HCT Outcome in Patients with Fanconi Anemia Transplanted at Adult Age
Authors: Bierings Marc , Bonfim Carmem , Peffault De La Tour Regis , Aljurf Mahmoud , Mehta Parinda A , Knol Cora , Boulad Farid , Tbakhi Abdelghani , Esquirol Albert , McQuaker Grant , Sucak Gulsan Ayhan , Othman Tarek Ben , Halkes Constantijn J.M. , Thomson Kirsty J , Niederwieser Dietger , Zecca Marco , Kröger Nicolaus , Michallet Mauricette , Risitano Antonio M , Ehninger Gerhard , Porcher Raphael , DuFour Carlo 
Published: October 2019

Abstract

Introduction
Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) due to a DNA repair mechanism defect. FA generally leads to marrow failure and/or leukemia-myelodysplasia in the first decades of life. Hematopoietic stem cell transplantation (HCT), using conditioning regimens adapted for the increased sensitivity for chemo- and radiotherapy induced damage, is the only curative therapy. The Severe Aplastic Anemia Working Party recently showed greatly improved HCT results, especially if patients were transplanted at a young age (Peffault de la Tour et al, Blood 2013). However, some patients are diagnosed at an adult age or are not transplanted at a young age for varying reasons. Data on HCT results in adult FA patients are very limited. We report here the final results of a retrospective study on transplant results in FA patients over 18 years of age at time of HCT.
Results
Both EBMT as well as non-EBMT centres contributed to this study, involving one hundred ninety nine patients, transplanted between 1991-2014. Median age of FA diagnosis was 16 years (ranging from birth up to the age of 48 years).In twenty nine cases (76% of evaluable patients) the genotype was A, in four it was C (11%). Median age at transplant was 23 years (range 18-48). Thirty seven patients (19%) aged more than 30 at time of HCT. Median time from diagnosis to transplant was 7 years (range1-14), also depending on donor availability (median 2 years for sibling donors, 9 years for an unrelated donor, up to 13 years for other/mismatched related donors).Indication for transplant was clonal disease in fifty four patients, 46 % of evaluable cases (14 leukemia/ 40 MDS). In ninety one patients (46%) the donor was an identical sibling, while forty seven (24%) received a matched unrelated donor, and forty patients (20%) a mismatched unrelated HCT. Stem cell source was bone marrow in 115 cases (58%), peripheral blood stem cells in 72 (36%) and cord blood in 11 cases (6%). The conditioning regimen contained cyclophosphamide in 173 cases (96%), fludarabin in 116 (64%), busulfan in 33 (18%) and low dose TBI in fifty five patients (29%). Engraftment occurred in one hundred fifty nine patients (82%, 95%CI 76-87).In eightteen patients there was a primary graft failure, in ten a secondary. Acute GvHD 2-4 occurred in thirty nine patients (22%, 95%CI 16-28). cGvHD was present in forty four patients (Cumulative incidence (CI) 26% at 96 months, 95%CI 20-33). CI of non relapse mortality at 96 months: 56% (95%CI 47-63). CI of secondary malignancies: 19 of 131 evaluable patients (17%) at 96 months post-HCT (95%CI10-25). Probability of overall survival at 96 months was 34% (95%CI 27-43). Main causes of death included infection (n=44, 37%), GvHD (n=29, 24%), organ damage (n=15, 12%) and secondary malignancies (n=12, 10%). In multivariate analysis identical sibling donor availability and the use of fludarabin in the conditioning regimen were statistically significantly associated with better chance of survival (p<0.0001 and 0.011 respectively). Over time 3 year OS improved from 31% for transplants performed between 1991-2000 to 50% for patients transplanted between 2009-2014 (p 0.026).
Conclusion.
This study reports on the largest dataset of adult patients with FA undergoing HCT. We confirm that adult age has a negative impact on HCT outcome, compared to younger patients with FA undergoing transplantation. The use of fludarabin in the conditioning regimen has a positive effect on outcome. HCT should be considered for every patient with FA at an early age, if deemed necessary. International efforts are necessary to treat adult FA patients in need of HCT in clinical trials, especially when only less well matched donors are available.

Disclosures
Peffault De La Tour: PFIZER: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Risitano:Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding; Alexion Pharmaceuticals: Other: lecture fees, Research Funding.