Allogeneic hematopoietic cell transplantation for partial RAG deficiency in children and adults: Excellent outcomes with a reduced-intensity posttransplantation cyclophosphamide-based approach.

Abstract

Partial recombinase activating gene deficiency (pRD) leads to combined immunodeficiency with immune dysregulation. It can be cured by allogeneic hematopoietic cell transplantation (HCT), but optimal referral criteria and approaches remain to be defined. Our study evaluated low-toxicity approaches to HCT for pRD. Thirteen children and adults with pRD received radiation-free, predominantly reduced-intensity conditioning (pentostatin/cyclophosphamide/busulfan) HCT with posttransplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis at median (range) age 20 (4-46) years. With median 2.6 years' follow-up, overall survival for the entire cohort was estimated at 92% and 83% at 1 and 2 years and 100% and 90% for reduced-intensity conditioning recipients (n = 12), with 2 deaths attributed to sepsis. Reversal of clinical manifestations was associated with immune reconstitution, with minimal de novo autoimmunity, 15% 1-year cumulative incidence of grade III-IV acute GVHD, and no chronic GVHD. Vα7.2-positive T-cell proportion increased rapidly after HCT, while mucosa-associated invariant T-cell reconstitution lagged. Dysreactive CD19^hiCD21^lo and 9G4⁺ B cells decreased after HCT, along with clinically relevant autoantibodies. However, baseline elevated anti-type I interferon antibodies, potentially predisposing to severe viral infections, decreased slowly, although neutralizing activity was reduced at last follow-up. Outcomes did not differ by donor carrier status or HLA matching. Bronchiectasis exacerbations incurred rehospitalizations in long-term follow-up of patients who entered HCT with irreversible lung disease. Reduced-intensity conditioning HCT with posttransplantation cyclophosphamide-based GVHD prophylaxis is safe and effectively reverses immune dysfunction in patients with pRD.