Impact of Donor Search Strategy for Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical or Matched Unrelated Donor for Patients Older Than 55 Years with Hematological Malignancies: Randomized Prospective Phase III Study
Authors: Harbi Samia , Boher jean Marie , Forcade Edouard , Chevallier Patrice , Régis Peffault De Latour , Malard Florent , Francois Sylvie , Charbonnier Amandine , Hermet Eric , Bulabois Claude-Eric , Huynh Anne , Berceanu Ana , Cluzeau Thomas , Rubio Marie Thérèse , Furst Sabine , Mohty Mohamad , Devillier Raynier , Blaise Didier 
Published: February 2021

Background
Allogeneic stem cell transplantation (Allo-SCT) from a matched related donor (MRD) is rarely performed for older patients because of lack of such a donor. Matched unrelated donor (MUD) is considered as an alternative for this population with limited access due to excessive expected toxicity. Recently, the development of allo-SCT from haploidentical donors (Haplo) with the use of high dose post-transplant cyclophosphamide showed promising results with outspreading diffusion despite HLA disparity. Donor search is early implemented when patients are referred to transplant team. The impact of this strategy on patients with high risk malignancies outcomes is not well known. We propose to address this question through an intention-to-treat trial. We also hypothesized that Haplo-SCT could be a valid alternative to MUD-SCT for older patients with hematological disease whenever allo-SCT is recommended.
Study design and methods
We performed a prospective, multicenter, open-label, randomized controlled trial (NCT02623309) comparing two strategies of allo-HSCT from UD or Haplo. Patients older than 55 years with hematological malignancies were randomly assigned to a Haplo and a MUD search soon after the absence of MRD was established. The goals of the study were to prospectively evaluate feasibility, safety and efficacy of these approaches in an intent-to-treat analysis and a HSCT-performed analysis.
Results
From February 2016 to June 2018, 108 patients were enrolled. One hundred and six patients were analyzed. Median age was 65 years (range 55-70). Diseases were myeloid malignancies in 84 patients (79%).DRI was low, intermediate and high in 5(5%), 59(55%) and 42(40%),respectively. Fifty-five patients were assigned to Haplo group and 51 patients to MUD group. Fifteen patients in Haplo group could not proceed to allo-SCT because of progression (n=9), contraindication (n=5), no donor (n=1) and 14 patients in MUD group because of progression (n=8), contraindication (n=4) and loss of indication (n=2).
Among 40 patients in Haplo group, 9 patients (22%) actually received allo-SCT from MUD because of donor contraindication (n=6), donor specific antibodies (n=1), no Haplo identified (n=2). Eleven patients out of 37 patients (30%) in MUD group received allo-SCT from Haplo because of no MUD identified (n=7), donor refusal (n=2), donor contraindication (n=1), excessive search delay to identify a MUD (n=1). After cross over, 42 and 35 patients actually underwent per protocol allo-HSCT from a Haplo and a MUD, respectively. Median time from randomization to allo-SCT was 3 months (range 0.7-10).
In intention-to-treat analysis from date of randomization, 2-year PFS and OS did not differ between the two groups (Haplo vs MUD arm: PFS: 42 vs 48 %, p=0.463; OS: 44 vs 61%, p=0.126). Non-relapse mortality (NRM) at 2 years was 31% for both groups while the 2-year cumulative incidence of relapse (CIR) was 14% and 18 % (p=0.99) after Haplo and MUD arm, respectively.
In per-protocol analysis, with a median follow up of 26 months (range 3-34) after transplant 2-year NRM was 37% and 35% (p=0.893) after Haplo and MUD SCT, respectively. The cumulative incidence of grades 3-4 acute GVHD at 100 days was 21% and 17% (p = 0.402) in the Haplo and MUD SCT, respectively. No difference was observed in 2-year extensive chronic GVHD (Haplo vs MUD: 10% vs 15%, p = 0.534). 2-year CIR was 17% and 18% (p=0. 952) after Haplo and MUD SCT, respectively. No significant difference in 2-year PFS (Haplo vs MUD: 46% vs. 47%, p = 0.948) and OS (Haplo vs MUD: 55% vs. 52%, p = 0.944) was observed.
Conclusion
In an intent-to-treat analysis from the time of randomization, outcomes do not differ between the 2 groups. However, we observed that almost half of the patients did not receive the randomly attributed treatment 1/ Twenty-nine (27%) patients did not succeed to go to transplant 2/ Twenty (19%) patients were transplanted from another donor source that the one initially randomized to. It notably indicates that defining an early donor choice may be somehow dogmatic and should invite to more flexibility. We were able to demonstrate for older patients with high risk malignancies (IR: 17% Haplo; 18% MUD) a good disease control. Our per protocol analysis prospectively confirm in randomized study that Haplo-HSCT is a valid alternative in older patients. This suggests that HLA matching should not be necessarily considered as the most important factor for donor choice

Disclosures
Harbi: Sanofi: Honoraria. Chevallier:Incyte Corporation: Honoraria. Malard:JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Theralos/Mallinckrodt: Honoraria; Keocyt: Honoraria; Sanofi: Honoraria; Biocodex: Honoraria; Janssen: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Rubio:Neovii: Research Funding; Novartis: Honoraria; MSD: Honoraria; Gilead: Honoraria; Medac: Consultancy. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Blaise:Jazz Pharmaceuticals: Honoraria.