Outcome of Transformed Fanconi Anaemia Patients after Hematopoietic Stem Cell Transplantation: Analysis on Behalf of European Group for Blood and Marrow Transplantation
Authors: Giardino Stefano , Eikema Dirk-Jan , Peffault De Latour Regis , Bertrand Yves , Aljurf Mahmoud , Tbakhi Abdelghani , Holter Wolfgang , Bornhäsuer Martin , Rössig Claudia , Zecca Marco , Michel Gerard , Ganser Arnold , Afanasiev Boris , Al-Seraihy Amal , Bosman Paul , Miano Maurizio , Pierri Filomena , Faraci Maura , Lanino Edoardo , Risitano Antonio M. , Kröger Nicolaus , Dufour Carlo 
Published: October 2019

Abstract

INTRODUCTION
Fanconi anemia (FA) is an inherited bone marrow failure syndrome that carries a high risk of transformation to myelodysplasia (MDS) and acute leukemia. Hematopoietic stem cell transplantation (HSCT) is used to treat FA patients in clonal evolution.
The roles of chemotherapy before HSCT and the intensity of conditioning regimens in transformed FA patients are controversial, because of the high sensitivity of FA patients to DNA-damaging agents increases the risk of severe toxicities, the duration of aplasia, the risk of infective complications thus limiting the possibility to administer full dose cytoreductive treatments.
The sequence chemotherapy-HSCT has been reported by some groups (MehtaPA et al Pediatr Blood Cancer 2007, Talbot A et al Haematologica 2014, Mitchell R et al Br J Haematol 2014, Ayas M et al J Clin Oncol 2013), but conclusive information is lacking because of small number of patients described without a risk factors' analysis.
The aim of this retrospective study is to report the outcome of a large cohort of transformed FA who underwent allo-HSCT and to define the factors that may impact on its outcome.
PATIENTS AND METHODS
The study was conducted on behalf of the Severe Aplastic Anemia (SAAWP) and Chronic Malignancies Working Parties (CMWP) of the EBMT and was based on data of patients who underwent allo-HSCT between 1999-2016 for transformed FA, defined as a diagnosis of FA in presence of any hematological malignancies or cytogenetic abnormalities, registered in the EBMT Data Base. Clinical and biological information of the disease and details on transplant procedures and outcome were collected by a specific form distributed to Centres participating in the study.
RESULTS
Data of 71 patients (35 males-36 females) affected by transformed FA (42 MDS, 25 AL, 4 with cytogenetic abnormalities but without blasts) undergoing allo-HSCT were collected from 25 Centres . A matched related donor (MRD) was used in 31% of cases, an unrelated donor (UD) in 56.3% and a mismatched related donor (MMRD) in 12.7%. Bone marrow was the main source of cells (54.3%) followed by cord blood (22.9%), peripheral blood (21.4%) and bone marrow plus peripheral blood (1.4%).
The median age at allo-HSCT was 12.7 years (range 9.3-23.4).
Thirty seven (52.1%) patients received a chemotherapy before HSCT. Pre-HSCT status of malignancy in available patients was complete remission (CR) in 24% (n = 12/50) and an active disease (no-CR) in 76 % patients (n = 38/50).
The conditioning regimen included total body irradiation (TBI) in 37 (52.1%) (radiation dose: ≤ 4.0 Gy in 30; > 4.0 Gy in 7), busulphan (BUS) in 16 (22.6%), no-TBI nor BUS in 18 (25.3%). Median follow-up was 93.7 months (71-110.6). GvHD prophylaxis and transplants' details are summarized in Table 1.
All patients engrafted. Median time for neutrophils was 17 days (14-23) and it was 25 days (23-42) for platelets. The 2-and 5-year overall survival (OS) probability were 54% (41-66%) and 45% (32-57%) respectively; the 2- and 5-year event-free survival (EFS) (events being death, relapse and graft loss) 52% (40-65%) and 45% (32-58%). The cumulative incidence of relapse were 15% (7-24%) and 21% (11-31%), , of non-relapse mortality (NRM) were 37% (25-49%) and 39% (27-51%) respectively at 2 and 5-year. Most frequent causes of death were GvHD (33.3%), infections (23.3%) and relapse of malignancy (16.7%). Patients transplanted in CR, (neither blasts, nor major dysplastic features) and from matched related donor had a significantly better outcome (5-year OS: CR 83% (62-100%) vs no-CR 36% (19-52%) [p 0.01], MRD 60% (37-83%) vs UD 47% (31-64%) vs MMRD 12% (0-35%) [p 0.03]; 5-year EFS: CR 83% (62-100%) vs no-CR 34% (17-51%) [p 0.01], MRD 61% (38-83%) vs UD 48% (31-64%) vs MMRD 12% (0-35%) [p 0.02]; 5-year NRM: CR 0% vs no-CR 44% (27-61%) [p 0.007]) vs those engrafted in no-CR and from no-MRD. (Fig 1 a, b, c). No other tested variable (therapy before transplant and conditioning regimen) significantly affected the outcome.
CONCLUSION
This study on large cohort of FA patients transplanted because of transformation shows that allo-HSCT from MRD has a better outcome and that CR from malignancy before transplant appears to be a major determinant for a favorable outcome.

Disclosures
Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amyndas Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.