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

Pietro Merli, Daria Pagliara, Federica Galaverna, Giuseppina Li Pira, Marco Andreani, Giovanna Leone, Donato Amodio, Rita Maria Pinto, Alice Bertaina, Valentina Bertaina, Angela Mastronuzzi, Luisa Strocchio, Emilia Boccieri, Daniela Pende, Michela Falco, Matteo Di Nardo, Francesca Del Bufalo, Mattia Algeri, Franco Locatelli, Pietro Merli, Daria Pagliara, Federica Galaverna, Giuseppina Li Pira, Marco Andreani, Giovanna Leone, Donato Amodio, Rita Maria Pinto, Alice Bertaina, Valentina Bertaina, Angela Mastronuzzi, Luisa Strocchio, Emilia Boccieri, Daniela Pende, Michela Falco, Matteo Di Nardo, Francesca Del Bufalo, Mattia Algeri, Franco Locatelli

Abstract

Several nonmalignant 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. The median age at transplant was 3.5 years (range 0.3-16.1); the 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 (eg, aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at the time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade 1-2 acute GVHD was 14.4% (no patient developed grade 3-4 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 of children with NMDs. Prompt donor availability, low incidence of GVHD, and TRM make this strategy an attractive option in NMDs patients. The study is registered at ClinicalTrial.gov as NCT01810120.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Graft failure. (A) Cumulative incidence of GF for the whole cohort. (B) Cumulative incidence of GF for patients affected by diseases at high risk (ie, children affected by HLH, thalassemia, SAA, or osteopetrosis; red line) or at standard risk (blue line) for the complication.
Figure 2.
Figure 2.
Graft-versus-host disease. (A) Cumulative incidence of grade 1-4 acute GVHD. (B) Cumulative incidence of grade 2-4 acute GVHD.
Figure 3.
Figure 3.
Survival. (A) Overall survival (OS) and transplant-related mortality (TRM) of the whole cohort. (B) Event-free survival of the whole cohort. (C) Disease-free survival of the whole cohort (excluding 2 patients with ALD, who had CNS involvement at the time of HSCT). (D) OS according to infectious status at transplant (ie, active or recent infection at the time of HSCT versus no infection).
Figure 4.
Figure 4.
Time-averaged area-under-the-curve (AAUC) AAUC180 for CMV and ADV.
Figure 5.
Figure 5.
Immune reconstitution. (A) Absolute number after haplo-HSCT of CD3+ cells (mean and 95% CI). (B) TCRαβ+ and TCRγδ+ cells (mean and 95% CI). (C) CD4+ and CD8+ T cell subsets (mean and 95% CI). (D) CD20+ B cells (mean and 95% CI).

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