Abstract Introduction Post-transplant cyclophosphamide (PTCy) has nearly revolutionized the field of haploidentical hematopoietic cell transplantation (Haplo-HCT). The original protocol employed a non-myeloablative approach; however, the ideal conditioning regimen for haplo-HCT has not yet been established. Here, we present a single-center analysis of a prospective study with a total marrow irradiation-based reduced-intensity conditioning (RIC) regimen in Haplo-HCT.Methods Patients were included in the current study between 2018 and 2025. Patients received Haplo-HCT with a conditioning regimen consisting of intravenous busulfan (total area under the curve, AUC, of 9,600 µM*min), fludarabine (total dose of 150 mg/m²), and total marrow irradiation (6 Gy, administered in two days with two daily doses of 1.5 Gy). In one patient, melphalan 50 mg/m2 was substituted for busulfan. Two patients received busulfan with a total AUC of 8,000 or 9,000 µM*min. Central nervous system or spleen radiotherapy boost was allowed, according to the attending physician. All patients received PTCy (80-100 mg/kg total dose), tacrolimus, and mycophenolate. This study was registered at ClinicalTrials.gov under NCT02129582.Results We included 19 patients, with a median follow-up of 22 months. Median age was 57 years, and there were only 3 patients with a female donor to a male patient. Diagnoses were acute myeloid leukemia (15), chronic myelomonocytic leukemia (2), non-Hodgkin lymphoma (1), or myelodysplasia (1). Interestingly, 10 patients (53%) had refractory or active disease. 79% received a peripheral blood graft, while 21% received a bone marrow transplant. All evaluable patients had neutrophil engraftment (median: 19 days), but one patient died at D+18 without neutrophil engraftment (95% neutrophil engraftment). Rate of platelet engraftment was 84%, with a median of 33 days. 18-month overall survival and progression-free survival were 59% (95% CI 40-88%) and 53% (95% CI 34-84%). Progression-free survival was 71% for patients in remission and 31% for patients with active disease (p=0.02). The 18-month relapse/progression rate was 19%, and 18-month non-relapse mortality was 25%. Rate of grades II-IV acute GVHD was 42% and, III-IV acute GVHD, 26%. 18-month chronic GVHD rate was 12%.Discussion In this unicenter analysis of a prospective multicenter study, we have shown promising results with total marrow irradiation, RIC-intensified regimen for Haplo-HCT. Despite the very poor prognosis of patients, with more than half having refractory or active disease prior to the transplant, overall survival was relatively high, with few relapses/progression. Moreover, neutrophil engraftment was very high (95%), with low rates of non-relapse mortality. These results show a good balance between the effectiveness of the conditioning regimen and toxicity. Future studies should confirm these promising results in haplo-HCT with TMI-based RIC conditioning using a larger patient cohort.Acknowledgements The authors declare no conflict of interest.
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