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

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.