A phase III trial showed that sole posttransplant cyclophosphamide (PTCy) is feasible in HLA-matched bone marrow (BM) hematopoietic cell transplants (HCT) but leads to high graft-versus-host disease (GVHD) rates with peripheral blood grafts (PBSC). We hypothesized that adding low-dose ATG could reduce GVHD.

Assess the feasibility of HLA-matched PBSC HCT using only ATG and PTCy, without calcineurin inhibitors, sirolimus, or antimetabolites for GVHD prophylaxis.

Prospective, single-center phase I/II trial (NCT06299462) involving patients aged 18–60 years with acute leukemia in CR1/CR2, myelodysplasia with less than 20% blasts, or lymphoma; HLA 8/8 donor; PBSC graft. Exclusion: liver dysfunction. Primary endpoint: grades III–IV acute GVHD. ATG 4–5 mg/kg was given before HCT, and PTCy 50 mg/kg on days +3 and +4. No other GVHD prophylaxis was used. Minimum follow-up was 3 months, ensuring all patients were eligible for acute GVHD assessment.

Ten patients were enrolled; six received myeloablative conditioning, and four received reduced-intensity conditioning. All engrafted; one experienced secondary graft failure amid a cluster of failures under investigation. Early after infusion, 40% developed grade 3–4 CRS, all of which responded to treatment. Three patients developed grade II acute GVHD, all steroid-responsive: one after donor lymphocyte infusion (DLI) for immune reconstitution, another after protocol violation (CD34 dose 6.7 × 106/kg). One patient died from mesenteric thrombosis, while another with refractory Hodgkin lymphoma experienced disease progression; all others are alive in complete remission. One DLI-treated patient developed moderate, steroid-refractory chronic GVHD, now managed with sirolimus. Six-month overall survival (OS) and progression-free survival (PFS) were 100% and 83%. CMV reactivation occurred in 80%, without CMV disease. Three patients experienced hemorrhagic cystitis (one grade 2, two grades 3–4). At 6 months, median CD4+ and B-cell counts were 225/mm³ and 135/mm³, respectively.

This ATG+PTCy-only regimen for HLA 8/8 PBSC HCT was feasible, with no grades III–IV acute GVHD. Avoiding calcineurin inhibitors may lower toxicity and expenses (> R$25,000 for tacrolimus and monitoring over 3 months), potentially allowing resources to be redirected to patient care. Despite frequent viral reactivations, immune reconstitution was adequate at 6 months. Letermovir and tocilizumab were unavailable; CRS cases were managed with high-dose dexamethasone, which may have contributed to viral reactivations. Strategies to address CRS and viral reactivation are in development, and we plan to move to phase II of the trial soon. These early results support the potential of sole ATG+PTCy prophylaxis in HLA 8/8 PBSC HCT.