Reduced Intensity Conditioning Allogeneic Haematopoietic Stem Cell Transplantation - a Treatment Option in Elderly or Comorbid Patients with Acute Lymphatic Leukemia
Authors: Vucinic Vladan , Tumewu Theresa , Franke Georg-Nikolaus , Schwind Sebastian , Jaekel Nadja , Heyn Simone , Poenisch Wolfram , Al-Ali Haifa Kathrin , Leiblein Sabine , Krahl Rainer , Jentzsch Madlen , Behre Gerhard , Niederwieser Dietger 
Published: October 2019

Abstract
Introduction: Prognosis of patients (pts) with high risk acute lymphatic leukemia (ALL) in first complete remission (CR) or ALL >CR1 is poor. For years, myeloablative conditioning followed by allogeneic stem cell transplantation (HCT) was the only curative treatment option for eligible pts. Over the past years, reduced intensity conditioning (RIC) regimens have been introduced to provide a curative treatment for elderly pts or ones with comorbidities ineligible for myeloablative chemotherapy. In this retrospective survey we analyzed the outcomes of ALL pts not eligible for conventional myeloablative HCT who were treated with RIC-HCT.
Patients and Methods: Twenty-eight (55% male, 45% female) consecutive pts, who underwent RIC-HCT from sibling (MRD) or unrelated donors (MUD) between 2003 and 2013 in our institution were analyzed. The median age at transplantation was 58 (range 23 to 71) years. The conditioning regimen consisted of Fludarabine 30 mg/m2 from days -4 to -2 and a 200 cGy total body irradiation on days -1 or 0 before HCT. Reasons for RIC HCT as opposite to myeloablative chemotherapy was age over 50 years for MUD, and age over 55 years for MRD HCT. Eight (28.5%) pts were younger than 50 years and had comorbidities, making them ineligible for a myeloablative conditioning regimen. Median follow up was 2.4 years for pts alive.
Three pts (10.7%) underwent second HCT, one after early transplant failure and two after late rejections. Six HCTs (19.4%) were performed from sibling donors, 17 (54.8%) from human leukocyte antigen (HLA) matched unrelated donors and eight (25.8%) from HLA mismatched (>1 allele) donors. Eight of our patients (28.5%) were Philadelphia chromosome (Ph) positive.
Results: After two years the overall survival (OS) was 49±10% and event-free survival (EFS) was 40.5±9.4% with a non-relapse mortality incidence of 34±9.6%. The cumulative incidence of relapse (CIR) amounted 37±9.6% at two years. There was no statistically significant difference in two years OS in pts after RIC-MRD vs RIC-MUD, however CIR was higher in pts with MRD than in pts with MUD, though without reaching statistical significance. Patients in CR1 had higher two years OS 63.1+12.1 compared to patients in CR2 or worse 42.4+14.8 though without reaching statistical significance. Noteworthy, six of eight patients in the high-risk Ph+ cohort are still alive and only one of them relapsed after HCT.
Of the three pts who underwent second HCT, one died due to Graft versus Host Disease (GvHD) eight months after the second transplantation. The other pts are still in persistent CR seven and two years after the second HCT.
Conclusion: RIC-HCT can be used in pts with ALL and is certainly a curative option for pts with higher age (up to 71 years) or severe comorbidities. In the high-risk Ph+ cohort we observed remission rates of 62.5%. Prospective studies are needed to define the role of RIC-HCT in high risk ALL or in remission after relapse even if only an one antigen mismatch unrelated donor is available.

Disclosures
Jaekel: Novartis: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.