AFFILIATIONS
1 Memorial Sloan Kettering Cancer Center, New York, New York, United States
2 City of Hope National Medical Center, Duarte, California, United States
3 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
4 University of Minnesota, Minneapolis, Minnesota, United States
5 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
6 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
7 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
8 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
9 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
10 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
11 Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
12 Fred Hutchinson Cancer Center, Seattle, Washington, United States
13 University of Virginia, Charlottesville, Virginia, United States
14 The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, Ohio, United States
15 The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, Ohio, United States
16 Stanford Medicine, Palo Alto, California, United States
17 University of Minnesota, Minneapolis, Minnesota, United States
18 Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States
19 Moffitt Cancer Center, Tampa, Florida, United States
20 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
21 Mayo Clinic, Phoenix, Arizona, United States
22 CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States
23 Mayo Clinic, Jacksonville, Florida, United States
24 University of North Carolina Hospitals, Chapel Hill, North Carolina, United States
25 Colorado Blood Cancer Institute, Denver, Colorado, United States
26 St David’s South Austin Medical Center, Austin, Texas, United States
27 Sylvester Comprehensive Cancer Center, Miami, Florida, United States
28 CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States
29 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
30 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
31 CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States
32 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
33 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
34 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
35 CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, Minnesota, United States
36 Oregon Health and Science University, Portland, Oregon, United States
37 Dana-Farber Cancer Institute, Boston, Massachusetts, United States
ABSTRACT
Introduction: In the ACCESS (NCT04904588) trial, standard dose (SD) post-transplantation cyclophosphamide (PTCy) (50 mg/kg on days 3 and 4) used as graft-versus-host disease (GvHD) prophylaxis yielded favorable survival in patients receiving mostly cryopreserved (75%) HLA-mismatched unrelated donor (MMUD) peripheral blood stem cells (PBSCs) (Al Malki et al. J Clin Oncol 2025). However, SD PTCy is associated with significant infection burden by 100 days (D100) (Auletta et al. Blood Adv 2026). Therefore, we evaluated whether reducing PTCy dose could improve infection-free survival (IFS) while preserving GvHD prevention.
Methods: We conducted a prospective, multicenter, 2-stage, phase II trial (OPTIMIZE, NCT06001385) to define safety and efficacy of reduced dose (RD) PTCy (25 mg/kg on D3 and 4) combined with mycophenolate mofetil (MMF) and tacrolimus as GvHD prophylaxis in adults with hematologic malignancies receiving MMUD PBSC transplant. 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 PBSC allografts. Eligible donors were matched by high resolution at 4-7/8 HLA-loci (HLA-A, -B, -C, and -DRB1) and were ≤40 years. The primary endpoint was D100 IFS defined as survival without Blood and Marrow Transplant Clinical Trials Network (BMT CTN) grade 2 or 3 infection. The D100 IFS null and alternative hypotheses were 42.5% and 57.5%, respectively. Key secondary endpoints included 1-year OS, GvHD-free, relapse free survival (GRFS), and non-relapse mortality (NRM). Kaplan-Meier method was used to estimate survival. Cumulative incidence was used to estimate neutrophil and platelet recovery, acute and chronic GvHD, relapse, and infections. Here, we report 1-year results for the RIC/NMA stratum.
Results: For 89 patients (53 males) receiving RIC/NMA enrolled at 18 sites, median age was 66 years (range 22-78) and 31 (35%) patients self-reported as ethnically diverse. Most patients had AML (n=43, 48%) and received fludarabine/melphalan (n=51, 57%) followed by 7/8 MMUD PBSC allografts (n=88, 99%) infused fresh (n=76, 85%) with a median CD34+ dose of 5.8x106/kg (range 0.8-14.2). Seventy-six (85%) patients completed 12-month evaluation. Median donor age was 27 years (range 19-39). Estimated IFS at D100 was 69.7% (90% CI, 60.8-76.9%), exceeding the prespecified alternative benchmark, and was 52.6% (90% CI, 41.4-62.5%) at 1 year. Estimated 1-year OS was 88.7% (95% CI, 80-93.8%) and GRFS was 56.4% (95% CI, 45.2-66.2%). Median times to absolute neutrophil (ANC≥500/µL x 3 days) and platelet (≥20,000/µL x 7 days) recovery were 14 (range 10-27) and 18.5 (range 4-74) days, respectively. No primary graft failure (ANC<500/µL by D28) was observed.
Cumulative incidences of grades 2-4 and 3-4 acute GvHD by D180 were 39.3% (95% CI, 29.1-49.3%) and 13.5% (95% CI, 7.4-21.5%), respectively. Incidence of overall and moderate to severe chronic GvHD at 1 year were 39% (95% CI, 28.3-49.5%) and 19% (95% CI, 11.3-28.2%), respectively. Disease relapse rate at 1 year was 15.8% (95% CI, 9.1-24.1%). NRM at D100 was 2.3% (95% CI, 0.4-7.1%) and 5.7% (95% CI, 2.1-11.9%) at 1 year. For comparison, the ACCESS 7/8 MMUD RIC/NMA cohort (n=131 patients) showed: cumulative incidences for grades 2-4 and 3-4 acute GvHD at D180 of 43.5% (95% CI, 34.9-51.8%) and 8.4% (95% CI, 4.4-14%), respectively; cumulative incidences for overall and moderate to severe chronic GvHD at 1-year of 16.3% (95% CI, 10.5-23.2%) and 10.9% (95% CI, 6.2-17.1%), respectively; relapse rate at 1 year of 16.1% (95% CI, 10.4-22.9%); and NRM at D100 of 5.3% (95% CI, 2.4-10.1%) and 14.5% (95% CI, 9.1-21.1%) at 1 year.
Twenty-six (29%) patients experienced 36 BMT CTN grade 2-3 infections by D100, 25 were grade 2 and 11 were grade 3. Cumulative incidence of infection by D100 was 28.1% (95% CI, 19.2-37.7%), with bacteria and viruses predominating.
Conclusion: In this RIC/NMA cohort receiving predominantly fresh 7/8 MMUD PBSC allografts, RD PTCy produced favorable D100 IFS, excellent 1-year OS, low NRM, rapid engraftment, and preserved relapse control. In descriptive comparison with ACCESS using SD PTCy, acute GvHD and relapse appeared similar, NRM appeared lower, and moderate/severe chronic GvHD was higher. Overall, these results position RD PTCy as a promising, lower-toxicity MMUD transplantation backbone, with chronic GvHD reduction remaining a key target for refinement.