HLA-Mismatched Microtransplantation Vs HLA-Matched Nonmyeloablative Transplantation for Acute Myeloid Leukemia in Intermediate-Risk: Comparable Survival but Avoids of Gvhd

The optimal therapy for intermediate-risk patients with acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Recent studies shown that microtransplantation (MST) can improve survival in AML-CR1 patients. However, a comparison study between the MST and nonmyeloablative stem cell transplantation (NST) is lacking. 156 intermediate-risk AML-CR1 patients aged 9 to 59 years were enrolled in this study. 57 patients who had a HLA-identical donors were assigned to receive NST therapy with graft-versus-host disease (GVHD) prophylaxis. The other 99 who had no HLA-identical donors including 86 family-related, 9 distantly related and 4 unrelated donor were assigned to receive MST therapy but without GVHD prophylaxis. The probabilities of 10-year overall survival and leukemia-free survival was comparable in the MST-group and NST-group (70.7% vs. 61.4% and 59.6% vs. 57.9%). The NST-group exhibited a higher full donor chimerism (96.5%) and higher GVHD (33.3%), whereas the MST-group produced a higher donor microchimerism (75%), slightly higher relapse (32.3% vs. 22.8%) and significantly lower non-relapse mortality (6.9% vs. 19.3%, P=0.021) but without GVHD. In the MST-group, the patients with increase of WT1+ CD8+ T cells exhibited significantly higher leukemia-free survival and lower relapse than those without (92.0% vs. 40.0%, P=0.003; 8.0% vs. 50%, P=0.009). These results indicate that, compared to NST, MST produced a comparable survival, less transplantation-related mortality, avoidance of clinical GVHD and overcome limitations of HLA-barrier, suggesting a much safe and effective therapy for intermediate-risk AML-CR1, particularly for those without a HLA-identical donor. Disclosures No relevant conflicts of interest to declare.

Nonmyeoablative Allogeneic Conditioning with Bendamustine in Combination with Fludarabine and Rituximab for Lymphoid Malignancies: Immunosuppression without Myelosuppression and without Acute Gvhd

Abstract 894 Background: We previously reported the use of fludarabine, cyclophosphamide and rituximab as a nonmyeloablative allogeneic conditioning for CLL and non-Hodgkin's lymphomas (Khouri et al, Blood 2008;111:5530). Bendamustine is a novel compound which was found to be effective in pts who were refractory to alkylating agents. In order to improve outcomes in nonmyeloablative stem cell transplantation (NST), we substituted cyclophosphamide with bendamustine in the conditioning. Methods: Bendamustine was given iv in an escalated dose of 70, 90, 110, 130 mg/m2 daily on days −5 to - 3 prior to NST, together with 30 mg/m2 of fludarabine given on the same days. Rituximab was given at a dose of 375 mg/m2 on day –13 and 1000 mg/m2 on days −6, +1, and +8, as previously described. Tacrolimus and methotrexate was used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days −2, and −1 in pts receiving an unrelated donor. Results: The study included 23 pts [Mantle cell=9, CLL=6 (2 with 17p- and 1 Richter's), Follicular =4, Diffuse large cell =3]. All pts had relapsed disease after the best conventional therapy (-ies) available. Median age was 60 (range, 30–70) years. Median prior treatments was 2 (range, 1–5); 3 pts (13%) had failed a prior autotransplant. At NST, 11 pts (48%) were in CR, 7 (31%) in PR, 1 (4%) induction failure/sensitive, and 4 pts (17%) had refractory disease. Fifteen pts (65%) received their transplants from HLA-compatible siblings and 8 (35%) from unrelated donors. Continual Reassessment Method based on target toxicity at day 30 post NST was used for dose finding. The number of pts who received the 70, 90, 110, 130 mg/m2 daily doses of bendamustine were 2, 3, 3, and 15 pts, respectively. No dose-limiting toxicity was observed. Fourteen pts (61%) did not nadir to an ANC< 500; 3 pts did not require neupogen for ANC recovery; 19 (83%) did not experience a platelet count < 20,000/mm3. All pts engrafted donor cells. Median donor T cells at day 30 was 93%. Only one pt developed acute GVHD (it was grade 3); none had acute grade 2 or 4. Chronic extensive GVHD was observed in 2 of 22 (9%) evaluable pts. Fungal infection was the cause of the only death observed. Twenty pts (87%) achieved CR, 2 (9%) have ongoing PR, and 1 (4%) had SD. With a median follow-up time of 8 months (range, 3–25 months), the OS and PFS rates were 92% and 79%, respectively. Conclusions: Our results represent the first report to suggest that combining bendamustine at a dose up 130 mg/m2 daily × 3 days, together with fludarabine and rituximab is safe and constitutes a well tolerated conditioning for NST. We are treating pts with this regimen in the outpatient setting. The study is currently ongoing to assess its efficacy in a larger cohort of pts. Disclosures: Khouri: Cephalon: Research Funding. Off Label Use: Bendamustine use in SCT.

Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.