Paper Details

ABSTRACT

Introduction: Standard dose (SD) post-transplantation cyclophosphamide (PTCy) (50 mg/kg on days 3 and 4) effectively prevents graft-versus-host disease (GvHD) following HLA-mismatched related and unrelated (MMUD) peripheral blood stem cell transplant (PBSCT). In ACCESS (NCT04904588), combined 1-year overall survival (OS) exceeded 80% across conditioning intensity and level of HLA mismatch (Al Malki et al. J Clin Oncol 2025). However, SD PTCy carried substantial infection-related toxicity (Auletta et al. Blood Adv 2026). Lowering PTCy dose may reduce infectious and noninfectious toxicity, but its safety in <7/8 MMUD HCT is unknown. Therefore, we evaluated intermediate dose PTCy in a safety run-in for patients undergoing <7/8 MMUD PBSCT.

Methods: We conducted a prospective, multi-center, 2-stage phase II clinical trial (OPTIMIZE, NCT06001385) to assess safety and efficacy of reduced dose (RD) PTCy (25 mg/kg on days 3 and 4), mycophenolate mofetil (MMF), and tacrolimus used as GvHD prophylaxis in adult patients with hematologic malignancies receiving MMUD PBSCT. The study included four strata, two based on conditioning intensity (MAC and RIC/NMA), one for patients with myelofibrosis, and a safety run-in for patients receiving <7/8 HLA MMUD allografts. Patients enrolled in the safety run-in received intermediate dose (ID) PTCy (37.5 mg/kg days 3 and 4), MMF, and tacrolimus. The run-in stratum used D100 grade 3-4 acute GvHD as the key safety endpoint (threshold 15%). If the run-in demonstrated safety, then subsequent patients receiving <7/8 MMUD could receive RD PTCy. Eligible donors were matched at 4-6/8 HLA-loci (HLA-A, -B, -C, and -DRB1) and age ≤40 years. Key endpoints included infection-free survival (IFS), defined as survival without Blood and Marrow Transplant Clinical Trials Network (BMT CTN) grade 2 or 3 infection, OS, and GvHD-free, relapse-free survival (GRFS). Kaplan-Meier method was used to estimate survival. Cumulative incidence was used to estimate neutrophil and platelet recovery, acute and chronic GvHD, relapse, and grade 2-3 infections. Here, we report 1-year results for the run-in stratum. 

Results: For 29 patients (19 females) enrolled at 11 sites, median age was 59 years (range 29-77) and 20 (69%) self-reported as ethnically diverse. Most had AML (n=17, 59%). Ten patients received MAC, either busulfan/fludarabine (n=6, 21%) or fludarabine/cyclophosphamide/total body irradiation (n=4, 14%). Nineteen patients received RIC/NMA, most commonly fludarabine/melphalan (n=12, 41%). Twenty-two (76%) patients completed 12-month evaluation. Median donor age was 26 years (range 19-40). Level of donor HLA-mismatch included 6/8 (n=23, 79%), 5/8 (n=5, 17%), and 4/8 (n=1, 3.4%). Most allografts were infused fresh (n=24, 83%) with a median CD34⁺ dose of 5.2x10⁶/kg (range 2.7-10.3). Estimated IFS at D100 was 62.1% (90% CI, 45.5-74.9%) and 46.3% (95% CI, 27.1-63.5%) at 1 year. Estimated 1-year OS was 78.8% (95% CI, 58.7-89.9%) and GRFS was 62.1% (95% CI, 42.1-76.9%). NRM at D100 was 0% and 10.3% (95% CI, 2.5-24.7%) at 1 year.

Percentage of patients with ≥95% donor chimerism at D100 was 88% (95% CI, 70-98%). Median times to absolute neutrophil count (ANC≥500/µL x 3 days) and platelet (≥20,000/µL x 7 days) recovery were 15 (range, 14-23) and 21 (range, 9-39) days, respectively. No primary graft failure was observed. Cumulative incidences of grades 2-4 and 3-4 acute GvHD at D100 were 58.6% (95% CI, 38.1-74.4%) and 6.9% (95% CI, 1.2-20%), respectively. Cumulative incidences of grades 2-4 and 3-4 acute GvHD by D180 were 58.6% (95% CI, 38.1-74.4%) and 6.9% (95% CI, 1.2-20%), respectively. Cumulative incidence of moderate-severe chronic GvHD at 1 year was 17.2% (95% CI, 6.1-33.1%). Relapse rate at 1 year was 17.2% (6.1-33.1%).

One (3.4%) patient experienced American Society for Transplantation and Cellular Therapy grade 2 cytokine release syndrome. Twelve (41%) patients experienced 21 BMT CTN grade 2-3 infections by D100, 13 grade 2 and 8 grade 3. Cumulative incidence of infection by D100 was 34.5% (95% CI, 17.8-51.8%) with bacteria and viruses predominating.

Conclusion: In this prospective, multicenter safety run-in of <7/8 MMUD PBSCT, ID PTCy yielded favorable IFS, rapid engraftment, low grade 3-4 acute GvHD, no D100 NRM, and encouraging 1-year OS. These results support feasibility of ID PTCy in predominately 6/8 MMUD HCT and provide a strong rationale for continued evaluation of PTCy dose optimization and combination strategies.