TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

Abstract

Several non-malignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders or metabolic diseases, lacking a fully-matched donor or requiring urgent transplantation, underwent TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study (#NCT01810120). Median age at transplant was 3.5 years (range 0.3-16.1); median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (e.g., aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade I-II acute GvHD was 14.4% (no patient developed grade III-IV acute GVHD). Only one patient at risk developed mild chronic GvHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment for children with NMDs. Prompt donor availability, low incidence of GvHD and TRM make this strategy an attractive option in NMDs patients.

NK cell content does not seem to influence engraftment in ex vivo T cell depleted haploidentical stem cell transplantation

“…To further corroborate our statement, we retrospectively analyzed 2 cohorts of pediatric patients transplanted after ex vivo T cell depletion: TCRαβ/CD19-depletion (thus with a graft containing, among the others, CD34+, NK, and TCRγδ cells) was used in Rome ( Locatelli et al., 2017 ; Merli et al., 2022 ) while CD3/CD19-depletion (thus with a graft containing CD34+ and NK cells) was used in Tübingen ( Lang et al., 2014 ). These experiences resemble the models used by Lobo de Figueiredo-Pontes and colleagues.…”

Unresolved issues in allogeneic hematopoietic cell transplantation for non-malignant diseases

“…This depletion also preserves TCR-γδ + T cells and natural killer (NK) cells for retaining GVL effect and immunoprotective activity against opportunistic infection [21]. Incidence of GVHD and TRM were reported to be lower in these patients than in those undergoing allogeneic HCT following conventional graft manipulations, such as CD34-positive selection and complete depletion of T cells, although the incidence of GF (20-30%) in the former remains unsatisfactory [22,23]. The choice of PTCY or TCR-αβ/CD19 depletion for allogeneic HCT from HLA-haploidentical related donors for NMDs largely depends on the type of disease and the characteristics of the donor and recipient.…”

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective

“…Thus, most but not all the studies use this graft engineering approach with related HLA-mismatched donors. This newer therapy has largely been studied in children, comprising 95% of the nearly 700 total patients reported in the literature, and a still small cohort compared to other alternative donor approaches (129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141). More data is needed to evaluate the success of this approach in adult HCT recipients and would be beneficial in pediatric cohorts as well.…”