Meta Analysis of Grade 3 and/or 4 Toxicities in Follicular (FL) and Mantle Cell (MCL) Non-Hodgkin Lymphoma (NHL) Patients Receiving Maintenance Rituximab (MR): Impact of Schedule, Histology, and Induction Regimen

MR has improved the outcome and progression-free survival (PFS) of patients (pts) with FL and MCL. However, maintenance schedules have been empirically designed with no consensus on the optimal regimen. While toxicities are usually predictable, the impact of MR schedule on toxicities has not been previously reported and could influence selection of maintenance regimens. We analyzed grade 3 and/or 4 adverse events (AE) in FL and MCL pts enrolled in prospective MR trials in order to compare AEs by MR schedule, histology, and setting (front-line and relapsed).

A systematic search of the Medline (Pub-Med, Google Scholar, Cochrane Library) electronic database was performed to identify prospective clinical trials employing MR in FL and MCL. The following search terms were used: “MR, maintenance immunotherapy, maintenance therapy, low-grade lymphoma, NHL, MCL, and FL”. Abstracts and studies using MR after autologous stem cell transplantation or radioimmunotherapy were excluded. The number of AE reported was considered as the unit of analysis. Data for overall Grade 3 and/or Grade 4 toxicity (AE reported at any phase of treatment) were further categorized as an AE occurring during the induction phase or the maintenance phase. The incidence, severity, and type of toxicity were analyzed by type of induction (R vs. R+chemotherapy), histology (FL, MCL and FL plus other low-grade histologies), setting (front-line vs. relapsed), and MR schedule (one dose every 2 months vs. one dose every 3 months vs. 4 weekly doses every 6 months; all given for 2 years) and analysis was performed using t-tests or one-way ANOVA weighted means by either the total sample or the MR phase sample. Means were calculated using both fixed-effect and random-effect models

Thirteen clinical trials met criteria, including six trials which were randomized controlled in the MR phase. Of the total 3,100 pts, 1,263 received MR. The mean percentage of Grade 3/4 toxicities during any phase of treatment was 26% (95% CI = 0.12–51.88) but in the MR phase, it was only 12.88% (95% CI = 6.50–19.26). The overall mean number of grade 3/4 toxicities during any phase of treatment was 173.85 (95% CI = 167.76–179.95) and it was 60.5 (95% CI 58–63) in the MR phase. Toxicities were significantly different between induction therapy regimens, front-line and the relapsed settings and histologies (all P < 0.001). Pts receiving MR every 2 months encountered more grade 3 and 4 toxicities (mean percentage = 33%, mean = 97.46, 95% CI = 94.15–100.77) compared to 3 months (mean percentage = 21%, mean = 29.24, 95% CI = 27.92 –30.57) and 6 months (mean percentage = 13%, mean = 11.62, 95% CI = 10.70–12.54) schedules (P < 0.001). Pts receiving R+ chemo induction had more AEs compared to those receiving R induction [(mean=73.9 (95% CI 70.8–77.0) vs. 7.5 (95% CI 6.4–8.5), P<0.001]. Pts receiving MR in front-line had more AEs compared to those receiving MR in relapsed disease [mean= 73.1 (95% CI 69.9–76.6) vs. 43.3 (95% CI 41.3–45.3), P<0.001]. Pts with FL had more AEs compared to those with MCL [mean=72.9 (95% CI 69.8–75.9) vs. 15.3 (95% CI 13.2–17.3), P<0.001] Neutropenia and infections were the most common reported individual toxicities.

Approximately 13% of patients receiving MR experience grade 3 and/or 4 toxicities, mainly neutropenia and infections. MR given every 6 months appears to cause fewer toxicities. Importantly, this meta-analysis did not compare relative efficacy amongst the three most commonly used MR schedules, but may be helpful in advising patients of relative risks amongst the three schedules.

Nabhan:Genentech: Research Funding, Speakers Bureau. Ghielmini:Roche: Honoraria, Research Funding. Smith:Genentech/Roche: Data Safety Monitoring Board and advisory Board attendance Other.