Allogeneic Hematopoietic Stem-Cell Transplantation In AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: 10 Years Later

Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings. There is paucity of data on the long-term outcome (beyond 10 years) following RIC due to the relative recent introduction of this approach. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). We showed that overall survival (OS) was similar with MAC and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post SCT relapse rates. We have now updated SCT outcomes in the same cohort with a median follow up of 10 years (range, 8.5-12.5) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. The median age at SCT was 50 years (18–70). Eighty-five pts had AML and 17 had MDS (IPSS int2 or high). 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) or matched-unrelated (n=48). Twenty-nine pts (26%) had poor risk cytogenetics. Forty-five pts met eligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide (BuCy). Sixty-seven pts were considered non-eligible for standard MAC due to advanced age, extensive prior therapy, organ dysfunction or poor performance status. These pts were given RIC with fludarabine and ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative doses of ivBu (12.8 mg/kg, FB4, n=26). The median age of RIC/RTC and MAC recipients was 55 and 42 years, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelated donors (p=0.01). In all, 38 pts are alive and 74 have died, 48 relapse, 26 non-relapse mortality (NRM). Overall survival (OS) at 10 years was 44% and 31% after MAC and RIC/RTC, respectively (p=0.22). Active disease at SCT and poor-risk cytogenetics were the most significant factors predicting reduced OS in multivariable analysis, HR 2.0 (p=0.05) and 2.7 (p=0.003), respectively. Advanced age, secondary disease, donor and conditioning type had no prognostic significance. MAC and RIC/RTC had similar outcomes when leukemia was in remission at SCT; 10-year OS been 47%, 50% and 47% after BuCy, FB4, and FB2, respectively (p=0.97). OS rates of pts with active disease at SCT was 43%, 19% and 0%, respectively (p=0.01) suggesting an advantage for more intense regimens in this setting. Relapse rates were higher after RIC/RTC than MAC throughout the follow-up period. The rate was 30% and 18%, 1 year after SCT (p=0.03), 37% and 20% after 2 years (p=0.08), 49% and 27% after 5 years (p=0.02) and 51% and 29% after 10 years (p=0.02), respectively. NRM rates were higher after MAC than RIC/RTC in the initial 2 years after SCT but approached each other in the late post SCT course. NRM rate was 22% and 9%, 1 year after SCT (p=0.05), 22 and 10% after 2 years (p=0.08), 22% and 15% after 5 years (p=0.27), and 27% and 19% after 10 years (p=0.35), respectively. Thus, OS was similar within the first 2 years after SCT, 56% and 52% after MAC and RIC/RTC, respectively (p=0.86), but there was a trend for better OS after MAC later on, 51% and 36%, 5 years after SCT (p=0.26) and 44% and 31%, 10 years after SCT (p=0.22), respectively. Forty-seven pts were alive 5 years after SCT (42%). Nine of them died later on. Four of 24 RIC/RTC survivors at this point later died, 3 of second malignancies, 1 of relapse. Five of 23 MAC survivors at 5 years later died, 2 of relapse, 2 of chronic GVHD, 1 of MI. For pts surviving 5 years after SCT, the expected OS for the next 5 years was 86% and 87%, respectively (p=0.76). In conclusion, with a long-term follow-up of more than 10 years, RIC/RTC is an acceptable alternative to MAC in ineligible pts. NRM is lower after RIC/RTC in the early post SCT period, but late NRM negates this early advantage. Relapse rates are higher after RIC/RTC throughout the course. Due to these observations, it seems an advantage of MAC may become apparent 5-10 years after SCT. Pts who are alive 5 years after SCT can expect similarly good further OS with both approaches. Long-term follow-up studies (beyond 10 years) are of significant importance when assessing SCT outcomes in general and RTC SCT in particular.