Phase II Trial of R-CHOP Plus Bortezomib Induction Therapy Followed By Bortezomib Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601

Background

Mantle cell lymphoma (MCL) is incurable with current standard therapies, and there is no consensus for the optimal induction regimen. Bortezomib, a 26S proteasome inhibitor, is active as a single agent in this disease, and preclinical data suggest that combination with chemotherapy may be synergistic. A recent randomized trial found that maintenance rituximab after R-CHOP led to a survival benefit, suggesting maintenance strategies are worth investigating in MCL. The SWOG cancer research cooperative group conducted a phase II study (S0601) to evaluate the safety and efficacy of combining bortezomib with R-CHOP for induction, followed by bortezomib maintenance for 2 years.

Methods

Patients were eligible if they had previously untreated stage III, IV, or bulky stage II evaluable mantle cell lymphoma. Induction therapy consisted of six cycles of R-CHOP (375 mg/m² rituximab, 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine, and 100 mg prednisone daily for 5 days) plus bortezomib 1.3 mg/m² on days 1 and 4 of every 21 day cycle. Patients achieving at least stable disease after induction were eligible for bortezomib maintenance therapy 1.3 mg/m² days 1, 4, 8, and 11 every 3 months for 8 cycles (one cycle was defined as 3 months for the maintenance phase). The study was designed to estimate the 2 year PFS rate to within 13% (95% CI).

Results

Of the 68 enrolled patients, 65 were eligible and evaluable for toxicities. The patient population had a median age of 61 (range 36-85), with 80% male sex, 15% bulky disease, 98% stage III-IV, 37% elevated LDH, and MIPI scores of: 45% low-risk, 43% intermediate risk, and 12% high-risk. In general, the treatment was well-tolerated, with 48% of patients experiencing grade 4 hematologic toxicities during induction therapy, and 38.5% grade 3 non-hematologic and 6% grade 4 non-hematologic toxicities. During maintenance therapy, 13% of patients experienced grade 3 non-hematologic toxicities. Grade 3 peripheral neuropathy was experienced by 8% of patients during induction and 2% of patients during maintenance bortezomib, and there was no grade 4 neuropathy. One patient died of toxicities possibly related to therapy: complete heart block in the setting of pneumonia and acute respiratory distress syndrome. With a median follow-up time among surviving patients of 5.9 years, 52 patients have progressed or died. The estimate of 2-year progression-free survival (PFS) was 62%, and 2-year overall survival (OS) was 85%. At 5 years, the PFS was 28% and OS was 66%. Based on prior studies, the historical 2 year PFS rate for R-CHOP alone in this population is 30%. MIPI scores were significantly associated with outcome, with 2-year PFS of 72%, 61%, and 25% for low, intermediate, and high risk MIPI groups, respectively. However, in a regression analysis to identify prognostic factors associated with a ≥ 5 year PFS, the only significant factor found was absence of splenic involvement. Additional correlative studies are planned to identify predictive biological markers associated with long-term remissions.

Conclusions

Combination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared with historical data of R-CHOP alone, doubling the historical 2 year PFS rate, with nearly one third of patients achieving a PFS of 5 years or longer. These results suggest that the addition of bortezomib to induction chemotherapy and/or maintenance is promising and warrants further exploration.

Support: CA32102, CA38926, and in part by Millennium Pharmaceuticals, Inc.