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4948 Outcomes and Late Complications after Umbilical Cord Blood Transplantation for Fanconi Anemia: A Study on Behalf of Eurocord and Severe Aplastic Anemia Working Party - EBMT

Program: Oral and Poster Abstracts
Session: 723. Allogeneic Transplantation: Long-term Follow-up and Disease Recurrence: Poster III
Hematology Disease Topics & Pathways:
Research, Acquired Marrow Failure Syndromes, Bone Marrow Failure Syndromes, Inherited Marrow Failure Syndromes, Clinical Research, Diseases, patient-reported outcomes, registries
Monday, December 11, 2023, 6:00 PM-8:00 PM

Hanadi Rafii, MD1*, Regis Peffault De Latour2*, Marc Bierings, MD3, Jean-Hugues Dalle4*, Mouhab F. Ayas, MD5*, Rawad Rihani, MD, MSc6*, Edoardo Lanino, MD7*, Chantal Kenzey, RA1*, Fernanda Volt, MSc1*, Monica M. M Rivera Franco, MD, PhD1*, Barbara Cappelli, MD8,9*, Graziana Scigliuolo, PharmD8,9*, Vanderson Rocha, MD, PhD, MS1,10*, Annalisa Ruggeri, MD, PhD1,11*, Antonio M Risitano, MD, PhD12,13 and Éliane Gluckman, MD, PhD1,8

1Eurocord, Hôpital Saint Louis APHP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris Cité, Paris, France
2Hôpital Saint-Louis,, Paris, France
3Princess Máxima Center, University Hospital for Children, Utrecht, Netherlands
4Pediatric hematology and immunology department, Robert-Debré Hospital, GHU APHP Nord Université Paris-Cité, Paris, France
5Department of Pediatric Hematology and BMT, King Faisal Specialist Hospital & Research Center, Riyadh, Middle, SAU
6Pediatric Blood and Marrow and Cellular Therapy Program, King Hussein Cancer Center, Amman, Jordan
7Istituto Giannina Gaslini, Genova, ITA
8Monacord, Centre Scientifique De Monaco, Monaco, Monaco
9Eurocord, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris Cité, Paris, France
10Service of Hematology, Transfusion and Cell Therapy, and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), Hospital das Clínicas, Faculty of Medicine, São Paulo University, São Paulo, Brazil., São Paulo, Brazil
11Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy
12University of Naples, Avellino, Italy
13A.O.R.N. San Giuseppe Moscati, Avellino, Italy

Fanconi Anemia (FA) remains a disease with poor prognosis for which hematopoïetic cell transplantation (HCT) offers the only available curative option, with particular good results observed after matched sibling donor transplants. This study aimed to assess transplant outcomes and describe late complications in a large cohort of patients with FA who underwent umbilical cord blood transplantation (UCBT) in the European Society for Blood and Marrow Transplantation (EBMT) affiliated centres.

Methods: We retrospectively reviewed all cases of FA who received UCBT as first allogeneic transplant between 1988 and 2021. Data on late effects were collected with a questionnaire completed by transplant centres for patients who survived >2 years (y) after UCBT.

Results: A total of 205 patients with FA received UCBT (55 related and 150 unrelated) in 77 transplant centres. Indications for UCBT were bone marrow failure in 191 patients (BMF, 93%) and acute leukemia/myelodysplasia in 14 patients (AL/MDS, 7%). Median age at transplant was 8.8 y (1.2-43) and 90% (n=185) were children <18y old. Graft sources included single (n=164), double (n=23) or UCB co-infused with other cell sources (n=18). Recipients and UCB pairs had 0-1/6 HLA mismatches in 48% (n=99). Most patients (n=196, 97%) received reduced intensity conditioning. Flu Cy-based (n=116; 57%) and Bu Cy ± Flu (n=48, 23%) were the most frequently used regimens. Total body irradiation (TBI) or total lymphoid irradiation (TLI) were administered to 28% (n=58) of patients at doses < 8 Gy. Serotherapy consisted of anti-thymocyte globulin (ATG, n=159; 78%) or alemtuzumab (n=8; 4%). Graft-vs-host disease (GVHD) prophylaxis was mainly based on CSA ± steroids (65%) or MMF ± steroids (32%).

Median follow-up was 88 months (3-345). The cumulative incidence (CI) of neutrophil recovery was 79% (67-79) at day 60, with a median time of 20 (7-62) days (d). The 100d CI of grades II-IV acute GVHD (aGVHD) was 29.8% (24-37). The 5y CI of chronic GVHD (cGVHD) was 30.4% (24-38) with 12% extensive forms. The 1y-CI of non-relapse mortality (NRM) was 37.4% (31-45). At 5y follow-up, event-free survival (EFS) was 54% ± 3 and overall survival (OS) was 55% ± 3.

In multivariate analysis, HLA matching 0-1/6 (HR 2.0, p=0.01) and related UCBT (HR 2.4; p=0.001) were predictive of better engraftment. None of the tested factors had statistical significant impact on incidence of aGVHD or cGVHD. Negative recipient CMV serology (HR 0.29, p=0.003) and transplant year ≥2013 (HR 0.29; p=0.004) were the only factors associated with improved OS. Both factors were also predictive of better NRM and EFS.

Fifty-one recipients of UCBT (3 related and 48 unrelated) experienced primary graft failure (GF). Twenty-six patients underwent subsequent allogeneic HCT within a median of 1.8 months (0.8 -6.8) after first UCBT. Seven subsequent HCT recipients (1 related bone marrow (BM), 1 related peripheral blood, 1 unrelated BM, and 4 unrelated UCB) were alive at last follow-up.

Second neoplasms developed in 8 patients (4%) within a median interval of 9.7 y post-UCBT (3.6-13.5) and included one donor derived-AML and 7 solid tumors (1 skin, 2 upper GI, 4 oral cavity) .

A total of 93 patients (45%) died from transplant related toxicity (n=85, including 42 who died after GF), second neoplasms (n=6) or unknown cause (n=2).

Survival >2y was observed in 106 patients, but comprehensive data for late transplant complications were available only in 45 long-term survivors. For these 45, median post transplant follow-up was 8.7y (2.7-28.8). Late organ impairments (table 1) included: endocrine disorders (32%), lung (24%), eyes (20%), kidneys (20%), immune system (18%), liver (16%), musculoskeletal, and bone (16%) diseases. Other dysfunctions involved: oral mucosa (11%), neurologic system (7%), gastrointestinal (4%), genital (13%) and urinary tracts (4%). Cardiovascular complications were rare (1 case of chronic pericarditis).

Conclusion: Improved outcomes have been observed in recent years in FA patients receiving unrelated UCBT likely due to improved conditioning regimens, effective post-transplant care and better HLA parity. With longer survival, late multi-organ complications are observed. Identification of risk factors and life-long screening for early management of organ impairments and second neoplasms are mandatory to improve quality of life of transplant survivors and decrease late mortality.

Disclosures: Peffault De Latour: Jazz Pharmaceuticals: Honoraria. Dalle: Jazz Pharmaceuticals: Honoraria. Risitano: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Research Funding.

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