Outcome of Children with Wiskott-Aldrich Syndrome (WAS) Given TCR Alpha-Beta/CD19 Depleted Hematopoietic Stem Cell Transplantation (HSCT) from an HLA-Haploidentical Relative

Background: WAS is a rare X-linked recessive disorder, characterized by thrombocytopenia with low platelet volume, recurrent infections, eczema, autoimmunity, vasculitis and increased incidence of malignancies. Patients with classical WAS have chronic morbidities, severely impaired quality of life and a decreased life expectancy. Allogeneic HSCT is the only well-established curative treatment, gene therapy being still an experimental approach. Excellent outcome have been reported in patients transplanted at early age from either matched related and unrelated donors, with 5-year overall survival (OS) exceeding 90%. However, experience with HLA-haploidentical HSCT is limited and has been historically associated with inferior results. Haploidentical HSCT after selective depletion of α/β+ T-cells and CD19+ B-cells (TBdepl-haploHSCT) was shown to be safe and effective in children with multiple types of non-malignant disorders (Merli et al, Blood Adv 2021). To further optimize this approach and accelerate the recovery of adaptive immunity, we conducted a phase I/II trial evaluating the safety and efficacy of post-transplant infusion of a titrated number of donor T-cells transduced with the inducible caspase-9 (iC9) suicide gene (BPX-501, or rivogenlecleucel, cells) in children with either malignant or non-malignant disorders (ClinicalTrials.gov identifier: NCT02065869). We report the outcome of a cohort of 12 children affected by WAS who received a TBdepl-haploHSCT at our Center.

Patients and methods: Between 2014 and 2021, 12 patients affected by WAS received a TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù in Rome, Italy. Patients and transplant characteristics are depicted in Table 1. All patients received a myeloablative conditioning regimen, combining pharmacokinetic-adjusted busulfan with Thiotepa and Fludarabine. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab was administered on day -1 to prevent PTLD. No post-transplant pharmacological GvHD prophylaxis was employed. Eight subjects, enrolled in NCT02065869 trial, additionally received post-transplant infusion of BPX-501 cells (dose: 1x10 ⁶ cells/kg) at a median time of 16 days after HSCT (range 12-20).

Results: 11 patients achieved primary donor cell engraftment, while one patient experienced secondary graft failure (GF), likely triggered by CMV reactivation. Median time to neutrophil and platelet recovery was 15 (range 8-33) and 10 days (range 9-16), respectively. The patient with secondary GF was successfully re-transplanted with a second TBdepl-haploHSCT from the same donor. Grade I/II skin acute GvHD (aGvHD) occurred in 3 patients, the cumulative incidence of aGvHD being 25.9% (95% CI 0-47.7). None of these 3 patients required activation of iC9 with rimiducid and no cases of chronic GVHD (cGvHD) were observed. No patient died. With a median follow-up of 58 months (range 1 - 78), the 5-year probability of OS and event-free survival is 100% and 90.7% (95% CI 50.8-98.7), respectively. Considering the successful second allograft, the 5-year disease-free survival is 100%. Platelet recovery is reported in Figure 1A. Two months after the allograft, all evaluable subjects had a platelet count above 50.000/microL (median 202.000, range 53.000-353.000). All subjects but one have full donor chimerism at last follow-up, the remaining patient having stable mixed chimerism (40% of donor cells) without any WAS manifestation. All subjects with a follow-up of at least 6 months are independent of immunoglobulin replacement. Details on reconstitution of lymphocytes subsets are reported in Figure 1B,C,D.

Conclusions: TBdepl-haploHSCT after Bu-based conditioning regimen is an highly-effective curative option for children with WAS, being characterized by high-engraftment rate with fast recovery of both neutrophils and platelets, low incidence of aGvHD and no occurrence of cGVHD. Given the prognostic impact of age in determining HSCT outcome in WAS and prompt availability of haploidentical family donors, our data suggest that this approach should be offered without delay to those patients with WAS who lack a matched donor. Infusion of BPX-501 cells contribute to accelerate the recovery of adaptive T-cell immunity, further increasing the safety of the procedure.

Figure 1

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Figure 1

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