A Journey Towards Better Outcomes : The Evolution of Haploidentical HSCT from Ptcy to Αβ T-cell Depletion and Memory Addback in LMIC Context

Inborn Errors of Immunity (IEI) are a diverse group of disorders predisposing children to recurrent infections, autoimmunity, and malignancies. Hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. However, only about 30% of patients have an HLA-matched donor, making haploidentical HSCT the main curative option for the majority. This study analyses haploidentical HSCT for IEI over 16 years at our centre, focusing on the transition from post-transplant cyclophosphamide (PTCy) to TCRαβ/CD19 depletion and the introduction of CD45RO+ memory T-cell add-back. This retrospective study was conducted at Apollo Hospitals, Chennai, between April 2009 and September 2025, including all children aged 0–18 years who underwent HSCT for IEI. Transplant-related data were obtained from patient records and analysed using SPSS software. Between 2009 and 2024, 230 children with IEI underwent HSCT, of which 105 (45%) received haploidentical transplants. Among these, 65 (62%) underwent TCRαβ/CD19-depleted HSCT, while 40 (38%) received T-cell replete grafts with PTCy. Engraftment rates were comparable between groups. Acute GVHD occurred in 7.5% vs. 15% and chronic GVHD in 14% vs. 17% in the TCRαβ/CD19-depleted and PTCy cohorts, respectively. Viral reactivation was more frequent in the TCRαβ/CD19-depleted group (65% vs. 45%), but overall survival was higher (66% vs. 55%). Most deaths were due to viral infections and delayed immune reconstitution in TCR alpha beta group as compared to organ toxicity in PTcy group. From January 2025, CD45RO+ memory T-cell add-back protocol was started, and 9 children are enrolled so far. The median CD34+ cell dose was 10 × 10⁶/kg, with CD45RO+ add-back (1 × 10⁶/kg) administered on day +7. Median neutrophil engraftment occurred on day +10. Median CD4 counts improved from 10 cells/mm³ at day +30 to 90 cells/mm³ at day +60. Viral reactivation occurred in six (66%) children, predominantly CMV and adenovirus, but all responded to antiviral therapy. None had persistent viremia or virus-related deaths as compared to our historical cohort. Seven CD45RO+ add-backs were given in six children; five received stem cell top-ups. All patients were alive at last follow-up (28–180 days), with no grade III–IV GVHD or ongoing viral reactivation. The evolution from PTCy-based to TCRαβ/CD19-depleted haploidentical HSCT has significantly improved outcomes in children with IEI. Incorporating CD45RO+ memory T-cell add-back has further enhanced immune reconstitution without increasing GVHD risk. Although viral reactivation remains common, early immune recovery and effective antiviral therapy have reduced mortality. With additional measures such as letermovir prophylaxis and virus-specific T-cell infusions, survival outcomes in low- and middle-income countries could approach that of high-income setting.