Phase II study of R-CVP followed by rituximab maintenance therapy for patients with advanced marginal zone lymphoma: consortium for improving survival of lymphoma (CISL) study

Sung Yong Oh, Won Seog Kim, Jin Seok Kim, Seok Jin Kim, Dok Hyun Yoon, Deok-Hwan Yang, Won Sik Lee, Hyo Jung Kim, Ho-Young Yhim, Seong Hyun Jeong, Jong Ho Won, Suee Lee, Jee Hyun Kong, Sung-Nam Lim, Jun Ho Ji, Kyung A Kwon, Gyeong-Won Lee, Jae Hoon Lee, Ho Sup Lee, Ho-Jin Shin, Cheolwon Suh, Sung Yong Oh, Won Seog Kim, Jin Seok Kim, Seok Jin Kim, Dok Hyun Yoon, Deok-Hwan Yang, Won Sik Lee, Hyo Jung Kim, Ho-Young Yhim, Seong Hyun Jeong, Jong Ho Won, Suee Lee, Jee Hyun Kong, Sung-Nam Lim, Jun Ho Ji, Kyung A Kwon, Gyeong-Won Lee, Jae Hoon Lee, Ho Sup Lee, Ho-Jin Shin, Cheolwon Suh

Abstract

Background: The response rate and survival improvement for rituximab, a CD20-targeting monoclonal antibody, have been demonstrated in marginal zone lymphoma (MZL) as monotherapy and in combination with chemotherapeutic regimens, yet relapses still occur despite treatment completion. Thus, extending the period of remission in MZL patients remains an essential goal. This multicenter, single-arm, open-label phase II study evaluated the survival efficacy of 2 years of rituximab-maintenance therapy in patients with stage III-IV CD20-positive MZL who had responded to first-line R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone). The objective of this study was to determine whether rituximab maintenance following R-CVP warrants further investigation.

Methods: Prior to rituximab-maintenance therapy, patients received 6-8 cycles of first-line R-CVP therapy for stage III-IV MZL. Rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and vincristine (1.4 mg/m2; maximum 2 mg) were administered via an intravenous infusion on day 1 of each 3-week cycle, while oral prednisolone (100 mg) was given on days 1-5 of each 3-week cycle. The patients who achieved complete response (CR), partial response (PR), or stable disease (SD) to R-CVP treatment, were prescribed rituximab-maintenance therapy which was administered intravenously at a dose of 375 mg/m2 every 8 weeks for up to 12 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment safety.

Results: 47 patients were enrolled, of whom, 45 (96%) received rituximab-maintenance treatment. Fifteen (33%) patients had nodal MZL. Following R-CVP first-line therapy, 20 (44%), 22 (49%), and 3 (7%) patients achieved CR, PR, and SD, respectively. After a median follow-up of 38.2 months, their observed 3-year PFS rate was 81%. During the rituximab-maintenance, 6 PR and 1 SD patients achieved CR following the administration of R-CVP. Elevated LDH and the presence of B symptoms were found to be significant prognostic factors for PFS (P = 0.003) and demonstrated a 3-year OS rate of 90%. Rituximab-maintenance therapy was well tolerated, and the common treatment-emergent adverse events were sensory neuropathy (18%), myalgia (13%), fatigue (9%), and neutropenia (9%).

Conclusion: Rituximab-maintenance therapy following first-line R-CVP demonstrated good PFS in patients with stage III-IV MZL, in addition to a favorable toxicity profile. Trial registration clinicaltrials.gov: NCT01213095.

Keywords: Advanced stage; Cyclophosphamide; Lymphoma; Maintenance; Marginal zone; Multicenter; Open label; Rituximab; Survival; Vincristine.

Conflict of interest statement

DHY has received research funding from Roche. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Patient disposition. Flow chart showing the number of patients who were enrolled, commenced rituximab-maintenance treatment, and completed the rituximab-maintenance treatment. AE adverse event, PD progressive disease
Fig. 2
Fig. 2
PFS following R–CVP and rituximab-maintenance therapy in the intent-to-treat population. Kaplan–Meier plot of PFS in patients with advanced MZL treated with rituximab-maintenance following first-line R–CVP therapy. MZL marginal zone lymphoma, PFS progression-free survival, R–CVP rituximab cyclophosphamide vincristine prednisolone
Fig. 3
Fig. 3
OS following R–CVP and rituximab-maintenance therapy in the intent-to-treat population. Kaplan–Meier plot of OS for patients with advanced MZL treated with rituximab-maintenance following first-line R–CVP therapy. MZL marginal zone lymphoma, OS overall survival, R–CVP rituximab cyclophosphamide vincristine prednisolone

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