Rituximab Maintenance Significantly Prolongs Event Free (EFS) and Progression Free Survival (PFS) In Male Patients With Aggressive B-Cell Lymphoma In The NHL13 Study

Abstract

Rationale. Improved outcome of female patients treated with rituximab (R) has been reported for first-line diffuse large B-cell lymphoma (DLBCL) (Müller C, et al. Blood 2012; 119: 3276-84), maintenance treatment of relapsed DLBCL (Gisselbrecht C, et al. J Clin Oncol 2012; 30: 4462-9), and induction as well as maintenance treatment of follicular lymphoma (Jäger U, et al. Haematologica 2012; 97: 1431-8; Salles G, et al. Lancet 2011; 377: 42-51.). This sex-specific response has been attributed to lower body weight or a smaller volume of distribution of the drug in women. Rituximab maintenance in DLBCL and FL grade 3 in complete remission (CR) or CR unconfirmed (CRu) after R-CHOP-like therapy did not significantly prolong EFS or PFS in the NHL13 trial conducted by the Austrian Study Group (AGMT) (http://www.clinicaltrials.gov/ct2/show/NCT00400478?term=ML+18223&rank=1). However, a trend for improved EFS (p value = 0.067), a 44% reduction of relapses, as well as a particularly good outcome in patients with an International Prognostic Index (IPI) of 0 or 1 was noted (Jaeger U, et al. Hematol Oncol 2013; 31 (Suppl. 1): 96-150 (abstract 119)). In the second interim analysis imbalances in toxicity between male and female patients treated with R were observed. This prompted us to analyse sex specific outcome in the final analysis.Patients and Methods. In the NHL13 multicenter, prospective trial 683 previously untreated adult patients with DLBCL (N=662) or FL G3B (N=21) were randomized for R maintenance (375 mg/m2 every 2 months for 2 years) (N=338) or observation only (N=345) between June 2004 and September 2008. Patients at all clinical stages in CR or CRu after treatment with 4 to 8 cycles of R-CHOP like therapy were included. Median age was 58 years (range 19-88) with 48.2% or 52.8% male patients in the R or observation arms, respectively. Median observation time from inclusion was 45 months. The primary endpoint of this study was EFS. Secondary endpoints included PFS, OS and safety. Data were analysed using a Cox regression model.Results. Event free survival in male patients was superior in the rituximab maintenance treatment arm compared to observation (EFS at 3 years 84.1% vs. 74.4%; HR 0.58, 95% CI 0.36-0.94; p=0.0267) while no difference was observed in female patients (EFS at 3 years 76.8% vs. 78.7%; HR 1.5, 95% CI 0.67-1.66; p=0.8246) (Fig.1).The effect was particularly pronounced in male patients with low IPI (<1) (EFS at 3 years 91.2% vs. 78.2%), while this benefit was not as strong in male patients with IPI>1 (77.1% vs. 70.2%) or women with IPI<1 (79.5% vs. 82.5%) or >1 (74.7% vs. 75.7%) (Fig.2). In a multivariate analysis of factors associated with EFS in male patients R treatment together with age (<60 vs. >60 years), continent (Africa, America, Asia, Australia, Europe) and clinical stage (1/2 vs. 3/4) remained independent, while this was not observed in female patients. When IPI was included as a separate variable in the model, R treatment was the only independent factor in men. Similar analysis conducted for PFS showed a significant effect of R in men (PFS at 3 years 89.0% vs. 77.6% for observation; HR 0.45, 95% CI 0.25-0.79; p=0.0058) but not in women (83.7% vs. 80.5%; HR 0.79, 95% CI 0.47-1.33; p=0.3693). Again, R treatment and age were independent factors in multivariate analysis in men. PFS in patients with IPI<1 treated with R at 3 years was 96.1% in men vs. 89.2% in women. No significant differences in OS were observed at this time. Of note, more female patients receiving R maintenance had at least one adverse event CTC grade 3/4 (21.7% vs.12.3% in males, p=0.0297). Infections and infestations (all grades) occurred most frequently in female patients in the R arm (40.6% vs. 29.4% (male R) vs. 33.7% (male obs.) vs. 26.4% (female obs.); p=0.0341).Conclusion. This unforeseen subgroup analysis by sex from a large randomized prospective trial provides surprising but clear evidence that 2-monthly R maintenance for 2 years significantly improves EFS and PFS of male patients with DLBCL (and FL G3B). Maintenance therapy may be compensating for underdosing in men with current R containing induction regimens and indicates the necessity to prolong or increase rituximab dosing for men with aggressive B-cell lymphoma, particularly in the low IPI subgroup.▪▪ Disclosures:Jaeger:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab as maintenance treatment for DLBCL. Trneny:Roche: Honoraria, Research Funding. Fridrik:Roche: Honoraria. Hedenus:Vifor Pharma: Consultancy, Honoraria. Thaler:Roche: Honoraria, Research Funding. Keil:Roche: Honoraria. Dittrich:Roche: Honoraria, Research Funding. Greil:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldstein:Roche: Membership on an entity's Board of Directors or advisory committees.