Allogeneic Stem Cell Transplantation In Adults With High Risk Acute Lymphoblastic Leukemia (ALL) In 1. Remission (CR1): Promising, But Strongly Influenced By ALL Subtypes
Authors: Arnold Renate , Terwey Theis H. , Vuong Giang Lam , Ostendorf Benjamin , Penack Olaf , Massenkeil Gero , Gökbuget Nicola , Hemmati Philipp 
Published: October 2019

Abstract
Stem cell transplantation (SCT) has contributed to improved overall survival particularly in high risk adult ALL patients and the indication for SCT is a matter of ongoing discussion. We report the results obtained over a period of 18 years in a large center. Patients received first line treatment according to three consecutive trials of the German Multicenter Study group for Adult ALL (GMALL) and risk stratification was performed accordingly. In the most recent trial patients with high risk and very high risk factors are candidates for allogeneic stem cell transplantation (SCT) in CR1 from matched sibling or unrelated donors. The risk factors are: very high risk (VHR): Philadelphia chromosome positive ALL (Ph+ALL); high risk group (HR) of B-lineage ALL (HR-B): leukocytes > 30/nl at diagnosis and/or delayed CR > 3 weeks (other B) or pro B-ALL and of T-lineage ALL (HR-T): early-T-All and mature T-ALL. In addition standard risk patients were candidates for SCT in case of molecular failure or molecular relapse (SR-Mol). 106 high risk ALL patients in CR1 underwent allogeneic SCT between 1995 and 2012 at our center. Median age was 38 years (17 – 67). 40/106 patients had Ph+ALL (VHR), 57/106 patients were HR patients (HR-B n = 32: pro-B-ALL n = 15, other B n = 17; HR-T n = 25: early T n = 17, mature T n = 4, thymic n = 4). 9/106 patients belonged to the SR-Mol group. Stem cell donors were matched related donors (MRD) in 42 patients and compatible unrelated donors in 64 patients. The conditioning regimen was 12 Gy TBI ± Cyclophosphamide or VP16 in 86 patients, other n = 1, and in patients > 55 years 8 Gy TBI + Fludarabine (n = 5) or Fludarabine + Busulfan (n = 14). ATG as GvHD and rejection prophylaxis was given since 5/2005 in all patients with unrelated SCT and in reduced intensity conditioning regimens (RIC).

Results
60/106 (57 %) patients with high risk ALL transplanted in CR1 are alive, 46/106 (43 %) patients are dead. The median follow-up of the surviving patients is 64 months (5 – 172). Causes of death were leukemia in 16/106 patients (15%) and transplant-related mortality (TRM) in 30/106 patients (28%), mainly infections ± GvHD (n = 24), secondary malignancies (n = 2) and other (n = 4). In Ph+ALL 19/40 patients (47 %) are alive in CR (CCR), 12/40 are dead due to TRM and 9/40 due to leukemia. In HR-B ALL 23/32 patients (71 %) are in CCR, 8/32 are dead due to TRM and 1/32 due to leukemia. In HR-T ALL 11/25 patients (44 %) are in CCR, 10/25 died due to TRM and 4/25 due to leukemia. In SR-Mol patients 7/9 patients (77 %) are in CCR, 2/9 died due to leukemia. Probability of survival (OS) for all patients at 96 months is 0.48, probability of disease free survival (DFS) at 96 months is 0.47, probability of TRM at 96 months is 0.34. OS was 0.50 for patients with myeloablative conditioning (MAC) (n = 86) and 0.38 for patients with RIC (n = 19), n.s. OS was different for the 4 risk groups: VHR 0.42, HR-B 0.67, HR-T 0.27, SR-Mol 0.74, but not significant (0.095). DFS: VHR 0.42, HR-B 0.68, HR-T 0.24, SR-Mol 0.76 (0.041) and TRM: VHR 0.34, HR-B 0.26, HR-T 0.58, SR-Mol 0. (0.026). In HR-B OS was better for pro-B-ALL than other B-lineage (0.73.vs. 0.66, resp.). OS was lower in early-T-ALL (0.24). In mature T-ALL 3/4 patients are dead, in thymic ALL 1/4 patients.

In Conclusion
Long term survival and probably cure can be reached in high risk ALL patients after allogeneic stem cell transplantation in CR1. OS in pro-B-ALL and B-lineage-HR-ALL patients is better than in Ph+ALL or in HR-T-ALL due to lower relapse rate and lower TRM. Whether the quality of remission before allogeneic SCT could be improved in Ph+ALL and HR-T-ALL, has to be studied. Allogeneic SCT in SR with molecular failure or relapse show promising data, though in a small patient cohort. For all patients the TRM-rate due to GvHD and infection has to be improved due to better supportive care.

Disclosures:
No relevant conflicts of interest to declare.