Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: Long-Term Follow-up.
Authors: Shimoni Avichai , Rand Avital , Hardan Izhar , Shem-Tov Noga , Volchek Yulia , Yerushalmi Ronit , Nagler Arnon 
Published: April 2020

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 (&gt;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.