Maintenance Rituximab Following R-CHOP Chemotherapy in Patients with Composite or Discordant, Indolent and Aggressive, B-Cell Non-Hodgkin Lymphomas

Background:

Patients with follicular lymphoma (FL) who achieve a complete (CR) or partial (PR) response to rituximab-containing chemotherapy followed by maintenance rituximab (MR) experience improved progression-free survival (PFS). In contrast, MR does not improve outcomes in chemo-sensitive patients with diffuse large B-cell lymphoma (DLBCL). There are no published data describing the impact of MR in patients presenting with indolent and aggressive histology lymphoma simultaneously in the same biopsy (composite, COM) or two separate sites (discordant, DIS).

Methods:

Patients with newly-diagnosed COM/DIS lymphomas composed of an indolent B-cell non-Hodgkin lymphoma (excluding CLL/SLL, mantle cell lymphoma, and grade 3B FL) and DLBCL were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. All patients received first-line chemotherapy with R-CHOP. In early 2006, a treatment policy was introduced recommending MR 375 mg/m² IV every 3 months for 2 years in patients with COM/DIS lymphomas achieving a CR/PR to R-CHOP induction. PFS, time to progression (TTP) and overall survival (OS) were calculated from the time of diagnosis and compared between treatment groups.

Results:

98 patients with COM/DIS lymphomas were identified between January 2001 and December 2013: median age 64 y (range 22 - 86), 56% male, 48% elevated LDH, 30% performance status ≥ 2, 87% stage III/IV, and 51% high-intermediate or high IPI. 58 (59%) and 40 (41%) patients had COM and DIS lymphoma, respectively. FL was the indolent component in 65% of all cases. 35/40 patients with DIS had low-grade histology in the bone marrow. Following R-CHOP, 77 (79%) and 21 (21%) patients achieved CR and PR, respectively. 43 patients were treated with R-CHOP alone before the MR policy introduction, and 55 were treated with R-CHOP+MR; the latter group received a median of 8 (range 1 - 8) MR doses. There were no significant differences in baseline characteristics or response rates between the two groups with the exception of a higher proportion of patients with poor performance status in the group not given MR.

With a median follow-up of 10y (range 1.5 - 13.6) in living patients treated with R-CHOP and 6y (range 0.9-9.5) in patients treated with R-CHOP+MR, there were 20 (47%) and 15 (27%) relapses, respectively (p=0.26). Of these, 11 relapsed with indolent histology, 11 relapsed with DLBCL, 3 relapsed in the central nervous system (CNS), and 10 had no biopsy at relapse (8 had aggressive and 2 indolent clinical behavior on review of medical records). There were 6 (30%) indolent and 14 (70%) aggressive relapses in patients treated with R-CHOP, while there were 7 (47%) indolent and 8 (53%) aggressive relapses in patients treated with R-CHOP+MR (p=0.31). 19 patients eventually died from lymphoma (8 with DLBCL relapse, 5 without a biopsy at relapse, and all 3 with CNS recurrence).

The 6-y PFS was 60% (standard error [SE] 5%) with no difference between patients treated with or without MR (Hazard ratio (HR) 0.74, 95% CI 0.39 - 1.37, p= 0.33). The 6-year TTP was 64% (SE 5%), again with no differences between the two groups (HR 0.68, 95% CI 0.34 - 1.33, p= 0.25). The 6-year OS was similar between the two groups (p= 0.89). In the subgroup of patients with FL (21 R-CHOP and 43 R-CHOP+MR) the addition of MR did not impact PFS (p= 0.90), TTP (p= 0.99), or OS (p=0.55).

An additional 52 patients were diagnosed after the treatment policy introduction in 2006, but did not receive MR for several reasons including physician non-adherence, progressive disease on R-CHOP, toxicity from R-CHOP or patient refusal. In an intent-to-treat analysis (43 pre-policy and 107 post-policy) there were no differences in outcomes. In a per-protocol analysis (95 R-CHOP and 55 R-CHOP+MR), there were no significant differences in outcomes.

Conclusion:

The addition of MR does not appear to improve PFS, TTP or OS in patients with COM/DIS lymphomas achieving CR/PR to R-CHOP, although comparisons are likely underpowered and 6-year median length of follow-up in the MR group may not be sufficient. However, the majority (63%) of relapses are aggressive and unlikely to be impacted by MR. The role of MR in these uncommon lymphomas requires further exploration.