Up-Front Matched Unrelated Donor Transplantation in Pediatric Patients with Idiopathic Aplastic Anemia: A Phase II Feasibility Study, on Behalf of Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC) and French Reference Nation

Introduction: For patients (pts) <40y with severe aplastic anemia (SAA), allogeneic stem cell transplantation (HSCT) from matched sibling donor (MSD) represents the 1st line curative therapy with a reproductible long-term overall (OS) and event free survival (EFS) rates above 85 and 75%, respectively where immunosuppressive therapy leads to statistically worse results for long-term EFS. For this reason -thanks to the enhanced results of HSCT from matched unrelated donor (MUD) in other diseases- some authors proposed such HSCT as front-line therapy for pts < 18y. However, there is no evidence about the feasibility and safety of this approach, especially regarding the delay between diagnosis and HSCT as compared to the risk of infection, hemorrhages or transfusion related events. Methods: We conducted a prospective multicentric open phase 2 single arm study to evaluate feasibility and safety of frontline HSCT from 10/10 MUD in pts < 18y with SAA. The primary objective was to realize up-front HSCT within 60 days after identifying MUD (targeting >45% rate) and secondary objectives were OS, graft failure, cumulative incidence (CI) of both graft versus host disease (GvHD), relapse, and non-relapse mortality (NRM), chimerism, quality of life and immune reconstitution. A Simon minimax 2-stage phase 2 design was used to test the strategy after 12 (first stage) pts and if 5 or fewer satisfied the primary objective, to terminate the trial up to a total of 25 pts. Inclusion criteria were: having idiopathic SAA (i.e.no evidence of IBMF) requesting treatment; <18 years at diagnosis; no MSD; no previous immunosuppressive therapy for SAA; having at least 3 10/10 MUD identified in BMDW registry. Stem cell source was bone marrow only. Conditioning regimen was fludarabine (30mg/m2/d) and cyclophosphamide (30mg/m2/d) D-6 to D-3 and either anti-thymoglobuline (Genzyme, France) 15mg/kg TD or total body irradiation 2Gy + ATG 7,5mg/kg TD depending on the age, below 14y or above. GvHD prophylaxis was ciclosporine A from D-1 to D365 associated to methotrexate 8mg/m2 D+1,+3 and+6. Rituximab was given at D+5 as EBV-PTLD prophylaxis. Results: Interim analysis was based on 16 pts (median age: 9.6y, IQ:3.7-12.5), 50% of male were included and 15 received the conditioning regimen as per protocol followed by HSCT. The last one did not fulfil inclusion criteria. Median time from donor identification to HSCT was 67 days (CI95%: 57.5-79) and 5 pts received transplantation within 60 days where the 10 remaining received it above D60. All pts engrafted at a median time of D+30 (95%CI: 28.5-32.5). D+150-CI of acute GvHD was 23% (95%CI: 4.7-49.9) and 1 pt developed chronic GvHD. 1 pt died from EBV-PTLD at D+60 post-HSCT. At a median follow-up of 12 months, there were no primary nor secondary graft failure. 1 year-OS was 93.3% (95%CI 81.5-100). Discussion-Conclusion: This study felt to meet the primary end-point and according to the rules has been prematurely ended. However, the cutoff of 60 days from donor identification to transplant was arbitrarily decided while the median time to HSCT was 67 days, with all but one pts transplanted within 80 days and none experienced severe infection postponing or canceling HSCT. The OS rate at 1y appears at least comparable to this reported for HSCT from MSD and the GvHD CI is acceptable. Even though it's too early to be affirmative, long-term side effects should be the same than with MSD. Finally, up-front HSCT from MUD for pts below the age of 18y presenting with SAA appears safe when the donor is available within 75-90 days. Rituximab is mandatory to lower the risk of EBV-PTLD for both prophylaxis and early pre-emptive treatment.If the donor recruitment is delayed, immune-suppressive therapy has to be preferred and promptly started.