Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine and Melphalan (FM) Reduced Intensity Conditioning (RIC) for High-Risk AML/MDS.
Authors: Oran B. , Saliba R. , Giralt S. , Couriel D. , Carrasco-Yalan A. , Hosing C. , Shahjahan M. , de Meis E. , Anagnostopoulos A. , Anderlini P. , Ghosh S. , Khouri I. , Champlin R. , de Lima M. 
Published: April 2020

Abstract
RIC with FM has extended the use of HSCT to patients otherwise not eligible for this treatment. Longer follow-up and larger number of patients now allow for more robust evaluation of risk factors and outcomes. Herein are the results of such an evaluation.
Patients and Methods: We evaluated outcomes of 112 patients with high-risk AML/MDS treated from August 1996 to December 2003 with FM (fludarabine 100–180 mg/m2 and melphalan 100–180 mg/m2) and unmanipulated HSCT. Eligibility included age &gt;54 yrs. or comorbidity precluding an ablative preparative regimen. Disease status at HSCT was relapsed/refractory (n=43, 38.4%), primary induction failure (n=32, 28.6%), untreated (n=7, 6.3%) or complete remission (CR, n=30, 26.8). Cytogenetic risk was intermediate (n=59, 53%), high (n=47, 42%), low (n=3, 2.5%) or unknown (n=3, 2.5%). Donors were HLA matched related (MRD; n=59) or unrelated (UD; n=53). GVHD prophylaxis was tacrolimus based in all but one patient. Anti-thymocyte-globulin was added in 31 UD HSCT. Stem cell sources were bone marrow (n=56) or peripheral blood (n=57). Median age was 55 (range 22–74). Evaluated were the following variables and their influence on disease progression and overall survival: - age, donor type, duration of first CR, disease status at transplant (categorized as CR, No CR with (NoCR/CB) and without circulating blasts (NoCR/NoCB)), cytogenetics, acute and chronic GVHD (time dependent variables), and blood counts on day 30 (lymphocytes, monocytes and platelets). We used a Cox’s regression analysis.
Results: Median time of follow up among survivors (n=43) was 28.4 mo (3.3–88.9). CR rate at day 30 post transplant was 87% (n=97), 8 patients died early and 7 did not respond. 25 (26%) of 97 patients progressed after day 30. All but 3 patients relapsed within the first year post HSCT, and only one relapsed more than 2 years after HSCT. In a landmark analysis, disease status at transplant was the only significant risk factor for progression among these 97 patients (HR of 3.7 for the NoCR/CB group compared to the CR group). 69 of 112 patients died with a median survival of 4.6 mo. Seven deaths (10% of all deaths) were observed more than 2 yrs. after HSCT, due to GVHD (n=3), infection (n=2), relapse (n=1) and unknown causes (n=1). Two-year OS and PFS was 44% and 69% respectively. Disease status at HSCT and grade II-IV aGVHD were the only significant predictors of OS on univariate and multivariate analysis. Blood counts on day 30 were associated with disease status at transplant, donor type and aGVHD. Their independent effect on outcome could not be evaluated given sample size.
Conclusion: A significant portion of older patients with high-risk AML/MDS may achieve long-term PFS, but early relapses are the major cause of treatment failure in this context.
Prognostic factors for event-free and overall survival Variables Multivariate analysis for disease progression CB=circulating blasts Disease status n Events (n) HR 95% CI p 2-yr PFS CR 30 6 1.0 57% (39–72) NoCR/NoCB 41 7 1.1 0.4–3.2 0.9 46% (30–60) NoCR/CB 26 12 3.7 1.4–9.8 0.001 22% (9–38) Multivariate analysis for overall survival (OS) Disease status HR 95% CI p 2-yr OS CR 30 12 1.0 66% (48–80) NoCR/NoCB 49 29 1.8 0.9–3.5 0.06 40% (26–53) NoCR/CB 34 28 2.8 1.4–3.5 0.002 23% (11–37) gd II-IV aGVHD 2.8 1.8–4.6 &lt;0.001