Impact of Donor Type on Outcome after Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia Patients: Analysis of the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG)
Authors: Kuchenbauer Florian , Bunjes Donald W. , Herr Wolfgang , Heuser Michael , Späth Daniela , Casper Jochen , Horst Heinz-August , Brossart Peter , Held Gerhard , Kobbe Guido , Ringhoffer Mark , Wattad Mohammed , Salih Helmut R , Götze Katharina , Wulf Gerald , Theobald Matthias , Rummel Mathias J , Fiedler Walter , Westermann Jörg , Salwender Hans , Petzer Andreas L. , Hartmann Frank , Lübbert Michael , Martens Uwe , Greil Richard , Kirchner Hartmut H. , Paschka Peter , Gaidzik Verena I. , Teleanu Veronica , Thol Felicitas , Göhring Gudrun , Döhner Konstanze , Ganser Arnold , Döhner Hartmut , Schlenk Richard F. 
Published: October 2019

Abstract
Background:Despite recent advances in identifying novel molecular targets in AML patients, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) still remains a cornerstone of AML therapy. However, outcome of HSCT depends on the availability of a donor and the donor type. Prior studies comparing HSCT from HLA-matched related donors (MRD) with matched unrelated donors (MUD), demonstrated conflicting results with regards to outcome. These conflicting results might be attributed to the genetic heterogeneity of AML.
Aims:To analyze outcome with respect to donor type of 952 AML patients who received HSCT in first complete remission (CR) and were treated within prospective AMLSG trials.
Methods:Within the AMLSG trials conducted between 1993 and 2013, of a total of 4991 patients (excluding acute promyelocytic leukemia), 3408 (2744 younger (<61 years old), 664 older (≥61 years old)) patients achieved a first CR after intensive double induction therapy. Of these, 867 (31%) younger and 85 (13%) older patients received HSCT in first CR. Distributions of donor types were 511 matched related donors (MRD), 435 matched unrelated donors (MUD) and 6 haplo-identical donors. The latter were grouped together with MUD.
Results:Distributions of donor type over time are illustrated in table 1 indicating two clear trends with increasing numbers of MUD transplants and increasing median age in MUD- and MRD-transplants in recent years. There was no significant difference in overall survival, cumulative incidence of relapse (CIR) and death (CID) all estimated at 4 years according to the three time periods for MRD (p=0.56, p=0.15, p=0.10, respectively) and MUD (p=0.27, p=0.20, p=0.88, respectively).
Table 1 Time period 1993-2002 2003-2007 2008-2013 Total no. 1036 1102 1270 MRD  No. 186 (18%) 182 (17%) 143 (11%)  Median age 42.7yrs 46.0yrs 51yrs  4-yr-OS (95%-CI) 59% (53-67) 66% (59-73) 61% (53-72)  4-yr-CIR (SE) 21% (3%) 25% (3%) 29% (4%)  4-yr-CID (SE) 25% (3%) 15% (3%) 18% (3%) MUD  No. 42 (4%) 131 (12%) 268 (21%)  Median age 41.1yrs 47.9yrs 50.6yrs  4-yr-OS (95%-CI) 52% (39-70) 46% (38-58) 54% (47-61)  4-yr-CIR (SE) 21% (3%) 25% (3%) 29% (4%)  4-yr-CID (SE) 25% (3%) 15% (3%) 18% (3%)
Table 2 ELN risk category low inter-1 inter-2 high Total no. 867 711 433 318 MRD  No. 78 (9%) 122 (17%) 66 (15%) 57 (18%)  4-yr-OS (95%-CI) 84% (76-93) 50% (51-69) 53% (41-67) 57% (44-72)  4-yr-CIR (SE) 7% (3%) 24% (4%) 35% (6%) 49% (7%)  4-yr-CID (SE) 13% (4%) 23% (4%) 23% (6%) 12% (4%) MUD  No. 21 (2%) 139 (20%) 76 (18%) 109 (36%) 4-yr-OS (95%-CI) 69% (52-93) 58 (49-68) 52% (41 67) 35% (26-46)  4-yr-CIR (SE) 0% 28% (4%) 32% (6%) 44% (5%)  4-yr-CID (SE) 31% (11%) 20% (4%) 17% (5%) 28% (4%)
There were no differences in stratified survival analyses for time period between MRD and MUD-transplants in the low, intermediate-1 and intermediate-2 risk groups with respect to OS (p=0.12, p=0.86, p=0.98), CIR (p=0.28, p=0.54, p=0.94) and CID (p=0.09, p=0.57, p=0.39). In the high risk group, OS was significantly superior after MRD-transplant compared to MUD-transplant (p=0.02), but without significant differences in CIR (p=0.74) and CID (p=0.08). Equivalent efficacy could also be shown in a subgroup analyses focusing on all FLT3-ITD positive patients (MRD, n=103, MRD, n=147) for OS (p=0.71), CIR (p=0.53) and CID (p=0.69).
Conclusions: Our results based on prospective interventional studies support the perception that MUD-transplants are equal to MRD-transplants in patients with AML in first CR. Only within the ELN high risk group, patients with MRD-transplants showed superior OS but without differences in CIR and CID as compared to MUD-transplants.

Disclosures
Kobbe: Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Petzer:Celgene: Honoraria, unrestricted grant Other. Lübbert:Cephalon / TEVA: Travel support Other. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Döhner:Novartis: Research Funding. Döhner:TEVA: Research Funding.