Efficacy and safety assessment of prolonged maintenance with subcutaneous rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results of the phase III MabCute study

Abstract

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers a long-term benefit in terms of progression-free survival in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years' initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed progression-free survival in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 progression-free survival events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log-rank test; hazard ratio 0.76 [95% confidence interval: 0.37- 1.53]). The median progression-free survival was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non- Hodgkin lymphoma. (Clinicaltrials.gov identifier: NCT01461928).

Figures

Figure 1.

Study design.aWaldenström macroglobulinemia/lymphoplasmacytic lymphoma or marginal zone lymphoma. bChemotherapy options included bendamustine, CHOP, CVP, FCM, MCP, CHVP-IFN, chlorambucil, fludarabine-containing regimen or GIFOX. cMaintenance started within 8–12 weeks of completion of induction. R/R: relapsed or refractory; FL: follicular lymphoma; Gr: grade; NHL: non-Hodgkin lymphoma; R: rituximab; Cs: cycles; PD: disease progression; CR: complete response; PR: partial response; SD: stable disease; SC: subcutaneous; IV: intravenous; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; CVP: cyclophosphamide, vincristine and prednisone; FCM: fludarabine, cyclophosphamide and mitoxantrone; MCP: mitoxantrone, chlorambucil and prednisone; CHVP-IFN: cyclophosphamide, doxorubicin, etoposide and prednisone + interferon-α; GIFOX: gemcitabine, ifosfamide and oxaliplatin.

Figure 2.

Patients’ disposition during Maintenance II.aTwo additional patients originally intended for randomization failed to meet continuation criteria and were consequently not treated in Maintenance II. bDerived by subtracting patients who discontinued from treated patients.

Figure 3.

Survival outcomes during the randomized Maintenance II period. Kaplan-Meier analysis of progression-free (A) and overall survival (B) during the randomized Maintenance II period. R-SC: subcutaneous rituximab.

Figure 4.

Survival outcomes from enrollment to end of Maintenance I, according to induction chemotherapy. Kaplan-Meier analysis of progression-free (A) and overall survival (B) from enrollment to end of Maintenance I, according to induction chemotherapy received (bendamustine vs. CHOP and CVP). aIntent to treat population for Induction. Time to event calculated from first induction therapy up to the earliest date of event until randomization; data censored after randomization. CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; CVP: cyclophosphamide, vincristine and prednisone.