Paper Details

ABSTRACT

Introduction:

ACCESS (NCT04904588) is an NMDP-sponsored phase II, non-randomized, multicenter trial conducted by the CIBMTR that assessed cyclophosphamide (50mg/kg on days 3 and 4), tacrolimus, and mycophenolate mofetil (PTCy) as graft vs host disease (GVHD) prophylaxis following mismatched unrelated donor (MMUD) peripheral blood stem cell transplantation (PBSCT). The study had two adult strata: myeloablative conditioning (MAC) and reduced intensity or nonmyeloablative (RIC) conditioning. MMUDs were ≤35 year and 4-7/8 matched at HLA-A, B, C and -DRB1. The primary outcome was overall survival (OS) at 1-year post-HCT and was 78.6% in the initial RIC cohort (n=70, Al Malki et al. JCO 2025) and 80.3% in the planned expansion cohort (n=123, Shaffer et al. Am J Hematol 2026). Here we report longer term outcomes in the combined RIC strata and compare to a landmark trial using full dose PTCy in the HLA-matched donor setting.

Methods:

We used long-term outcome data from the CIBMTR registry to assess 2-year outcomes among patients enrolled in the full RIC ACCESS cohort. We then compared outcomes with those from Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1703 (NCT03959241), which was a randomized phase III trial of PBSCT using full-dose PTCy in matched related and unrelated donor RIC HCT. Outcomes included overall survival (OS), GVHD-free/relapse-free survival (GRFS), relapse-free survival (RFS), relapse, non-relapse mortality (NRM), chronic GVHD (cGVHD), cGVHD requiring systemic immune suppression therapy, graft failure and patient-reported outcomes (PRO) including PROMIS physical function and Lee Symptom score (LSS). The Kaplan-Meier method was used to estimate OS, GRFS, and RFS, and cumulative incidence functions were used to estimate relapse, NRM, graft failure, and chronic GVHD. A mixed effect model with repeated measures was used for analysis of PRO assessments.

Results:

Among 193 ACCESS and 208 BMT CTN 1703 enrollees, 153 (80%) and 196 (94%), respectively, consented to CIBMTR registry follow-up. Patients excluded were slightly more Hispanic (16% vs 25%) and received more flu/mel conditioning (58% vs 70%). Other donor, recipient, disease and transplant characteristics were similar. When comparing ACCESS vs 1703 patients, median age was similar (64.8 vs 66.2 years), while ACCESS included more patients from underrepresented groups (46% vs 12%). Median follow-up was 25 vs 54 months. Disease distribution was similar, with acute leukemia most common (ACCESS: 50% AML,10% ALL; 1703: 48% AML, 6% ALL), followed by MDS (22.2% vs 31.6%) and NHL (11.1% vs 10.7%). HLA matching differed as expected (ACCESS: 69% 7/8, 31% <7/8; 1703: 96% 8/8, 3.5% 7/8, 0.5% <7/8). Median donor age was 25.6 vs 30.2 years. HCT years differed, but both trials occurred during the COVID-19 era, with similar graft cryopreservation rates (58.2% vs 61.7%). Both trials used predominantly flu/mel conditioning (58.2% in each cohort).

For ACCESS and 1703, 2-year OS was 67.2% (59.1-74.0%) and 66.3% (59.2-72.5%) and GRFS was 43.7% (31.5-51.5%) and 35.6% (28.8-42.3%), respectively. RFS at 2 years was 59.9% (51.6-67.3%) on ACCESS and 52.1% (44.8-58.9%) on 1703. Relapse rates at 2 years were 22.0% (15.8-29.0%) on ACCESS and 35.4% (28.7-42.2%) on 1703. NRM at 2 years was 18.0% (12.3-24.6%) on ACCESS and 12.4% (8.2-17.5%) on 1703. Overall cGVHD at 2 years was 30.7% (22.5-39.2%) on ACCESS and 34.1% (26.2-42.1%) on 1703. cGVHD IST at 2 years was 15.0% (9.9-21.2%) and 18.4% (13.3-24.1%) on ACCESS and 1703, respectively. Graft failure at d28 (10.5% vs 10.2%)  and second HCT (8.5% vs 9.7%) was similar in ACCESS and 1703. Physical function scores did not differ at any timepoints (d100, d180 or d365) between ACCESS and 1703. LSS scores only differed for skin at d100 (p<0.01) with higher scores in the ACCESS cohort and no differences between groups at d180 or d365. 

Conclusions:

PTCy-based GVHD prophylaxis after MMUD PBSCT resulted in favorable 2-year OS, GRFS, relapse, NRM, chronic GVHD and 1 year PRO outcomes. Outcomes in ACCESS were broadly comparable to those observed in BMT CTN 1703, despite ACCESS using MMUDs and enrolling a larger proportion of patients from underrepresented groups. Together, these findings continue to support MMUD PBSCT with PTCy-based prophylaxis as a viable option when fully matched related or unrelated donors are unavailable, with the potential to expand donor access across ancestry groups.