Leckrone, Erin

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received <7/8 MMUD grafts; 82.4% of the <7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the <7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the <7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

Abstract Allogeneic hematopoietic cell transplantation (HCT) using an HLA mismatched unrelated donor (MMUD) with calcineurin inhibitor-based graft versus host disease (GVHD) prophylaxis results in increased incidence of non-relapse mortality (NRM) and lower survival compared to matched donor HCT. The NMDP sponsored 15-MMUD study demonstrated that post-transplant cyclophosphamide (PTCy)-based prophylaxis following bone marrow derived MMUD HCT resulted in reduced incidence of GVHD and favorable survival. Because marrow grafts can be difficult to procure and vary in quality, we conducted a phase II, prospective, multicenter study to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell (PBSC) allografts. The primary study aim was to estimate the probability of one-year overall survival (OS) post HCT. Secondary aims were to assess other key clinical endpoints and determine the rate of severe infections. Initial results of the first 70 recipients who received reduced intensity conditioning (RIC) were previously reported by Al Malki et al (JCO 2025) demonstrating a 1-year OS of 78.6% (95% CI, 67% to 86.5%). Here, we report results from a planned expansion of the study that included 123 additional RIC recipients, with updated results from the initial cohort of 70 patients (total N = 193 subjects) treated at 33 centers. Study participants received cyclophosphamide 50 mg/kg (ideal body weight) administered on days 3 and 4 post HCT with tacrolimus and mycophenolate mofetil as previously described (Al Malki, JCO, 2025). The median study participant age was 65.0 (range: 22.9-78.9); 92 (47.7%) of participants were male, and 84 (43.5%) identified as having other than non-Hispanic white ancestry. The HCT comorbidity index was high-risk (>3) in 65 (33.7%). Underlying histologic diagnosis was AML in 96 (49.7%) participants, MDS in 43 (22.3%), ALL in 20 (10.4%), lymphoma or CLL in 24 (12.4%), and CML/other leukemias in 10 (5.2%). Conditioning regimens used were fludarabine and melphalan (100 or 140 mg/m2) (N=120; 62.2%), 2-day busulfan and fludarabine (N=38; 19.7%), and fludarabine, cyclophosphamide and total body irradiation (200 cGy) (N=32; 16.6%). Donor HLA matching (considering HLA-A, -B, -C, and -DRB1) was 7/8 in 131 (67.9%) of participants, 6/8-matched in 51 (26.4%), and 4-5/8-matched in 11 (5.7%) participants. Median donor age was 25.5 years (range: 18.7-35.7). The one-year overall OS estimate was 79.6% (95% confidence interval [CI]: 73.2-84.7). Survival was similar among HLA 7/8-matched donor recipients (77.8%, 69.7-84%) and <7/8 matched donor recipients (83.7%, 71.8-90.9%). The one-year GVHD-free, relapse-free survival (GRFS) was 49.9% (42.6-56.9%) and the one-year progression-free survival was 70.2% (63.2-76.2%). The one-year cumulative incidence (CI) rates of NRM and relapse were 12.5% (8.3-17.6%) and 17.3%(12.3-23%), respectively. The 6-month CI of grade II-IV and grade III-IV acute GVHD were 40.0% (33.0-46.8%) and 7.8% (4.6-12.1%), respectively. The one-year incidence of all chronic GVHD and severe chronic GVHD were 15.6% (10.7-21.2%) and 3.7% (1.6-7%), respectively, by NIH consensus criteria. The CI of grade 1-4 cytokine release syndrome (CRS) by day 7 post HCT was 28.0% (21.8-34.9%), and grade 3-4 CRS was 0.5% (0-2.9%). Primary engraftment failure occurred in 9 (4.7%) participants. Among 145 evaluated participants, 85.5% were >95% donor in blood chimerism at day 100 post HCT. Within the first 100 days after HCT, CTCAE grade 2-5 infections occurred in 113 (58.5%) of participants and grade 3-5 infections occurred in 59 (30.6%) of participants. The most common etiologies of grade 2-5 infections were bacterial (N=78), followed by viral (N=48). The most common grade 3-5 non-infectious toxicities were cardiac disorders, which occurred in 4 (2.1%) of participants. In conclusion, the results including this expansion cohort demonstrate encouraging 1-year OS, NRM and relapse rates in RIC recipients of PTCy-based GVHD prophylaxis and PBSC allografts from MMUDs. This larger cohort of 193 recipients re-affirm the results from the initial cohort with greater robustness.Measures to mitigate infection risk are likely to further improve outcomes. Reducing the dose of PTCy is a candidate approach currently being tested in the ongoing OPTIMIZE trial (NCT 06001385).These results support the extension of PBSC MMUD using PTCy to individuals who lack an HLA-matched donor and require RIC HCT.

Abstract Allogeneic hematopoietic cell transplantation (HCT) remains inaccessible to many patients, particularly those of non-European ancestry, due to the limited availability of matched unrelated donors (URD). While single-HLA mismatched donors (7/8) often yield acceptable outcomes, URD HCT mismatched at ≥ 2 HLA alleles (<7/8) has historically been associated with poor survival and prohibitive toxicity. Post-transplant cyclophosphamide (PTCy) has improved outcomes following mismatched unrelated donor (MMUD) HCT, potentially enabling less stringent donor matching. Whether the degree of donor-recipient HLA disparity remains prognostic after MMUD HCT when PTCy is used is unknown. The ACCESS trial (NCT04904588) was conducted by the Center for International Blood and Marrow Transplant Research Clinical Research Organization and prospectively evaluated PTCy-based graft versus host disease (GVHD) prophylaxis in adult recipients of 4–7/8 (HLA-A, -B, -C and -DRB1) MMUD peripheral blood stem cells (PBSC) from donors age ≤35 years old following either myeloablative (MAC) or reduced intensity/non-myeloablative (RIC/NMA) conditioning. This analysis focused on all adult recipients of <7/8 grafts enrolled on the study across both conditioning strata, with descriptive comparison to patients who received 7/8 MMUD PBSC grafts. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included primary graft failure (PGF), non-relapse mortality (NRM), relapse, acute and chronic GVHD, and GVHD-free relapse-free survival (GRFS). A total of 268 adults received MMUD PBSC grafts: 85 with <7/8 matches (MAC: n=23; RIC/NMA: n=62) and 183 with 7/8 matches (MAC: n=52; RIC/NMA: n=131). Among <7/8 recipients, median age was 57 years old (range, 24–78), 49% were male, with diagnoses of acute myeloid leukemia (AML) (55%), myelodysplastic syndromes (MDS) (15%), and lymphoma (14%). HLA mismatch distribution in the <7/8 group was 6/8 in 82%, 5/8 in 14%, and 4/8 in 4%. Most received fludarabine/melphalan (44%) or myeloablative busulfan/fludarabine (21%). Median CD34+ cell dose was 5.5 ×10^6/recipient kg (range: 3.2-8.0) and 75% of grafts were cryopreserved prior to infusion. Median donor age was 25.8 (range: 18.7-35.7) in the 7/8 group and 25.0 (range: 18.3-34.8) in the <7/8 group. The <7/8 cohort was racially and ethnically diverse, with 61% identifying as other than non-Hispanic white. The 7/8 cohort had a median age of 63 years old (range, 20–79), with 52% male. Disease distribution, conditioning intensity, and infused cell doses were similar to the <7/8 group. A smaller proportion of grafts were cryopreserved (61%), and 47% of patients identified as other than non-Hispanic White. One-year OS for <7/8 recipients was 86% (95% CI: 76–92%), compared to 79% (95% CI: 72–84%) in 7/8 recipients. One-year incidence of relapse was 23% (95% CI: 14–33%) in the <7/8 group and 17% (95% CI: 12–23%) in 7/8 recipients; NRM was 8% (95% CI: 4–16%) and 14% (95% CI: 9–19%), respectively. GRFS was 55% (95% CI: 43–65%) for <7/8 and 51% (95% CI: 44–58%) for 7/8 recipients. PGF occurred in 8% (95% CI: 3–18%) of <7/8 RIC recipients and 3% (95% CI: 1–8%) of 7/8 RIC recipients; no MAC recipients had PGF. At 6 months post-HCT, grade II–IV acute GVHD occurred in 34% (95% CI: 24–44%) of <7/8 patients and 39% (95% CI: 32–46%) of 7/8; grade III–IV acute GVHD was observed in 7% (95% CI: 3–14%) and 8% (95% CI: 5–13%), respectively. Moderate to severe chronic GVHD (NIH consensus criteria) at one year occurred in 8% (95% CI: 3–15%) of <7/8 recipients and 11% (95% CI: 7–16%) of 7/8 recipients. When grouped by conditioning intensity, 1-year outcomes within the <7/8 cohort were: OS 91% after MAC and 84% after RIC/NMA; relapse in 32% after MAC and 20% after RIC/NMA, respectively; GRFS was 53% for MAC and 55% for RIC/NMA; and NRM remained low at 9% after MAC and 8% after RIC/NMA. In this cohort of adult recipients of <7/8 MMUD PBSC grafts with PTCy-based GVHD prophylaxis enrolled on the ACCESS study, 1-year OS exceeded 80% and was comparable to 7/8 recipients. Relapse, NRM, and GVHD rates were similarly favorable and consistent with outcomes reported in 7/8 donor recipients. These findings support extending suitable MMUD match considerations to include 4-6/8 in the context of PTCy, potentially enabling near-universal donor access, while allowing for optimization of other non-HLA donor factors.