Swapping bortezomib for vincristine improves PFS in mantle cell lymphoma

CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.

In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.

The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.

The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.

R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.

Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.

The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m² was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m² was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.

A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.

At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).

Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.

However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).

Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).

Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).

Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.

Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.

Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.

The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."

Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.

The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.

CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.

In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.

The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.

The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.

R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.

Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.

The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m² was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m² was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.

A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.

At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).

Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.

However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).

Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).

Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).

Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.

Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.

Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.

The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."

Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.

The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.

CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.

In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.

The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.

The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.

R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.

Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.

The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m² was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m² was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.

A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.

At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).

Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.

However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).

Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).

Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).

Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.

Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.

Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.

The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."

Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.

The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.