HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia

Abstract

We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Outcome and immune reconstitution of patients enrolled in the study. Cumulative incidence of (A) aGVHD and (B) cGVHD in the study population. Probability of (C) EFS and (D) OS. (E) Reconstitution kinetics of αβ+, γδ+ T cells and NK cells in patients receiving TCRαβ+/CD19+-depleted haplo-HSCT. A rapid recovery of γδ+ T and NK cells was observed within the first few weeks posttransplant followed by a progressive increase of αβ+ T and B lymphocytes over time. Reconstitution kinetics of (F) CD4+ and CD8+ T cells and (G) B lymphocytes. (H) Kinetics of immunoglobulin serum level recovery: median (dashed thick line), 25th and 75th percentiles (dotted thin lines), and ranges are represented in violin plots. Immunoglobulin recovery was observed in parallel to B-cell reconstitution. Peripheral blood samples were obtained 1, 3, 6, and 12 months after HSCT. Absolute numbers of each cell subset are shown together with standard error of the mean. E, events; LNN, lower limit of normal; N, number; yr, year.