Upfront Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Idiopathic Aplastic Anemia: A Study on Behalf of the Saawp of EBMT
Authors: Petit Audrey Françoise , Eikema Dirk-Jan , Maschan Alexey , Adjaoud Dalila , Kulagin Aleksander , Rambaldi Alessandro , Fagioli Franca , Griškevičius Laimonas , Snowden John A , Johansson Jan-Erik , Dalle Jean-Hugues , Byrne Jenny , Risitano Antonio , Peffault De Latour Regis 
Published: February 2021

Introduction Young patients with idiopathic aplastic anemia (AA) respond better to immunosuppressive therapy (IST) but the long-term outcome is suboptimal with non-response in 30% of patients as well as significant risks of relapse, ciclosporine (CSA) dependence and clonal evolution. Excellent results of up-front unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) have been reported in a cohort of 29 children with idiopathic AA using an Alemtuzumab-based regimen, with low Graft versus Host Disease (GvHD) rates and only 1 death (Dufour C, BJH 2015). We took advantage of the SAAWP registry of the European Blood and Marrow Transplantation (EBMT) to analyze the outcomes of 65 young patients who received up-front UD HSCT in Europe.
Methods :
Patients who had received an UD HSCT for AA, between 2010 and 2018, registered in the SAAWP registry were included. Patients who had received IST (CSA or anti-thymocyte globulin (ATG)) before HSCT, cord blood, haplo-identical transplant were excluded as well as patients suffering from congenital bone marrow disorders. The primary endpoint was overall survival (OS) at 2 years. Secondary endpoints were GVHD-free/relapse-free survival (GRFS) - defined at 2 years as being alive, engrafted without acute GVHD grade III-IV, and extensive chronic GVHD during follow-up.
Results :
Sixty-five patients were included between 2010 and 2018; median age was 16 years old (9-26). Time to HSCT was 6.5 months (IQR 3.6-11.7). Thirty-nine patients were transplanted from a matched unrelated donor (at least 8/8 HLA matched), 11 patients had mismatched UD (HLA data missing for 14 patients).
The two-year overall survival rate was 92% (95% CI, 85-99%) (figure 1,A) with a median follow-up of 32 months (25-43). Main cause of death was infection (2 out of 5 deaths). Failure occurred in 8% (1-15%) of the patients. Acute GVHD grade II-IV was observed in 13% (5-22%) of the patients and Grade III and IV happened for two patients (3%). Chronic GVHD at 2 years occurred for 12% (4-21%) of the patients, with no extensive case. GRFS was 87% (77-96%) at 2-years (Figure 1, B). In our cohort, 57 patients received in vivo T cell depletion using either ATG (n=33, 60%) or anti-lymphocyte globulin (n=4, 7%) or alemtuzumab (n=20, 30%). Due to low rate of events happening during outcome, no risk factor analysis could be driven.
Conclusion: In this retrospective cohort of 65 patients with idiopathic aplastic anemia, up-front UD transplantation leads to promising results, confirming previous studies on a smaller cohort of patients. Moreover, we did not find any difference according to in vivo T-cell depletion type, suggesting excellent results are not exclusively related to alemtuzumab-based regimen. Because of obvious limitation related to retrospective studies, unreported events and information bias cannot be excluded. Prospective trials are on their way in the United States and in Europe to formally confirm upfront UD transplantation as standard of care for pediatric patients with idiopathic aplastic anemia.

Disclosures
Rambaldi: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Griškevičius:Novartis: Research Funding. Dalle:Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.