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.