The Impact of Cytogenetics on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Survey from the Acute Leukemia Working Party (ALWP) of EBMT
Authors: Poiani Monica , Labopin Myriam , Beelen Dietrich W. , Tischer Johanna , Finke Jürgen , Brecht Arne , Forcade Edouard , Ganser Arnold , Passweg Jakob R. , Labussiere-Wallet Helene , Yakoub-Agha Ibrahim , Schäfer-Eckart Kerstin , Kroeger Nicolaus , Lioure Bruno , Ruggeri Annalisa , Esteve Jordi , Nagler Arnon , Mohty Mohamad 
Published: October 2019

Abstract
Introduction: Diagnostic karyotype is one of the most important determinants of initial response to treatment, remission duration and overall survival in Acute Myelogenous Leukemia (AML). Moreover, risk stratification of AML based on cytogenetic abnormalities is a key parameter for the success rate and outcome of allogeneic stem cell transplantation (allo-SCT) in AML. However, while the prognostic significance of chromosomal abnormalities is well established during frontline therapy, its influence at time of salvage therapy in Primary Refractory (Ref) and Relapsed (Rel) AML and the role of allo-SCT in this subset, remains uncertain.
Patients and methods: This was a survey from the EBMT registry which included adult AML patients undergoing allo-SCT for Ref/Rel AML from HLA-matched related or 9/10 - 10/10 unrelated donor (UD) between 2000 and 2017. Patients were stratified according to cytogenetic risk as defined by Grimwade et al. (Blood 2010). Primary endpoint was Leukemia-Free Survival (LFS). Secondary endpoints were relapse cumulative incidence (RI), non-relapse mortality (NRM), overall survival (OS), acute and chronic GVHD and GVHD-relapse-free Survival (GRFS).
Results: 2089 patients with Ref AML (n=972) and Rel AML (n=1117) were analyzed: 154 patients had a favorable risk, 1283 were in intermediate risk and 652 had an adverse cytogenetic risk. Median follow-up was 49 months. Patients and transplant characteristics are summarized in table 1. Patients in the favorable risk group were younger and transplanted more frequently in first or second relapse. Patients in the adverse risk group received more frequently transplants from 9/10 UD. FLT3-ITD mutation was present in 18%, 43% and 16% of the favorable, intermediate and adverse risk groups, respectively (p<10-3). The 3 groups were not significantly different in terms of Karnosfky score, patient and CMV serology status and conditioning intensity (myeloablative or reduced).
Outcome correlated with cytogenetic category, with a percentage of complete remission within 100 days after transplant of 79%, 69% and 61% (p<10-3), RI at 2 years were 42%, 51% and 61% (p<10-5), LFS and OS rates were 34%, 27%, 18% and 41%, 33%, 22% in favorable, intermediate and adverse risk group (p<10-5 for both LFS and OS), respectively. Non-relapse mortality, on the contrary, did not differ among the three groups (24%, 21% and 21%, respectively; p=NS).
We performed a multivariate analysis adjusting for all factors differing between risk groups and factors known as influencing outcome of AML patients after allograft. Compared to the favorable risk group, intermediate risk group was associated with a higher RI (HR=1.58; 95% CI: 1.17-2.14; p=0.003), lower LFS (HR=1.39; 95% CI: 1.09-1.77; p=0.008), lower OS (HR=1;47; 95% CI: 1.14-1.90; p=0.003) and lower GRFS (HR=1;29; 95% CI: 1.03-1.61; p=0.03). The adverse risk group was associated with a higher RI (HR=2.27; 95% CI: 1.65-3.10; p<10-5), lower LFS (HR=1.86; 95% CI: 1.44-2.40; p<10-5), lower OS (HR=1.89; 95% CI: 1.44-2.47; p<10-5) and lower GRFS (HR=1.62; 95% CI: 1.28-2.06; p<10-4; Figure1).
In a subgroup analysis of patients in intermediate or adverse risk groups with available information on FLT3-ITD status, adverse cytogenetics remained an important prognostic factor for RI (HR=1.55; 95% CI: 1.22-1.97; p=0.0004), LFS (HR=1.37; 95% CI: 1.12-1.68; p=0.002), OS (HR=1.38; 95% CI: 1.11-1.70; p=0.003) and GRFS (HR=1.31; 95% CI: 1.08-1.59; p=0.006) compared to the intermediate risk group. Other poor prognostic factors in this population were presence of FLT3-ITD mutation, Rel vs Ref status at transplant, Karnofsky score <80%, use of bone marrow as stem cell source and patient CMV serology positivity. In vivo T cell depletion was associated with a lower risk of acute and chronic GVHD and a better GRFS.
Conclusion: In Rel and Ref AML karyotype remains an important prognostic factor for those patients undergoing allo-SCT in active disease phase, allowing to separate patients into different risk groups. Moreover, FLT3-ITD mutation remains a negative prognostic factor in this population.

Disclosures
Beelen: Medac: Consultancy, Other: Travel Support. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Mohty:MaaT Pharma: Consultancy, Honoraria.