The Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: An Analysis By the EBMT Complications and Quality of Life WP

Introduction: Rituximab (R), a CD20 monoclonal antibody, has been integrated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplants (HCT) in patients with B-cell malignancies, to decrease risk of recurrence. Single center data has suggested that R containing RIC regimens (R-RIC) may be associated with decreased chronic GVHD and better overall survival. We wanted to validate this finding in a larger registry cohort.

Methods: We conducted a retrospective analysis using the EBMT registry of adult patients with B-cell malignancies (FCC NHL, CLL/SLL, MCL NHL, DLBCL) undergoing a RIC HCT (2001-2013) with either rituximab (R-RIC) or non-rituximab (RIC). Patients undergoing myeloablative HCT (TBI > 6 Gy, or busulfan > 9 mg/kg) or alemtuzumab containing regimens were excluded. Umbilical cord and haploidentical HCT were excluded.

Results: A total of 3803 (RIC: 3453, 91%; R-RIC: 350, 9%) patients were included. Median age and median follow up were 55 years (range 19.1 -77.3) and 43.2 months (range 0.3 -179.8), respectively. There was no difference between the 2 groups in either diagnoses (FCC 29.2%, DLBCL 17.3%, MCL 17.2%, CLL/SLL 13.6% and unspecified CLL 22.7%) or disease status (PR 33.3%, relapse/progression 23.3%, CR/nCR 39.4%, primary refractory 3.1%, and other 0.8%). The following characteristics were significantly different in RIC vs R-RIC: median age higher in RIC (55 vs. 54.2 years, P=0.008); median year of transplant higher in R-RIC (2009 vs. 2010, P<0.0001); more matched related donor in R-RIC (51.9% vs. 57.7%, P=0.044); higher CMV D/R -/- in RIC and +/+ in R-RIC (25.7% vs. 16.1% and 39.2% vs. 46.3%, respectively, P=0.002); GVHD prophylaxis CSA/MMF 41.7% in RIC vs. 24.4% in R-RIC; CSA/MTX 31.1% in RIC vs. 45.9% in R-RIC (P<0.0001). There was no difference in sex mismatch, stem cell source or infused cell dose in the 2 groups. There was no difference in incidence of chronic GVHD (RIC: 56.3% vs. R-RIC: 54.3%) or extent of chronic GVHD (limited: 50% vs. 55.3%; extensive 50% vs. 44.7%) among the evaluable patients (RIC 1462; R-RIC 153). In MV analyses, the HR (95% CI) for R-RIC vs RIC for relapse incidence, non-relapse mortality, disease free survival, overall survival, and acute GVHD gr 3-4 were 0.93 (0.72-1.21), 1.02 (0.81-1.27), 0.97 (0.83-1.15), 1.01 (0.84-1.2), 0.98 (0.71-1.35), respectively. Subset analyses of patients (no ATG for GVHD prophylaxis) receiving R-RIC (n=257) versus RIC (n=2364) did not show any difference. Similarly, subset analyses of patients (non-FluBu2 regimens) receiving R-RIC (n=308) versus RIC (n=2742) did not show any difference. Outcome data to compute GVHD-free, relapse-free survival was not available.

Conclusion: In a large registry cohort, we were not able to show that, the addition of rituximab in conditioning regimens was associated with improved transplant outcome of patients undergoing RIC HCT for B-cell malignancies. The dose and schedule of rituximab in the preparative regimen may influence outcome and needs to be studied. This data may guide the further development of drugs targeting B-cell pathway for GVHD prophylaxis.

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