High-Dose Rituximab In The Conditioning Regimen Before Allogeneic Stem Cell Transplantation Decreases Deaths Related To Gvhd Without Affecting The Anti-Lymphoma Effect
Authors: Dodero Anna , Spina Francesco , Sarina Barbara , Carniti Cristiana , Patriarca Francesca , Carella Angelo Michele , Levis Alessandro , Bosi Alberto , Falda Michele , Di Bartolomeo Paolo , Onida Francesco , Dalto Serena , Vendramin Antonio , Rambaldi Alessandro , Corradini Paolo 
Published: October 2019

Abstract

Introduction
Allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed B-cell lymphomas. Different studies have shown that Rituximab (R) is implicated in the pathophysiology of acute and chronic GVHD. Methods: We analyzed 153 adult patients who received alloSCT for relapsed/refractory B-cell lymphomas. All patients received the same preparative conditioning consisting of thiotepa/cyclophosphamide/fludarabine, and GVHD prophylaxis consisting in cyclosporine and short course methotrexate. ATG (7 mg/kg) was added to patients allografted from class I antigen mismatched sibling or unrelated donors. Eighty-two patients (group A) received high-dose Rituximab (R 500 mg/ms on day -6) and were enrolled in a prospective multicenter study, whereas 71 consecutive patients (group B, control group) were part of a previous study without R. The two groups were not significantly different in terms of diagnosis (p=0.10), donor types (p=0.74), rate of complete remission at transplant (p=0.51). Results: The cumulative incidence (CI) of non-relapse mortality (NRM) at 2-years was 16% in group A and 18% in group B (p=0.84). Main cause of death were infections without GVHD in group A (7/13) and extensive GVHD in group B (6/14). Deaths associated to acute or chronic GVHD were significantly lower in group A (5 of 13) as compared to group B (13 of 14) (p=0.004). The CI of grade II-IV and III-IV acute GVHD was 23% versus 35% (p=0.11) and 7% versus 14% (p=0.11) in group A versus B, respectively. The CI of chronic GVHD was 48% versus 47% (p=0.73) in group A versus group B, respectively. The CI of acute GVHD and chronic GVHD in unrelated recipients was 20% versus 31% (p=0.41) and 32% versus 40% (p=0.83) in patients who received R in the conditioning comparing to group B. A delayed immune reconstitution of B-cells was still evident at 2 years after alloSCT in group A versus B [median value CD19+: 126/µL versus 300/µL with a significant higher percent of IgD+CD27- in group A and reduced immunoglobulin production: 502 versus 778 mg/dL of IgG (p=0.04)]. Progression free survival (PFS) and overall survival (OS) at 3-years were similar in group A and group B [PFS: 54% versus 58% (p=0.50); OS: 64% versus 67% (p=0.51)]. PFS at 3-years in indolent and aggressive lymphomas was 66% versus 75% and 42% versus 43% with and without R; OS at 3-years in indolent and aggressive lymphomas was 74% versus 78% and 55% versus 57% with and without R. In multivariate analysis, acute GVHD, extensive chronic GVHD and aggressive hystotype were associated to a lower OS [HR=3.6, p=0.0003; HR=2.3,p=0.03;HR=2.1,p=0.01] and only acute GVHD and aggressive hystotype to lower PFS [HR=2.7, p=0.002; HR=2.3, p=0.001]. Rituximab in the conditioning regimen, year of transplant and donor type did not influence the outcome. Conclusions: Rituximab administration in the setting of alloSCT is associated with reduced GVHD-related deaths and increased infection-related deaths, likely due to delayed B-cell immune-reconstitution.

Disclosures:
No relevant conflicts of interest to declare.