symptoms, as measured by the lymphoma subscale of the FACT-Lym (Lancet. 2016;387:770-78).

Ibrutinib, a first-in-class oral inhibitor of Bruton’s tyrosine kinase, is approved in the United States and the European Union at a dose of 560 mg per day for patients with mantle cell lymphoma who have received at least one previous line of therapy.

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is approved in the European Union for relapsed or refractory mantle-cell lymphoma, but does not have FDA approval for this indication.

The study, funded by Janssen, is ongoing. Future research, the investigators say, should examine ibrutinib-based combination approaches for patients with relapsed or refractory mantle-cell lymphoma and in front-line therapy.

Dr. Dreyling reported grants and personal fees from Janssen and Pfizer outside of the study. Several other authors reported grants from Janssen during the study and financial ties to the company.

Progression-free survival was significantly better when patients with relapsed or refractory mantle-cell lymphoma were treated with oral ibrutinib than with intravenous temsirolimus, based on results from 280 patients in an international, randomized, open-label phase III trial.

Study subjects had undergone one or more previous rituximab-containing chemotherapy regimens to receive intravenous temsirolimus or oral ibrutinib at a daily dose of 560 mg.

Compared with temsirolimus, ibrutinib resulted in a 57% reduction in the risk of disease progression or death at a median follow-up of 20 months. Median progression-free survival – the trial’s primary endpoint – was 14.6 months for the ibrutinib group and 6.2 months for the temsirolimus group.

Ibrutinib was also better tolerated, with 68% of patients having grade 3 or higher treatment-emergent adverse events as compared to 87% of patients in the temsirolimus group, despite a median 4-fold longer treatment duration for the ibrutinib group than the temsirolimus group. Additionally, 6% of patients discontinued ibrutinib because of adverse events versus 26% in the temsirolimus group, reported Dr. Martin Dreyling of Klinikum der Universität in Munich, Germany, and his associates.

Courtesy Wikimedia Commons/Nephron/Creative Commons

Based on results of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire, ibrutinib was associated with greater and more rapid improvements, and also with less worsening in lymphoma symptoms, as measured by the lymphoma subscale of the FACT-Lym (Lancet. 2016;387:770-78).

Ibrutinib, a first-in-class oral inhibitor of Bruton’s tyrosine kinase, is approved in the United States and the European Union at a dose of 560 mg per day for patients with mantle cell lymphoma who have received at least one previous line of therapy.

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is approved in the European Union for relapsed or refractory mantle-cell lymphoma, but does not have FDA approval for this indication.

The study, funded by Janssen, is ongoing. Future research, the investigators say, should examine ibrutinib-based combination approaches for patients with relapsed or refractory mantle-cell lymphoma and in front-line therapy.

Dr. Dreyling reported grants and personal fees from Janssen and Pfizer outside of the study. Several other authors reported grants from Janssen during the study and financial ties to the company.

Progression-free survival was significantly better when patients with relapsed or refractory mantle-cell lymphoma were treated with oral ibrutinib than with intravenous temsirolimus, based on results from 280 patients in an international, randomized, open-label phase III trial.

Study subjects had undergone one or more previous rituximab-containing chemotherapy regimens to receive intravenous temsirolimus or oral ibrutinib at a daily dose of 560 mg.

Compared with temsirolimus, ibrutinib resulted in a 57% reduction in the risk of disease progression or death at a median follow-up of 20 months. Median progression-free survival – the trial’s primary endpoint – was 14.6 months for the ibrutinib group and 6.2 months for the temsirolimus group.

Ibrutinib was also better tolerated, with 68% of patients having grade 3 or higher treatment-emergent adverse events as compared to 87% of patients in the temsirolimus group, despite a median 4-fold longer treatment duration for the ibrutinib group than the temsirolimus group. Additionally, 6% of patients discontinued ibrutinib because of adverse events versus 26% in the temsirolimus group, reported Dr. Martin Dreyling of Klinikum der Universität in Munich, Germany, and his associates.

Courtesy Wikimedia Commons/Nephron/Creative Commons

Based on results of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire, ibrutinib was associated with greater and more rapid improvements, and also with less worsening in lymphoma symptoms, as measured by the lymphoma subscale of the FACT-Lym (Lancet. 2016;387:770-78).

Ibrutinib, a first-in-class oral inhibitor of Bruton’s tyrosine kinase, is approved in the United States and the European Union at a dose of 560 mg per day for patients with mantle cell lymphoma who have received at least one previous line of therapy.

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is approved in the European Union for relapsed or refractory mantle-cell lymphoma, but does not have FDA approval for this indication.

The study, funded by Janssen, is ongoing. Future research, the investigators say, should examine ibrutinib-based combination approaches for patients with relapsed or refractory mantle-cell lymphoma and in front-line therapy.

Dr. Dreyling reported grants and personal fees from Janssen and Pfizer outside of the study. Several other authors reported grants from Janssen during the study and financial ties to the company.

Evaluating routinely available histopathological prognostic features from more than 500 MCL patients in prospective trials, researchers found that the Ki-67 index is a better prognostic factor than are cytology and growth pattern in mantle-cell lymphoma (MCL). In addition, the combination of the Ki-67 index with the Mantle Cell Lymphoma International Prognostic Index [MIPI] defined four prognostic groups with better discrimination than did MIPI or the two-category biologic MIPI (MIPI-b) alone.

Higher Ki-67 index was associated with poorer overall survival (OS) (hazard ratio [HR], 1.24 per 10% increase; P less than .001) and progression-free survival (PFS) (HR, 1.17; P less than .001). Consistent with an earlier, population-based study, results showed prognostic value for a 30% cutoff of the Ki-67 index. Quantitative levels below 30% provided no additional prognostic information.

“The Ki-67 index remains the only routinely available independent prognostic factor in addition to MIPI. In contrast to cytology and growth pattern, the Ki-67 evaluation has been standardized for routine application,” wrote Dr. Eva Hoster of University Hospital Munich, and colleagues. “The modified combination of Ki-67 index and MIPI integrates the most important clinical and biologic markers currently available in clinical routine and was shown to allow a simple and powerful risk stratification superior to MIPI and MIPI-b in our evaluation,” they added (J Clin Oncol. 2016 Feb. 29. doi: 10.1200/jco.63.8387).

Blastoid cytology was associated with inferior 5-year OS compared with nonblastoid cytology (35% vs. 68%; HR, 2.35; P less than .001) and PFS (29% vs. 44%; HR, 1.58; P = .007), but the effect was largely accounted for by a generally higher Ki-67 index in blastoid MCL. Diffuse growth pattern was associated slightly worse 5-year OS (61% vs. 72%; HR, 1.38; P = .048) and PFS (38% vs. 49%; HR, 1.25; P = .087), but the effect was largely explained by MIPI score.

Combining dichotomized Ki-67 (above or below 30%) with MIPI risk groups defined four prognostic groups by the sum of weights (total 0 to 3): Ki-67 of 30% or more (weight 1), intermediate-risk MIPI (weight 1), and high-risk MIPI (weight 2). The 5-year OS rates for the four groups ranged from 17% to 85%, with OS hazard ratios greater than 2 between adjacent risk groups.

The study analyzed pooled data from two randomized trials initiated in 2004 by the European Mantle Cell Lymphoma Network, MCL Younger and MCL Elderly. In total, 508 patients of median age 62 years were included. The proportion of low-risk, intermediate-risk, and high-risk MIPI were 41%, 35%, and 24%, respectively.

Research was supported in part by Roche. Dr. Hoster reported receiving funding from Roche Pharma AG and Celgene. Several of her coauthors reported ties to industry.

Evaluating routinely available histopathological prognostic features from more than 500 MCL patients in prospective trials, researchers found that the Ki-67 index is a better prognostic factor than are cytology and growth pattern in mantle-cell lymphoma (MCL). In addition, the combination of the Ki-67 index with the Mantle Cell Lymphoma International Prognostic Index [MIPI] defined four prognostic groups with better discrimination than did MIPI or the two-category biologic MIPI (MIPI-b) alone.

Higher Ki-67 index was associated with poorer overall survival (OS) (hazard ratio [HR], 1.24 per 10% increase; P less than .001) and progression-free survival (PFS) (HR, 1.17; P less than .001). Consistent with an earlier, population-based study, results showed prognostic value for a 30% cutoff of the Ki-67 index. Quantitative levels below 30% provided no additional prognostic information.

“The Ki-67 index remains the only routinely available independent prognostic factor in addition to MIPI. In contrast to cytology and growth pattern, the Ki-67 evaluation has been standardized for routine application,” wrote Dr. Eva Hoster of University Hospital Munich, and colleagues. “The modified combination of Ki-67 index and MIPI integrates the most important clinical and biologic markers currently available in clinical routine and was shown to allow a simple and powerful risk stratification superior to MIPI and MIPI-b in our evaluation,” they added (J Clin Oncol. 2016 Feb. 29. doi: 10.1200/jco.63.8387).

Blastoid cytology was associated with inferior 5-year OS compared with nonblastoid cytology (35% vs. 68%; HR, 2.35; P less than .001) and PFS (29% vs. 44%; HR, 1.58; P = .007), but the effect was largely accounted for by a generally higher Ki-67 index in blastoid MCL. Diffuse growth pattern was associated slightly worse 5-year OS (61% vs. 72%; HR, 1.38; P = .048) and PFS (38% vs. 49%; HR, 1.25; P = .087), but the effect was largely explained by MIPI score.

Combining dichotomized Ki-67 (above or below 30%) with MIPI risk groups defined four prognostic groups by the sum of weights (total 0 to 3): Ki-67 of 30% or more (weight 1), intermediate-risk MIPI (weight 1), and high-risk MIPI (weight 2). The 5-year OS rates for the four groups ranged from 17% to 85%, with OS hazard ratios greater than 2 between adjacent risk groups.

The study analyzed pooled data from two randomized trials initiated in 2004 by the European Mantle Cell Lymphoma Network, MCL Younger and MCL Elderly. In total, 508 patients of median age 62 years were included. The proportion of low-risk, intermediate-risk, and high-risk MIPI were 41%, 35%, and 24%, respectively.

Research was supported in part by Roche. Dr. Hoster reported receiving funding from Roche Pharma AG and Celgene. Several of her coauthors reported ties to industry.

Evaluating routinely available histopathological prognostic features from more than 500 MCL patients in prospective trials, researchers found that the Ki-67 index is a better prognostic factor than are cytology and growth pattern in mantle-cell lymphoma (MCL). In addition, the combination of the Ki-67 index with the Mantle Cell Lymphoma International Prognostic Index [MIPI] defined four prognostic groups with better discrimination than did MIPI or the two-category biologic MIPI (MIPI-b) alone.

Higher Ki-67 index was associated with poorer overall survival (OS) (hazard ratio [HR], 1.24 per 10% increase; P less than .001) and progression-free survival (PFS) (HR, 1.17; P less than .001). Consistent with an earlier, population-based study, results showed prognostic value for a 30% cutoff of the Ki-67 index. Quantitative levels below 30% provided no additional prognostic information.

“The Ki-67 index remains the only routinely available independent prognostic factor in addition to MIPI. In contrast to cytology and growth pattern, the Ki-67 evaluation has been standardized for routine application,” wrote Dr. Eva Hoster of University Hospital Munich, and colleagues. “The modified combination of Ki-67 index and MIPI integrates the most important clinical and biologic markers currently available in clinical routine and was shown to allow a simple and powerful risk stratification superior to MIPI and MIPI-b in our evaluation,” they added (J Clin Oncol. 2016 Feb. 29. doi: 10.1200/jco.63.8387).

Blastoid cytology was associated with inferior 5-year OS compared with nonblastoid cytology (35% vs. 68%; HR, 2.35; P less than .001) and PFS (29% vs. 44%; HR, 1.58; P = .007), but the effect was largely accounted for by a generally higher Ki-67 index in blastoid MCL. Diffuse growth pattern was associated slightly worse 5-year OS (61% vs. 72%; HR, 1.38; P = .048) and PFS (38% vs. 49%; HR, 1.25; P = .087), but the effect was largely explained by MIPI score.

Combining dichotomized Ki-67 (above or below 30%) with MIPI risk groups defined four prognostic groups by the sum of weights (total 0 to 3): Ki-67 of 30% or more (weight 1), intermediate-risk MIPI (weight 1), and high-risk MIPI (weight 2). The 5-year OS rates for the four groups ranged from 17% to 85%, with OS hazard ratios greater than 2 between adjacent risk groups.

The study analyzed pooled data from two randomized trials initiated in 2004 by the European Mantle Cell Lymphoma Network, MCL Younger and MCL Elderly. In total, 508 patients of median age 62 years were included. The proportion of low-risk, intermediate-risk, and high-risk MIPI were 41%, 35%, and 24%, respectively.

Research was supported in part by Roche. Dr. Hoster reported receiving funding from Roche Pharma AG and Celgene. Several of her coauthors reported ties to industry.