Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: The Role of Dose-Intensity.
Authors: Shimoni Avichai , Hardan Izhar , Shem-Tov Noga , Yeshurun Moshe , Yerushalmi Ronit , Ben-Bassat Isaac , Nagler Arnon 
Published: October 2019

Abstract
Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose-intensity we analyzed SCT outcomes of 112 consecutive patients (pts) with AML/MDS transplanted over a 5-year period. The median age was 50 years (18–70). Eighty-five patients had AML (39 secondary) and 17 had MDS (all with excess of blasts). Fifty-eight 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). Sixty-seven 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 22 months (2-62), 63 pts are alive and 49 have died (34 relapse, 15 non-relapse causes). Overall survival (OS) at 2 years was 50%, 49%, and 47% after ivBuCy, FB4, and FB2, respectively (p=NS). Non-relapse mortality was higher after ivBuCy, 22% Vs 8% and 8%, respectively (p=0.05) although these patients were younger and in a better medical condition. This difference was related to higher risk of acute GVHD grade III-IV after ivBuCy while deaths due to organ toxicity were rare in all groups. Relapse rates were lower after ivBuCy but not reaching statistical significance. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, p=0.0001). SCT from unrelated donor and poor prognosis cytogenetics had borderline significance while advanced age and secondary disease had no prognostic significance. Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT with a trend for better outcome with RIC; estimated 2-year OS been 60%, 68% and 80% after ivBuCy, FB4, and FB2, respectively (p=NS). However patients with active disease could only be salvaged by myeloablative conditioning (classical or modified). Among the later group, OS was 45% and 39% after ivBuCy and FB4, respectively, but no FB2 recipient survived (p=0.02). These observations suggest 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. Those not eligible for standard myeloablation could still tolerate modified myeloablation and enjoy its merits. The modified myeloablative regimen has low toxicity and similar cytoreductive effect and therefore can be further studied in prospective studies comparing it to standard myeloablative regimens even in pts eligible for the later.