Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Acute Lymphoblastic Leukemia: Better Outcome in Transplantation during First Complete Remission and with Myeloablative Conditioning
Authors: Shimoni Avichai , Rand Avital , Hardan Izhar , Shem-Tov Noga , Stanevsky Anfisa , Yerushalmi Ronit , Nagler Arnon 
Published: October 2019

Abstract
Allogeneic stem-cell transplantation (SCT) is potentially curative therapy in acute lymphoblastic leukemia (ALL). However, the timing of SCT during disease course and the prognostic factors for outcome are still under debate. We retrospectively analyzed all allogeneic transplants given for ALL over a 7-year period in a single institution. During this period we have used a uniform policy according to the GMALL protocols. Patients determined to be at high-risk at presentation were transplanted in the first complete remission (CR1) most often after first consolidation. Patients at standard risk at presentation were only transplanted after failure of induction or at relapse. Patients were transplanted from the best available donor and sibling donor availability was not a pre-request in any setting when referring to SCT. Patients considered eligible for myeloablative conditioning were given high-dose cyclophosphamide and TBI (12 cGy in 6 fractions). Patients considered non-eligible for myeloablative conditioning were given a reduced-intensity conditioning regimen (RIC) consisting of fludarabine and melphalan (total 140/m2). Patients with unrelated donors were also given ATG during conditioning. The study group included 81 patients, median age 40 years (range, 17–65). Immunophenotyping was B (n=31), T (n=48) and NK (n=2). Twenty-nine patients had high-risk cytogenetics [Ph+-24, t(4;11)-4, t(1;19)-1]. The donor was an HLA-matched sibling (n=48), matched unrelated (n=23), haplo-identical relative (n=8) and double umbilical cord blood (n=2). At the time of SCT, 36 patients were in high-risk CR1 (by the GMALL criteria), 12 were in CR after salvage therapy given for induction failure (CRIF), 13 patients were in CR2, and 20 patients were given SCT during active chemo-refractory disease. With a median follow-up of 27 months (range, 1–79), 31 patients are alive and 50 died (31 relapse, 19 non-relapse causes). Five patients are alive after relapse, all with isolated extra-medullary relapse (CNS-2, breast-1, bone-1, mediastinum-1). All patients with systemic relapse died of their disease. Overall and disease-free survival at 3 years were 33% (95CI, 22–44%) and 26% (95CI, 15–37%), respectively. The status of disease at SCT was the most important factor predicting for OS; the 3-year OS rates are 52%, 28%, 28% and 5% for patients transplanted in CR1, CRIF, CR2 and active disease respectively (p=0.0004). Donor type was also predicting for outcome in the univariable analysis; 3-year OS was 35%, 42% and 10% after sibling, unrelated and alternative donor transplants, respectively (p=0.04). OS rates after myeloablative conditioning and RIC were 37% and 20%, respectively (p=0.02). High-risk cytogenetics was not a risk factor for survival. Ph+ and Ph− patients had an OS of 38% and 30%, respectively, and when only analyzing patients in CR1, 48% and 53%, respectively (p=NS). Age, gender and immunophenotype were also not predicting for OS. Multivariable analysis identified two factors; SCT during CR1 was a favorable factor with HR of 0.3 (0.1–0.5, P=0.0005), while SCT with RIC was an adverse factor, HR 2.7 (1.4–5.2, P=0.004). Patients transplanted in high-risk CR1 with myeloablative conditioning had a 3-year OS of 55% (95CI, 36–75). In conclusion, best results are achieved in ALL in SCT during CR1. One can extrapolate that even better results may be expected in SCT in standard-risk ALL in CR1. Outcome after relapse and especially in chemo-refractory disease is poorer. RIC should only be used when there is an absolute contraindication for standard myeloablative conditioning.