Bortezomib Works First-line in Mantle Cell Lymphoma

Zosia Chustecka

March 04, 2015

Bortezomib (Velcade, Millennium Pharmaceuticals) recently had its approval extended to cover use in patients with newly diagnosed mantle cell lymphoma on the basis of data from a phase 3 clinical trial. The results from that trial have now been published in the March 5 issue of the New England of Journal of Medicine.

Bortezomib, a protease inhibitor originally developed and approved for use in multiple myeloma, was previously also approved for use in relapsed mantle cell lymphoma.

The new indication of first-line use in mantle cell lymphoma is supported by the results of the just-published study, which show that the addition of bortezomib to a combination regimen improved efficacy, nearly doubling progression-free survival, although it also increased hematologic toxicity.

"A significant prolongation of progression-free survival and improvements in secondary efficacy end-points were observed," note the authors, led by Tadeusz Robak, MD, from the Medical University of Lodz, Poland, with senior author Franco Cavalli, MD, from the Oncology Institute of Southern Switzerland in Bellinzona.

Mantel cell lymphoma is an incurable and aggressive hematological cancer with a poor prognosis (median survival, 4 - 5 years), the authors comment. It makes up about 5% to 6% of all non-Hodgkin's lymphomas, with about 5000 cases diagnosed per year in the United States.

For previously untreated patients who are ineligible or not considered for intensive chemotherapy and stem cell transplantation, the standard of care is the combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), the authors comment. This can produce complete responses in up to 48% of patients, but progression-free survival is limited (median, 16.6 months).

In the phase 3 trial that was used as the basis of approval for first-line use, the investigators compared the standard R-CHOP regimen with a similar one in which vincristine was replaced by bortezomib. This new regimen therefore contained bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone and was known as VR-CAP.

The trial involved 487 newly diagnosed patients who were randomly assigned to receive one of the two combination regimens, both administered in six 21-day cycles. Most patients received the planned doses of each drug, and treatment exposure was similar in the two groups, the authors note.

Median follow-up was 40 months, at which point 61% of the trial participants had died.

Median progression-free survival was 14.4 months with R-CHOP compared with 24.7 months with VR-CAP (hazard ratio, 0.63; P < .001).

The investigator assessment figures are slighter better, with 16.1 months with R-CHOP vs 30.7 months with VR-CAP (hazard ratio, 0.51; P < .001).

There was also an improvement in several secondary endpoints, including:

  • complete response rates (42% with R-CHOP vs 53% with VR-CAP),

  • median time to progression (16.1 vs 30.5 months),

  • median time to next antilymphoma therapy (24.8 vs 44.5 months), and

  • median treatment-free interval (20.5 vs 40.6 months).

Overall survival was not mature at the time of the report, the authors note, but there was a difference in 4-year survival (54% with R-CHOP vs 64% with VR-CAP).

Adverse events of any grade and discontinuations resulting from adverse events were similar across the two treatment groups, but patients in the VR-CAP group had higher rates of serious adverse events.

Hematologic toxic events were the most common adverse events. Patients taking the combination containing bortezomib had higher rates of thrombocytopenia and platelet transfusions (3% with R-CHOP vs 23% with VR-CAP). In the VR-CAP group, nearly all patients (48 of 54; 89%) received platelet transfusions during days 10 to 144 of the treatment cycles. Patients in the VR-CAP group also had higher rates of neutropenia and infections.

Rates of peripheral neuropathy were similar in the two groups (29% vs 30%), but there was a high rate of grade 3 or more events seen with the bortezomib-treated patients (4% with R-CHOP vs 8% with VR-CAP).

The authors note that bortezomib was administered intravenously in this study, but subcutaneous administration may offer a reduced risk for peripheral neuropathy and also is more convenient for the patient.

Dr Robak and colleagues also note that at the time their study began, the recommendation for rituximab maintenance therapy had not yet been established, but it has since been introduced. "The use of VR-CAP with rituximab maintenance therapy could further prolong progression-free survival and potentially extend overall survival," they conclude.

The study was funded by Janssen and Millennium, the manufacturer of bortezomib. Dr Cavalli reports receiving nonfinancial support from Janssen during the study, plus a grant from Roche and fees from Gilead and Novartis. Dr Robak reports receiving grants from Janssen, Roche, Celgene and Pharmacyclics. Three coauthors are employed by Janssen.

N Eng J Med. 2015;372:944-953. Full text


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