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).

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.