5.14 Rituximab in Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Chronic Lymphocytic Leukemia with Fludarabine Plus Total Body Irradiation Conditioning: Results of a Phase 2 Prospective Multicenter Study (ITAC 02-02)

Abstract

To evaluate the efficacy and toxicity of an RIC regimen including fludarabine, total body irradiation (TBI), and rituximab for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with stage B or C chronic lymphocytic leukemia (CLL), we conducted this prospective study in adults with CLL who were younger than 65 years, in response after salvage treatment following at least 2 lines of treatment, and had an HLA-identical sibling donor. Conditioning included rituximab 375 mg/m2 on day −5, fludarabine 30 mg/m2 from day −4 to day −2, TBI 2 Gy on day 0, and rituximab 500 mg/m2 on days 1 and 8. Graft-versus-host disease (GVHD) prophylaxis used cyclosporine A (3 mg/kg/d) from day –2 and mycophenolate mofetil (2 g/d) from day 1. Between April 2003 and December 2008, 40 patients were included; 34 (85%) were men and 6 were women. The median age was 54 years (range 35-65 years); 38 (95%) had stage B and 2 had stage C disease. Among 23 patients in whom cytogenetic analysis was done, there were 3 cases of del17, 1 case of trisomy 12, 1 case of t(8-11), and 1 case of del13. Before transplantation, 17 patients received 2 lines of treatment, 10 received 3 lines, 5 received 4 lines, and 8 received more than 4 lines. At allogeneic HSCT, 7 patients (17%) had complete remission, 29 (73%) had partial remission, and 4 (10%) had less than partial remission; 59% were sex-mismatched. For ABO matching, 19% were major incompatible and 13% were minor incompatible. The median interval between diagnosis and allogeneic HSCT was 58 months (range 6-177 months). Seven patients (17%) did not receive rituximab because the protocol did not include it at first and was amended later. Thirty-nine patients (98%) were engrafted, with a median time to neutrophil recovery of 20 days (range 11-70 days), and 79% of patients reached total donor chimerism at day 90. Seventeen patients developed acute GVHD of grade II or greater (8 with grade II, 8 with grade III, and 1 with grade IV), with a cumulative incidence at 3 months of 44% (range 36%-52%). The cumulative incidence of chronic GVHD 29% (range 21%-36%) for lim. and ext. at 12 months and 32% (24%-40%) for lim. and 42% (34%-50%) for ext. at 18 months. After a median follow-up of 28 months (range 3-71 months), median overall survival (OS) was not reached, with 5-year probability of 55% (range 41%-74%). The median event-free survival (EFS) was 30 months (range 15-70 months), with a 5-year probability of 46% (range 33%-66%). The cumulative incidence of relapse at 1 and 3 years was 17% (range 11%-23%) and 22% (range 15%-29%), respectively. The cumulative incidence of transplant-related mortality at 1 and 3 years was 10% (range 5%-15%) and 27% (20%-35%), respectively. Multivariate analysis showed a positive effect of rituximab on OS and EFS (hazard ratios, 0.1 [0-0.6] [p = 0.02] and 0.1 [0-0.4] [p = 0.035], respectively) (Figure). The introduction of rituximab provided a better outcome, especially in terms of acute GVHD. Nevertheless, the incidence of chronic GVHD remained high, leading us to propose increasing the number of rituximab injections after allogeneic HSCT or testing fludarabine/busulfan/antithymocyte globulin plus rituximab.