Cusatis, Rachel

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)

Importance Allogeneic hematopoietic cell transplant (HCT) is curative for hematologic cancers, yet access remains inequitable for racially and ethnically underrepresented and socioeconomically disadvantaged populations, making the goal of having a suitable donor for every patient who needs a transplant challenging. The ACCESS trial broadened access by enrolling patients without matched donors, who instead received an HCT from a mismatched unrelated donor. Objective To compare baseline characteristics of ACCESS trial participants with participants enrolled in a similar clinical trial and a patient-reported outcome (PRO) protocol cohort. Design, Setting, and Participants This cross-sectional study included adult participants (aged ≥18 years) from 3 cohorts—the ACCESS trial (2021-2024), BMT CTN 1703 trial (2019-2021), and Center for International Blood and Marrow Transplant Research (CIBMTR) PRO Protocol observational study (2020-2025)—who completed a baseline PRO survey. The ACCESS and PRO Protocol cohorts were stratified by conditioning intensity (myeloablative [MAC] vs reduced-intensity and nonmyeloablative [RIC/NMA]); all BMT CTN 1703 participants received RIC/NMA. Exposure Hematopoietic cell transplant. Main Outcomes and Measures Racial and ethnic diversity, insurance type, education, and income were compared among cohorts using counts and percentages, and socioeconomic and structural disadvantage were measured using the Social Vulnerability Index and Comprehensive Score for Financial Toxicity–Functional Assessment of Chronic Illness Therapy. Results Baseline surveys were completed by 208 participants in the ACCESS trial (median [range] age at transplant, 62.3 [20.4-78.9] years; 108 male [51.9%]), 122 participants in the PRO Protocol study (median [range] age at transplant, 63.9 [21.1-78.0] years; 67 male [54.9%]), and 342 participants in the BMT CTN 1703 trial (median [range] age at transplant, 66.9 [20.7-78.6] years; 218 male [63.7%]). Participants in ACCESS were more racially and ethnically diverse, with 15 (7.2%), 25 (12.1%), 46 (22.2%), 110 (53.1%), and 11 (5.3%) of Asian, Black or African American, Hispanic or Latino, White, and other race and ethnicity, respectively, compared with 4 (3.3%), 2 (1.6%), 8 (6.6%) 104 (85.2%), and 4 (3.3%), respectively, in the PRO Protocol and 10 (3.0%), 0, 16 (4.8%), 302 (91.0%), and 4 (1.2%), respectively, in the BMT CTN 1703 trial. Participants in ACCESS were more likely to have Medicaid (36 [18.1%]) vs PRO Protocol (8 [6.7%]) and BMT CTN 1703 (16 [5.1%]) participants and reported lower education (some college or an associate’s degree: 103 [49.5%] vs 73 [59.8%] in the PRO Protocol; postcollege education: 34 [17.3%] vs 35 [29.2%] in the PRO Protocol) and household income (<$40 000 annually: 25 [24.0%] vs 8 [11.6%] in the PRO Protocol and 7 [38.9%] in the BMT CTN 1703 trial). Median Social Vulnerability Index scores were highest among participants in the ACCESS MAC group (median [range], 0.72 [0.01-0.97] vs 0.61 [0.16-0.78] in the PRO Protocol MAC group), and 16 participants [27.6%] in the ACCESS MAC group reported moderate to severe financial toxicity. The ACCESS participants lived closer to transplant centers, especially in the RIC/NMA group (median [IQR], 28 [14-75] miles vs 47 [16-96] miles for BMT CTN 1703 participants and 49 [21-104] miles for PRO Protocol participants). Conclusions and Relevance This cross-sectional study of clinical trial participants and a clinical cohort found that the ACCESS trial enrolled a more racially and ethnically diverse and socioeconomically disadvantaged population. Trial designs that broaden eligibility could expand access to HCT, highlighting the need for systemic interventions to ensure equity.

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.

Abstract Background Light chain (AL) amyloidosis is a plasma cell neoplasm associated with high early mortality and severe morbidity that can cause severe disability. We explored the impact of AL amyloidosis on symptoms and well-being from the perspectives of patients and health care providers who regularly care for AL patients. We intended to develop a conceptual understanding of patient-reported outcomes in AL amyloidosis to identify the context of use and concept of interest for a clinical outcome assessments tool in this disease.Method Twenty patients and 10 professionals were interviewed. Patient interviews captured the spectrum of amyloidosis experience including time from diagnosis, type of organ involvement, and presence and type of treatment received. Interviews with professionals included physicians, advanced practice providers, registered nurse, and a patient advocate; these interviews covered similar topics. Results The impact of AL amyloidosis on patients’ life was multidimensional, with highly subjective perceptions of normality and meaning. Four major themes from patients and experts included diagnosis of AL amyloidosis, living with AL amyloidosis, symptom burden, and social roles. Barriers to patient-reported outcomes data collection in patients were additionally explored from experts. The themes provide a comprehensive understanding of the important experiences of symptom burden and its impact on daily life from AL amyloidosis patients’ and from the perspectives of professionals who care for patients with AL amyloidosis. Conclusion These findings further the conceptual understanding and identification of a preliminary model of concept of interest for development of a clinical outcome assessments tool for AL amyloidosis.