Umbilical Cord Blood Transplantation for Fanconi Anemia with a special focus on late complications: a Study on Behalf of Eurocord and SAAWP-EBMT

Background Hematopoietic cell transplant (HCT) remains the only available curative treatment for Fanconi Anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) transplant. Objectives To describe outcomes, with a special focus on late complications, in FA patients who underwent umbilical cord blood transplantation (UCBT). Study Design Retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT) affiliated centers. Results A total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. Median age at transplant was 9 (1.2-43) years, with only 20 patients over the age of 18. Among the donor-recipient pairs, 56% (n=116) had 0-1/6 HLA mismatch. Limited field radiotherapy was administered to 28% (n=58) and 78% (n=160) received a Fludarabine (FLU)-based conditioning regimen. Serotherapy consisted of anti-thymocyte globulin (ATG, n=159; 78%) or alemtuzumab (n=12; 6%). Median follow-up was 10 years for related and 7 years for unrelated UCBT.Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CI) of neutrophil recovery at 98.1% (93.9-100), a 100-day CI of grades II-IV acute graft-versus-host disease (GVHD) at 17.3% (9.5-31.6), and a 5-year CI of chronic GVHD at 22.7% (13.3-38.7; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS.In unrelated UCBT, the 60-day CI of neutrophil recovery was 78.7% (71.9-86.3), the 100-day CI of grade II-IV aGVHD was 31.4% (24.6-40.2) and the 5-year CI of cGVHD was 24.3% (17.8-32.2) (12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient CMV serology, FLU-based conditioning, age at UCBT less than 9 years and 0-1/6 HLA mismatch were associated with improved OS.A total of 106 patients, including 5 AL/MDS, survived for over 2 years after UCBT. Nine of these patients developed subsequent neoplasms (SN), including one donor-derived AML and 8 solid tumors, at a median of 9.7 (2.3-21.8) years post-UCBT (one related and 8 unrelated UCBT).In a subset of 49 patients with available data, late non-malignant complications affecting various organ systems were observed at a median of 8.7 (2.7-28.8) years post-UCBT. Conclusion UCB is a valid source of stem cells for transplantation in patients with FA, with best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients transplanted at a younger age, with FLU-based conditioning and better HLA parity. The incidence of organ specific complications and subsequent neoplasms was relatively low. Subsequent neoplasm incidence, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and life-long screening is crucial in Fanconi anemia patients transplant survivors. The long-term complications observed emphasize the need for long-life screening of transplant survivors.