Use of Post-Transplant Cyclophosphamide in One-Antigen Mismatched Unrelated Donor Transplantation Results in Similar Transplant Outcomes Than Haploidentical Hransplantation: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the EBMT
Authors: Battipaglia Giorgia , Galimard Jacques-Emmanuel , Labopin Myriam , Angelucci Emanuele , Blaise Didier , Ruggeri Annalisa , Gulbas Zafer , Díez-Martín José Luis , Koc Yener , Castagna Luca , Vitek Antonin , Sica Simona , Bruno Benedetto , Moiseev Ivan S. , Rovira Montserrat , Martino Massimo , Araujo Mercedes Colorado , Arat Mutlu , Grillo Giovanni , Martin Hans , Corral Lucía López , Pane Fabrizio , Ciceri Fabio , Nagler Arnon , Mohty Mohamad 
Published: November 2020

Introduction. In the absence of an HLA-identical sibling or a matched unrelated donor, whether to prefer a Haploidentical (Haplo) or a one antigen mismatched unrelated donor (MMUD) for allogeneic hematopoietic cell transplantation (HCT) remains an unanswered question. Implementation of graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) was initially pioneered in the Haplo and then also extended to MMUD setting, resulting in low rates of GVHD.
Methods. This was a retrospective study from the EBMT registry. Included were adults undergoing either Haplo- or MMUD-HCT for acute myeloid leukemia during the period 2010-2018 and who were in first or second complete remission at allo-HCT. Only patients receiving unmanipulated grafts with PTCY as GVHD prophylaxis were included. Ex vivo and in vivo T-cell depletion were exclusion criteria. Comparisons were made among three groups: MMUD-HCT with peripheral blood as stem cell source (PBSC; n=124); Haplo-HCT with bone marrow (Haplo-BM; n=560); Haplo-HCT with PBSC (Haplo-PB; n=769).
Results. Patients in Haplo-PB were older (median age of 55 years versus (vs) 52 and 51 years in MMUD-HCT and Haplo-BM, respectively; p&lt;0.01). Median time from diagnosis to transplantation was 6 months in all the groups. Class I (80%) were more frequent than class II mismatches (20%) in MMUD-HCT. A myeloablative conditioning regimen was used in 52%, 71% and 58% of patients in MMUD-HCT, Haplo-BM and Haplo-PB, respectively (p&lt;0.01). The most frequently used regimen in MMUD-HCT was busulfan-fludarabine (43%), while a thiotepa busulfan-fludarabine regimen was the most frequently used in Haplo-BM (64%) and Haplo-PB (35%). A calcineurin inhibitor in association to mycophenolate mofetil were the most frequently adjuvant immunosuppressive agents. Median time for neutrophil engraftment was 20 days in MMUD-HCT and Haplo-BM and 19 in Haplo-PB, with a cumulative incidence (CI) of neutrophil engraftment at day 30 of 91%, 88% and 89% for MMUD-HCT, Haplo-BM and Haplo-PB, respectively. The CI of grade II-IV acute GVHD was lower in Haplo-BM (21% vs 33% and 34% in MMUD-HCT and Haplo-PB, respectively, p&lt;0.01). Similarly, CI of grade III-IV acute GVHD was lower in Haplo-BM, being 6% vs 13% in both MMUD-HCT and Haplo-PB (p&lt;0.01). Due to longer follow-up in Haplo-BM, outcomes were calculated after censoring at 2 years. CI of chronic GVHD of all grades and of extensive chronic GVHD were significantly lower in Haplo-BM (for chronic GVHD of all grades 26% vs 36% and 35% in MMUD-HCT and Haplo-PB, p=0.01; for extensive chronic GVHD 9% vs 16% and 13% in MMUD-HCT and Haplo-PB, p=0.03, respectively). No differences were observed in the CI of relapse, this being 20% in both MMUD-HCT and Haplo-PB and 23% in Haplo-BM (p=0.39). The CI of non-relapse mortality (NRM) was significantly lower in MMUD-HCT as compared to Haplo-HCT (11% versus 20% and 25% in Haplo-BM and Haplo-PB, respectively; p&lt;0.01). We observed no differences in the probability of either overall survival (OS, 70% vs 62% and 60% in MMUD-HCT, Haplo-BM and Haplo-PB, p=0.12) or leukemia-free survival (LFS, 69% vs 56% and 55%, p=0.06) among the three groups. In Haplo-PB GVHD-free/relapse-free survival (GRFS) was lower (42% vs 49% in the other two groups, p&lt;0.01). In multivariate analysis, Haplo-HCT was associated to a lower LFS and a higher NRM as compared to MMUD-HCT (reference group) (hazard ratio (HR) for LFS 1.57, 95% CI 1.06-2.33, p=0.02; 1.52 (95% CI 1.05-2.22, p=0.03 for Haplo-BM and Haplo-PB, respectively) (HR for NRM 2.25, 95% CI 1.16-4.33, p=0.02; 2.58, 95% CI 1.37-4.86, p&lt;0.01 for Haplo-BM and Haplo-PB, respectively). On the other hand, Haplo-BM was associated to lower risk of grade II-IV (HR 0.64, 95% CI 0.42-0.96; p=0.03) and grade III-IV acute GVHD (HR 0.45, 95% CI 0.24-0.85; p=0.01) and also lower risk of chronic GVHD (HR 0.52, 95% CI 0.28-0.96; p=0.04). Of note, no differences in GRFS or OS were observed in multivariate analysis according to donor type.
Conclusion. According to our results, use of MMUD is associated to significantly higher LFS. However, our results highlight that both MMUD- and Haplo-HCT are valid options for transplant candidates, with no differences in GRFS. On the other hand, when choosing Haplo over MMUD, one should consider BM as stem cell source in order to better prevent GVHD. Further strategies to better prevent NRM are needed, particularly in Haplo-HCT.

Disclosures
Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.