Sequential Chemotherapy Followed by Reduced Intensity Conditioning and Allogeneic Stem Cell Transplantation (allo-SCT) in Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): A Survey From the Acute Leukemia Working Party of EBMT
Authors: Ringden Olle , Labopin Myriam , Kolb Hans Jochem , Michallet Mauricette , Kröger Nicolaus , Ganser Arnold , Bunjes Donald , Hallek Michael , Kanz Lothar , Schwerdtfeger Rainer , Holler Ernst , Arnold Renate , Huynh Anne , Nagler Arnon , Schmid Christoph , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 2025
Patients with refractory or relapsed AML have a very dismal outcome. In the light of poor results with conventional therapy, allo-SCT is the recommended treatment for refractory AML. However, results are limited by a high relapse incidence (RI) and high non-relapse mortality (NRM). To improve the dismal outcome of patients with refractory or relapsed AML, the sequential application of cytoreductive chemotherapy, followed by reduced-intensity conditioning (RIC) allo-SCT, may represent an attractive treatment option.
The aim of this multicentre analysis was to assess the outcome of 239 AML patients who received such a so-called sequential chemotherapy and allo-SCT and were reported to the EBMT registry. Sequential chemotherapy included fludarabine (30 mg/m2), cytarabine (2g/m2) and amsacrine (100mg/m2) for 4 days followed by RIC with busulfan (Bu) in 73 patients, or cyclophosphamide (80–120mg/kg) and 4Gy. TBI (Cy-TBI) in 166 patients. Median age was 62 and 51 years (range, 19–73) and median year of transplant was 2009 and 2008 in the two groups respectively (p=0.0001). Patients with primary induction failure (PIF), 1st or 2nd relapse AML did not differ significantly between the Bu and Cy-TBI patients. There were more unrelated donor transplants in the Bu group (p=0.05). CR rate post transplant, engraftment, acute and chronic GVHD were similar between the two groups. One year NRM, RI, OS and leukemia free survival (LFS) were 24+/−5% vs 16+/−3%, 44+/−6% vs 51+/−4%, 46+/−7% vs 47+/−3% and 32+/−6% vs 33+/−4% in the Bu and Cy-TBI groups respectively (p=ns). Recipients of unrelated grafts had a lower probability of RI (Hazards ratio (HR)=0.64, p=0.02) and better LFS (HR=0.67; p=0.02) compared to recipients of HLA identical sibling allo-SCT. One year probability of relapse and LFS were 43+/−4% and 38+/−4% using unrelated donors as opposed to 60+/−6% and 24+/−5% when the donors were HLA identical siblings. In the multivariate analysis, conditioning by Bu or Cy-TBI, age, disease stage or year of transplant had no significant impact on NRM, RI, OS or LFS.
In conclusion, the current data suggest that a sequential strategy of intensive chemotherapy, followed by RIC allo- SCT, might represent a step forward in the treatment of refractory AML. Results from the current survey suggest that this strategy might be considered early in the course of a patient with AML not responding to conventional chemotherapy. Controlled prospective studies are warranted and currently being performed (e.g. ClinicalTrials.gov Identifier: NCT01188174).

Disclosures:
Hallek: Roche: Consultancy, Honoraria, Research Funding.