Abstract
Background:Post-transplant cyclophosphamide (PTCy) has significantly improved the feasibility of mismatched unrelated donor (MMUD) hematopoietic cell transplant (HCT). The approach has expanded transplant access for patients lacking 8/8 human leukocyte antigen (HLA)-matched donors, particularly those from racially and ethnically diverse backgrounds. ACCESS (NCT04904588) evaluated the safety and efficacy of PTCy [50 mg/kg on days 3 (D3) and 4 (D4)], mycophenolate mofetil (MMF), and tacrolimus as Graft-versus-Host Disease (GvHD) prophylaxis in adult patients with hematologic malignancies receiving myeloablative (MAC) or reduced intensity conditioning (RIC) followed by peripheral blood stem cells (PBSC) MMUD HCT (4-7/8 HLA match, considering HLA-A, -B, -C and -DRB1). One-year overall survival (OS) was 78.6% (RIC) and 83% (MAC), respectively. Over 50% of enrolled patients were ethnic minorities, allowing nearly all eligible patients to identify suitable unrelated donors (Al Malki et al. JCO 2025).
Despite controlling acute and chronic GvHD, PTCy carries risks of serious acute- and long-term toxicities. Preliminary studies suggest that the PTCy dose can be reduced by 20-50% without compromising efficacy. However, larger multicenter studies are needed, particularly in MMUD HCT. OPTIMIZE (NCT06001385) is investigating reduced-dose PTCy (25 mg/kg on D3 and D4) in combination with MMF and tacrolimus following 4-7/8 MMUD HCT in adults with hematologic malignancies. The primary endpoint is D100 infection-free survival (IFS), defined as survival without grades 2-3 infections or subsequent transplant.
To improve outcomes after MMUD HCT, we designed ACCELERATE (NCT06859424) – a master platform protocol that will simultaneously evaluate multiple interventions of PTCy-based GvHD prophylaxis in MMUD HCT. Each comparator regimen will be separately described and approved as an intervention-specific appendix (ISA) or sub-study to the ACCELERATE platform protocol. Sub-studies will be designated by numerical order, such as ACCEL-001, ACCEL-002, etc. Outcomes for ISA treatment interventions will be compared to a control arm using standard-dose PTCy (50 mg/kg on D3 and D4) combined with MMF and tacrolimus as GvHD prophylaxis.
Study Design and Methods:The NMDP-sponsored, CIBMTR-led ACCELERATE is a prospective, multi-center, randomized platform protocol conducted across up to 60 U.S. centers. Adults with hematological malignancies receive MMUD PBSC HCT using MAC or RIC. MAC recipients must have an HCT-CI <5. Key exclusion criteria include the availability of a suitable HLA-matched related or 8/8 MUD and the presence of donor-specific HLA antibodies to any mismatched allele/antigen with a mean fluorescence intensity >3000. Donors must be 18-40 years old and matched at 4-7/8 alleles.
Two investigational ISAs will launch at study initiation, ACCEL-001 and ACCEL-002. ACCEL-001 evaluates the safety and efficacy of 25 mg/kg PTCy, tacrolimus, and abatacept (D5, 14, 28, 56), and ACCEL-002 evaluates outcomes using 25 mg/kg PTCy, tacrolimus, MMF, and ruxolitinib (5 mg twice daily starting D30 and initiating taper at D180 if no GVHD, then discontinue by D270) as GvHD prophylaxis following MMUD PBSC HCT using MAC or RIC conditioning.
A non-randomized safety lead-in phase will precede randomization. Participants in the randomized phase will be assigned 1:1 to intervention or control, stratified by conditioning regimen and HLA mismatch degree (<7/8 vs 7/8). If two ISAs are open at a site, 1:1:1 randomization will be applied.
The primary efficacy endpoint is GvHD-free, relapse-free survival (GRFS) at 1-year post-HCT. Lead-in and randomized phases will be analyzed separately. Continuous safety monitoring will be conducted and includes primary graft failure (PGF), grades 3-4 acute GvHD, and non-relapse mortality by Day 100. Quality of Life will be assessed through patient-reported outcomes surveys. An independent Data Safety Monitoring Board (DSMB) will advise on continuation, modification, or termination.
Study Accrual and Future Directions:As of July 2025, two sites have opened for enrollment, and the first participant has been successfully enrolled. The study will enroll 20 patients in each safety lead-in and 106 patients in each arm of the randomized study, for 358 participants. The safety lead-ins are anticipated to complete enrollment by early 2026, while the randomized study is scheduled to begin in Spring 2026.
