Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning Improves Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab).

Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m² IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m² IV daily on days -5 to -3) and rituximab (375 mg/m² IV on day –13 and 1000 mg/m² on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant.

Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin >3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR).  Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P <0.001) and 21 (81%) vs 39 (63%), respectively, did not require platelet transfusions (P=0.08). Median follow-up times for BFR and FCR groups were 29 (range 19-60), and 104 (range, 34-195) months. The 3-year overall survival (OS) estimates in the BFR and FCR groups were 82% vs. 51% (P=0.03) and the 3-year progression-free survival estimates were 63% vs. 27% (P=0.001). The 3-year OS improvements were seen across the prognostic factors studied for BFR and FCR respectively: MUD (93% vs 30%), presence of 17p deletion (86% vs 50%), and age >50 years (79% vs 50%), β2-microglobulin >3 mg/L (73% vs 45%), >3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR.  Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT.

Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen.