VcR‐CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study

Abstract

Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 days for 6 cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

“…Importantly, we did not observe excessive painful peripheral neuropathy using the dose and schedule of vincristine and bortezomib selected for this trial. 13 Nearly 90% of patients were able to complete all 6 cycles of induction therapy, compared with just 61% who were able to complete conventional R-hyperCVAD with alternating R-methotrexate and cytarabine in a SWOG study. 25 The CR rate of 68% is encouraging and possibly an underestimate of the true CR rate.…”

“…[14][15][16][17][18] In this pilot trial of 30 patients, median age 61, VcR-CVAD with MR demonstrated a CR rate of 77%, an OR rate of 90%, and 3-year PFS and OS of 63% and 86%, respectively. 13 These results were considered promising and worthy of additional study. Of note, 7 of the first 14 patients enrolled experienced painful peripheral neuropathy when bortezomib at 1.5 mg/m 2 was administered in combination with vincristine at 2 mg. With dose modification of both agents (vincristine 1 mg on day 3, bortezomib 1.3 mg/m 2 on days 1 and 4), only 1 in 16 final patients enrolled experienced painful peripheral neuropathy.…”

“…This study employed MR 3 5 years, and 25% of patients were unable to complete the planned MR because of development of hypogammaglobulinemia and recurrent infections. 13 With lessons learned regarding bortezomib/vincristine dosing and duration of MR, investigators within the Eastern Cooperative Oncology Group (ECOG) designed a large phase 2 trial (E1405) of VcR-CVAD induction chemotherapy following by MR for 2 years in patients with previously untreated MCL. Recognizing that many clinicians prefer intensive strategies for younger MCL patients, the protocol permitted the triage of patients to autologous stem cell transplantation (ASCT) rather than MR.…”

New Strategies in the Treatment of Mantle Cell Lymphoma

“…In previously untreated patients with MCL, bortezomib plus R-CHOP resulted in an ORR of 81%, CR of 64%, and PR of 17%, with median PFS of 23 months and median OS not reached at median follow-up of 34 months (106). Another study that incorporated bortezomib into modified R-hyperCVAD in untreated patients with MCL resulted in an ORR of 90%, CR of 77%, and PR of 13%, with 3-year PFS and OS of 63% and 86%, respectively (107).…”

Refining the Mantle Cell Lymphoma Paradigm: Impact of Novel Therapies on Current Practice

“…42), leading to extended FDA approval for bortezomib in previously untreated MCL in October 2014 (43). Because of hyper-CVAD-related toxicity (44), a modified combination (no cytarabine or methotrexate) was developed with results intermediate between R-CHOP and standard hyper-CVAD, but better tolerated, also offering a platform for bortezomib combinations (45). This benefit was confirmed in the multicenter setting by the ECOG E1405 study, in which VcR-CVAD followed by maintenance rituximab in newly diagnosed MCL showed an ORR of 95%, with a 68% CR/CR unconfirmed (CRu), and 3-year PFS of 72% (46).…”