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Prolonged maintenance with rituximab in indolent NHL
imab prolongs time to disease progression and increases overall survival (OS),8 but is associated with infusion reac- tions, which can be severe.9,10 Thus, a slow infusion is required during the first antibody administration, which generally takes at least 3.5–4 h.9-11 Faster infusion rates are used for subsequent infusions;10,11 nevertheless, infusion duration remains a challenge for patients and healthcare providers, particularly when multi-agent chemotherapy is being used.11
A subcutaneous (SC) formulation of rituximab and recombinant human hyaluronidase has been developed to address this concern.12 At fixed doses, rituximab SC has shown comparable efficacy and safety to intravenous ritux- imab in patients with NHL or chronic lymphocytic leukemia, with non-inferior serum trough rituximab con- centrations.12-16 Additionally, patients’ preference/satisfac- tion and time and motion data (active healthcare practition- er time and chair time for patients) favor the use of the SC formulation,17,18 which is currently approved in Europe, the USA and numerous other countries for multiple indications (chronic lymphocytic leukemia, diffuse large B-cell lym- phoma and FL).9,19 Dosing advantages over intravenous treatment include administration over 5–7 minutes, with a requirement for only 15 minutes of monitoring.9,19
Rituximab plus chemotherapy induction followed by rit- uximab maintenance is an approved treatment in FL,9,19 and has shown long-term progression-free survival (PFS) benefit in patients with indolent NHL.20-27 Tumor response and sur- vival data show improvements in outcomes that persist over the longer term when rituximab maintenance therapy is given for up to 2 years.27,28 Whether further and prolonged maintenance therapy (beyond 2 years) would benefit patients with relapsed/refractory (R/R) indolent NHL who have maintained their response to treatment remains unknown. MabCute (NCT01469128) is a phase III trial in which patients with R/R indolent NHL were randomized to prolonged rituximab SC maintenance or observation after completing rituximab SC-based induction and 2 years maintenance therapy, provided that they were in response and willing to continue treatment.
Methods
Study design
This was a phase III, open-label, multicenter, international, ran- domized interventional study enrolling patients from 141 centers worldwide (mostly in Europe). MabCute was divided into Induction (6–8 months), Maintenance I (24 months) and Maintenance II (minimum 15 months) phases (Figure 1).
The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice, local legislation and the approval of institutional review boards. Written informed consent was obtained from participants.
Study population
Adults aged ≥18 years with R/R CD20+ grade 1, 2 or 3a FL or other CD20+ indolent NHL (Waldenström macroglobulinemia/lym- phoplasmacytic lymphoma or marginal zone lymphoma), and Eastern Cooperative Oncology Group (ECOG) performance status ≤2 were recruited. Details of the baseline assessments are provided in the Online Supplementary Appendix.
Study treatments
Eligible patients received eight rituximab cycles, one intra-
venous (375 mg/m2) and seven SC (1,400 mg fixed-dose) with six to eight chemotherapy cycles as induction (Figure 1; further infor- mation is available in the Online Supplementary Appendix). Patients with complete or partial response received 2 years’ maintenance with rituximab SC (Maintenance I). Patients with continuing response at the end of Maintenance I were randomized to pro- longed maintenance with rituximab SC or to observation (Maintenance II).
Study endpoints and procedures
The primary endpoint was PFS from the time of randomization to extended maintenance with rituximab SC or observation in Maintenance II (PFSrand in the randomized intent-to-treat [ITTrand] population). Secondary endpoints included OS from the time of randomization in Maintenance II (OSrand), overall response rate (Cheson criteria29) at end of Induction, and partial response to complete response conversion rate at the end of Maintenance I. An exploratory analysis of PFS and OS from enrollment to end of Maintenance I (i.e., the non-randomized part of the study; PFSreg, OSreg) according to induction chemotherapy was also performed.
Safety was assessed in all patients who received at least one dose of study medication and included adverse events (using National Cancer Institute Common Toxicity Criteria Version 4.0 and coded with Medical Dictionary for Regulatory Activities ver- sion 2.0), laboratory tests and vital signs.
Analytical plan
Sample size was based on a phase III randomized study of 465 R/R FL patients. Overall, 129 PFSrand events were required to achieve 80% power for the log-rank-test at a two-sided significance level of 5%; therefore, approximately 700 patients needed to be enrolled to randomize 330 patients (allowing for a 10% dropout) after the 2.5-year Induction plus Maintenance I. Randomization to Maintenance II was 1:1, stratified by indolent NHL subtype and Follicular Lymphoma International Prognostic Index (FLIPI) cate- gory.30 The end of study was defined as the time when all patients randomized into Maintenance II had been followed up for ≥15 months, or earlier if at least 129 PFS events had been observed.
PFSrand, OSrand, PFSreg and OSreg were reported with medians, 95% confidence intervals (95% CI), and Kaplan-Meier estimates and their 95% CI. The randomized treatment arms (prolonged ritux- imab maintenance vs. observation in Maintenance II) were com- pared using log-rank testing stratified according in indolent NHL subtype and FLIPI category. Cox regression was used to estimate hazard ratios (HR).
Results
Patients
In total, 692 patients received rituximab plus chemother- apy as induction (ITT population for Induction); 60.5% of patients received bendamustine, 12.4% received cyclophosphamide, doxorubicin, vincristine and pred- nisone (CHOP) and 11.8% received cyclophosphamide, vincristine and prednisone (CVP) (Online Supplementary Table S1); very small numbers received fludarabine, cyclophosphamide and mitoxantrone (FCM) or mitox- antrone, chlorambucil and prednisone (MCP). The distribu- tion of patients who received each induction regimen was maintained out to Maintenance II (Online Supplementary Table S1). Of the patients who received induction therapy, 148 discontinued treatment because of adverse events (70 patients; 10.1%), disease progression (29; 4.2%), patients’ request (16; 2.3%), investigators’ request (7; 1.0%), loss to
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