Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan A Shimoni, I Hardan, N Shem-Tov, A Rand, C Herscovici, R Yerushalmi and A NaglerThe Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, IsraelReduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenousbusulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III-IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P ¼ 0.005) and acute graft-versus-host disease grade II-IV in 33 and 53%, respectively (P ¼ 0.01). Non-relapse mortality rate (NRM) was 16 and 40%, respectively (P ¼ 0.003). Active disease (HR 2.2, P ¼ 0.003) and prior autologous SCT (HR 1.7, P ¼ 0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P ¼ 0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies.

Graft-versus-host disease (GVHD) is

Allogeneic stem-cell transplantation (SCT) is potentially curative treatment for AML and MDS. New conditioning regimens are continuously explored trying to reduce toxicity while maintaining antileukemia effect. Treosulfan is an alkylating agent with in vitro cytotoxicity against leukemia as well as myeloablative and immunosuppressive properties when used in escalated doses. We explored a regimen of fludarabine (30 mg/m(2) x 5) and treosulfan (12 gr/m(2) x 3) in 24 patients, median age 55 years (range, 30-69), with AML (n = 19) or MDS (n = 5), not eligible for standard myeloablation. Donors were HLA-matched siblings (n = 11) or matched-unrelated (n = 13). Twenty-one patients engrafted within a median of 15 days. Extramedullary toxicity was relatively limited. The incidence of acute and chronic GVHD was 15% and 47%, respectively. With median follow-up of 19 months (range, 8 - 34), 16 patients are alive and 8 died (relapse-2, treatment-related-6). Two-year disease-free survival rate was 60% (95% CI, 39-81). The cumulative incidence of relapse was only 15% (95% CI, 5 - 44) while nonrelapse mortality rate was 25% (95% CI, 13-50). The fludarabine/treosulfan regimen can be considered a fully intensive, modified myeloablative regimen with effective antileukemia activity and acceptable toxicity in patients with AML/MDS not eligible for standard myeloablation, and merits further study in larger scale studies.

No abstract

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reducedintensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings and the long-term outcome is less defined. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given allogeneic SCT with different regimens (Leukemia 2006). We showed that survival was similar with myeloablative conditioning and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post transplant relapse rates. We have now updated SCT outcomes with an additional 3-year follow-up in the same cohort, to better predict long-term outcome and confirm that late events did not change the initial conclusions. The study group included 112 consecutive pts with AML/ MDS transplanted over a 5-year period. The median age at SCT was 50 years (18–70). Eighty-five pts had AML (39 secondary) and 17 had MDS (all with excess of blasts). Fiftyeight had active disease at SCT (>10% marrow blasts) and 54 were in remission. The donor was HLA-matched sibling (n=58), 1-ag mismatched related (n=6) and matched-unrelated (n=48). Forty-five pts met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). Sixtyseven pts were considered non-eligible for standard myeloablation due to advanced age (over 55 years for sibling SCT or over 50 years for mismatched or unrelated SCT), extensive prior therapy, organ dysfunction, recent fungal infection or poor performance status. These pts were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The median age of this group was 55 years compared with 42 years in the first group, and a larger proportion had SCT from unrelated donors. With a median follow-up of 5.1 years (3.3–8.6), 45 pts are alive and 67 have died (45 relapse, 22 non-relapse causes). Overall survival (OS) at 5 years was 48%, 31%, and 38% after ivBuCy, FB4, and FB2, respectively (p=NS). Active disease at SCT and poor-risk cytogenetics were the most significant factors predicting reduced survival in multivariable analysis with hazard ratios of 3.5 (p=0.0001) and 1.7 (p=0.04), respectively. Advanced age, secondary disease, donor and conditioning type had no prognostic significance. Myeloablative conditioning and RIC had similar outcomes when leukemia was in remission at SCT; estimated 5-year OS been 49%, 50% and 58% after ivBuCy, FB4, and FB2, respectively (p=NS). There was a non-statistically significant trend for lower non-relapse mortality (NRM) but higher relapse rate with FB2 resulting in similar OS in this setting. However pts with active disease could only be salvaged by myeloablative regimens (classical or modified). Among the later group, OS was 41% and 19% after ivBuCy and FB4, respectively, but no FB2 recipient survived (p=0.009). This was related to significantly higher relapse rates with the less intensive regimens in this setting (p=0.0005), while NRM was similar. These observations confirm with a longterm follow-up that RIC is associated with favorable outcome and low toxicity in pts in remission at SCT and therefore can be further studied in prospective trials comparing it to myeloablative regimens even in pts eligible for the later. However, RIC is a poor option for pts with active disease. Pts with active disease not eligible for standard myeloablation can still tolerate the modified myeloablative regimen (FB4) and a fraction can be salvaged. These observations merit further study in randomized prospective studies.