Substitution of Bortezomib for Vincristine in R‑CHOP Improves Progression-Free Survival in First-Line Therapy for Mantle Cell Lymphoma
In a phase III trial reported in The New England Journal of Medicine, Robak et al found that VR-CAP, a regimen replacing vincristine with bortezomib (Velcade) in R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone), significantly improved progression-free survival vs R-CHOP in patients with newly diagnosed mantle cell lymphoma ineligible or not considered for stem cell transplantation. VR-CAP was associated with greater hematologic toxicity.
Study Details
In the study, 487 adults with stage II, III, or IV disease from 128 sites in 28 countries in Europe, Asia, North America, and South America were randomly assigned between May 2008 and December 2011 to receive six to eight 21-day cycles of VR-CAP (n = 243) or R-CHOP (n = 244). Bortezomib was given at 1.3 mg/m2 on cycle days 1, 4, 8, and 11. The primary endpoint was progression-free survival on independent assessment.
The VR-CAP and R-CHOP groups were generally balanced for age (median, 65 and 66 years, 73% ≥ 60 years in both), sex (73% and 75% male), race (62% and 70% white, 36% and 28% Asian), International Prognostic Index risk category (low in 31% and 29%, intermediate in 40% and 38%, high in 29% and 33%), stage (II in 5% and 7%, III in 20% and 17%, IV in 75% and 76%), elevated lactate dehydrogenase (36% and 35%), bone marrow involvement (68% and 70%), extranodal involvement (57% and 56%), histologic subtype (blastoid in 11% and 12%, nodular in 46% and 41%), and reason for ineligibility for stem cell transplantation (age ≥ 60 years or medically ineligible for 84% and 83%, age < 60 years and not considered for 16% and 17%).
Increased Progression-Free Survival
After median follow-up of 40 months, median progression-free survival on independent radiologic review was 24.7 months in the VR-CAP group vs 14.4 months in the R-CHOP group (hazard ratio [HR] = 0.63, P < .001). On investigator assessment, median progression-free survival was 30.7 vs 16.1 months (HR = 0.51, P < .001).
Improvement in Other Outcomes
Complete response rate was 53% vs 42% (risk ratio = 1.29, P = .007) and median duration of complete response was 42.1 vs 18.0 months. Median time to next antilymphoma therapy was 44.5 vs 24.8 months (HR = 0.50, P < .001), and median treatment-free interval was 40.6 vs 20.5 months (HR = 0.50, P < .001). Median overall survival was not reached vs 56.3 months (HR = 0.80, 95% confidence interval = 0.59–1.10), and 4-year survival was 64% vs 54%.
Overall, 34% of patients in the VR-CAP group and 54% in the R-CHOP group received subsequent antilymphoma therapy, with 39% and 51% of these receiving at least two lines. Types of therapy were similar in the two groups; 4% and 19% received bortezomib in the VR-CAP group and R-CHOP group, respectively.
Toxicity
Grade ≥ 3 hematologic toxicity was more common in the VR-CAP group, including neutropenia (85% vs 67%), thrombocytopenia (57% vs 6%), leukopenia (44% vs 29%), and lymphocytopenia (28% vs 9%). The most common grade ≥ 3 nonhematologic adverse event was infection (21% vs 14%). Serious adverse events occurred in 38% vs 30%, and drug-related adverse events led to discontinuation of treatment in 8% vs 6%.
Fatal adverse events during treatment occurred in 5% of VR-CAP patients and 6% of R-CHOP patients, with 2% and 3% considered drug-related. Causes of drug-related deaths included infection in three patients, cardiac failure in one patient, and pulmonary embolism in one patient in the VR-CAP group and infection in three patients, cardiac failure in two patients, and hypotension, diarrhea, and renal failure in one patient in the R-CHOP group.
The investigators concluded: “VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity.”
Franco Cavalli, MD, of the Oncology Institute of Southern Switzerland, Ospedale San Giovanni, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Janssen Research and Development and Millennium Pharmaceuticals.
For full disclosures of the study authors, visit www.nejm.org.
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