OBJECTIVE:This study aimed to define the evolving indications for splenectomy and benchmark clinical outcomes in patients with hematologic malignancies. BACKGROUND:With the advent of new therapies for hematologic malignancies, the diagnostic and therapeutic indications for splenectomy have changed. However, the effectiveness of splenectomy and its postoperative complications are not well understood. METHODS:This retrospective study included consecutive patients with hematologic disorders who underwent splenectomy at an NCI-designated comprehensive cancer center between 2009 and 2024. Patients were grouped by indication as lymphoid or myeloid; patients with benign conditions constituted a small descriptive subgroup. The primary outcome was the postoperative complication rate (30 d). The secondary outcome was splenectomy success based on indications. RESULTS:A total of 79 patients were included: 37 lymphoid, 33 myeloid, 5 immune thrombocytopenic purpura (ITP), and 4 others. Indications included bridge-to-transplant (35.4%), transfusion dependence (24.0%), symptomatic cytopenia (22.8%), and splenic malignancy (17.7%). The 30-day complication rate was 49% overall (22% grade 3 or higher). While myeloid patients had a higher proportion of patients experiencing any complication compared to lymphoid patients (65.5% vs 46.4%) (P=0.482). Success rates were 91.7% for bridge-to-transplant but lower for achieving transfusion independence in cytopenia (38.5% lymphoid patients, 40% post-transplant myeloid patients, and 40% ITP patients). CONCLUSIONS:Our results benchmark postoperative outcomes of splenectomy in a contemporary cohort with hematological malignancies. The success of splenectomy varies according to indication. Appropriate splenectomy produces favorable outcomes across a broad range of hematologic malignancies, including improved transfusion independence and successful bridging to definitive therapies.

Background ACCESS (NCT04904588), a multi-center phase II trial, was designed to assess safety and efficacy of HLA-mismatched unrelated donor (MMUD) peripheral blood allografts in adult patients with high-risk hematologic malignancies receiving myeloablative (MAC) or non-myeloablative/reduced-intensity conditioning (NMA/RIC) and standard-dose post-transplantation cyclophosphamide (SD PTCy) as graft-versus-host disease (GvHD) prophylaxis. One-year overall survival (75%) was similar irrespective of conditioning intensity and degree of donor HLA MM (Al Malki et al., JCO 2025). However, 56% MAC and 64% RIC adult recipients experienced at least one Common Terminology Criteria for Adverse Events (CTCAE) grade (Gr) ≥2 infection within the first 100 days of transplant (D100). Herein, we describe infection burden in ACCESS patients within one year after transplant. Methods CTCAE Gr≥2 infections were analyzed by time after transplant (Days 0-30, 31-100, 101-180, 181-365), conditioning intensity, degree of donor HLA MM (HLA 7/8 vs. <7/8), pathogen type, and post-MMUD HCT outcomes (Gr2-4 acute GvHD, moderate/severe chronic GvHD, and American Society for Transplantation and Cellular Therapy (ASTCT) Gr≥2 cytokine release syndrome. Infection density was calculated as number of infections per 100 days at risk for enrolled patients. Infection data were summarized with standard descriptive statistics. Infection density with 95% confidence intervals (CI) were estimated using Poisson regression models; p<0.05 was considered statistically significant. Results Median (range) ages for 268 patients receiving MAC (n=75) and RIC/NMA (n=193) were 49.8 (20.4-65.6) and 64.4 (24.3-77.9) years, respectively. CTCAE Gr≥2 infections occurred in 183 (69%) patients: 49 (65%) MAC and 134 (69%) RIC/NMA recipients. Days 0-30 infection densities for Gr2-5 and Gr3-5 infections were higher relative to infection densities at other post-transplant periods and irrespective of conditioning intensity (Fig. 1A) and degree of donor HLA MM (Fig. 1B). When comparing infection densities by conditioning intensity, patients receiving RIC/NMA had higher infection densities at Days 31-180 for Gr3-5 infections (Fig. 1A). When comparing infection densities by degree of donor HLA MM, significant differences were noted only at Days 181-365 in the RIC stratum (Fig. 1B). Similar distribution of pathogen types by conditioning intensity were noted early (Fig. 1C) and late (Fig. 1D) post-transplant, with predominantly gram-positive bacteria and non-respiratory viruses, respectively. Finally, pathogen type frequencies by clinical outcomes were indistinct (Fig. 1E). Conclusion In the MMUD PBSC transplant setting, SD PTCy associates with significant infection burden. These findings provide insights into potential interventions to prevent infection or augment immune response after MMUD transplant.

Introduction Disease relapse is the leading cause of death in patients after allo-HCT for AML, ALL and MDS. TSC-101is a donor-derived TCR-T cell product targeting HA-2 on HLA-A*02:01 positive hematopoietic cells. Objective Pairing A*02:01 positive patients with A*02:01 negative donors should allow TSC-101 (TSC) to eliminate only residual patient blood cells post-HCT, thus preventing relapse. Methods ALLOHA is a multi-center, biologically controlled, Phase 1 dose escalation study evaluating TSC in adults with AML, ALL or MDS undergoing RIC-HCT. HA2-positive subjects receive either one or two infusions of TSC after count recovery (∼days 21 and 61 post-HCT). Control subjects receive RIC-HCT per standard of care. Primary endpoints are dose limiting toxicities and safety; other endpoints are efficacy, chimerism and minimal residual disease (MRD). Results As of 18 Jul 2025, endpoints were evaluated in 31 subjects (17 TSC and 14 control) without early post-HCT complications. Median follow-up (range) was 9.6m (2-29m) for the TSC arm and 11.9m (1-33m) in control. Baseline prognostic features were similar, including age and disease type. High-risk features were found in both arms including mutated TP53 (TP53m) in 4 TSC vs 2 controls, and pre-HCT MRD positivity in 10/15 TSC vs 8/14 control subjects.There were no DLTs after TSC. Safety was similar in both arms and included expected post-HCT adverse events. Acute graft-versus-host-disease of any grade occurred in 10/17 TSC vs 7/14 control subjects. Chronic GvHD occurred in 1 TSC and 2 controls. Following TSC, cytokine release syndrome occurred in 2/17 subjects (grade 1 and 2) and neurotoxicity in 1 subject (grade 1). There were no TSC-related deaths or graft failures.Efficacy analyses showed reduced relapses with TSC 3/17 vs control 5/14, with improved relapse-free survival (hazard ratio (HR) 0.48), relapse probability (HR 0.43) and overall survival (HR 0.44). Event-free survival, including clinical interventions, also improved (HR 0.41). Among mTP53, relapses occurred in 2/2 control vs. 1/4 TSC and 1 TP53m TSC subject was disease-free >2 years.Translational analysis showed complete donor chimerism in all cells (whole blood, CD33+, or CD3+) at ≥1 timepoint after TSC-101 in 15 evaluable subjects. In contrast, complete chimerism ≥1 timepoint after HCT occurred in 8/14 of controls. Bone marrow biopsies ∼Day 63 post-HCT, showed 0/13 TSC compared to 3/10 control subjects were MRD+. TCR-T cells were detectable in all TSC subjects at last follow-up (f/u) including 7 subjects with ≥ 1y post-infusion. Conclusions The safety seen with HCT followed by TSC-101 is generally consistent with post-HCT safety. Preliminary analyses show early elimination of residual recipient cells in all evaluable subjects and support the potential of TSC-101 to reduce relapses and improve relapse-free survival in RIC-HCT patients. Updated data will be presented.

Background The ACCESS trial is a multicenter phase II study that evaluated standard dose post-transplant cyclophosphamide in recipients of HLA mismatched unrelated donor (MMUD) hematopoietic cell transplantation (HCT) for hematologic malignancy. This study examines 1-year post-treatment quality of life (QOL) trajectories among 7/8 HLA matched versus <7/8 HLA matched unrelated donor recipients. Methods This longitudinal study included ACCESS (NCT04904588) trial participants who completed at least one patient reported outcome (PRO) for analysis. Patients completed QOL surveys at baseline, day (D)100, D180, and 1-year post-HCT, using the Lee Symptom Scale (LSS), nine Patient Reported Outcome Measurement Information System (PROMIS) domains, and a measure of financial toxicity (FT, COST-FACIT). Clinically meaningful differences were defined as >5 points, with PROMIS and COST-FACIT cut points and published norms used to interpret symptom burden. Fisher exact or Wilcoxon rank-sum test were applied to compare patient characteristics between <7/8 and 7/8 patients. Results Among the 268 patients enrolled into the ACCESS trial, 232 (87%) submitted at least one survey. Of those patients, 68% (n=158) had a 7/8 MMUD and 31% (n=74) had a <7/8 MMUD. Compared to <7/8 MMUD recipients, patients receiving <7/8 MMUD were younger (median age: 57.6 v. 63.4 years), were more likely to be of racial and/or ethnic minority ancestry (64% v. 42%) and were less likely to be retired (27% v. 43%).At baseline, both cohorts experienced mild FT: 23.9, Grade 1 for <7/8 MMUD recipients and 25.6, Grade 1 for 7/8 MMUD recipients (Fig 1a). At D180 and 1 year, patients receiving <7/8 MMUD continued to report mild financial toxicity while 7/8 MMUD recipients reported no significant financial toxicity at D180 or 1 year.LSS overall scores were similar between groups across all timepoints.PROMIS scores for 7/8 and <7/8 MMUD groups were within the normal limits of symptom burden across all domains except physical and sexual function. At baseline, <7/8 patients had a lower average physical function score (44.1, 95% Confidence interval, CI: 43.3–44.9), indicating mild dysfunction, compared to 7/8 patients (45.7, 95% CI: 44.7–46.7), who were within normal limits (Fig 1b). Both groups showed similar physical function trajectories, with declines at D100 (3.6-point decline for 7/8; 3.9 point decline for <7/8) and recovery to normal ranges by one year (mean 47 for 7/8; mean 46.3 for <7/8). Conclusions There were no clinically meaningful differences between patients with a 7/8 and <7/8 MMUD on overall QOL. Both cohorts demonstrated similar QOL trajectories, returning to baseline scores at 1-year post-HCT. Small differences involving physical function and FT warrant further study. These findings highlight the expansion of access to HCT through HLA mismatch does not come at the cost of QOL, with equal QOL experienced regardless of HLA match.

Background Access to allogeneic hematopoietic cell transplantation (HCT) remains limited for patients of non-European ancestry due to donor unavailability. While 7/8 mismatched unrelated donors (MMUD) provide acceptable outcomes, HCT with ≥2 allele mismatches (<7/8) have historically yielded poor survival and prohibitive toxicity. Post-transplant cyclophosphamide (PTCy) has significantly improved outcomes after MMUD HCT, but the prognostic effect of increasing HLA disparity in this setting is unclear. Methods The prospective ACCESS trial (NCT04904588) evaluated PTCy-based GVHD prophylaxis in adults receiving 4–7/8 HLA-mismatched peripheral blood stem cells (PBSC) from donors ≤35 years old after myeloablative (MAC) or reduced-intensity/non-myeloablative (RIC/NMA) conditioning. Primary endpoint was 1-year overall survival (OS). Secondary endpoints included graft failure, non-relapse mortality (NRM), relapse, acute and chronic GVHD, and GVHD-free relapse-free survival (GRFS). Results Among 268 adults, 85 received <7/8 and 183 received 7/8 MMUD PBSC grafts. The <7/8 cohort (median age 57, range 24–78; 49% male) was racially diverse, with the majority (61%) identifying as racial/ethnic groups other than non-Hispanic White, and included 6/8 (82%), 5/8 (14%), and 4/8 (4%) matches. Conditioning intensity in this group was MAC (n=23) and RIC/NMA (n=62). Diagnoses included AML (55%), MDS (15%), lymphoma (14%) and ALL (11%). Most received fludarabine/melphalan (44%) or myeloablative busulfan/fludarabine (21%); the median CD34+ cell dose was 5.5 × 10^6/kg, and 75% of grafts were cryopreserved. The 7/8 group (median age 63, range 20–79; 52% male) had similar disease distribution, conditioning intensity [MAC (n=52), RIC/NMA (n=131)], and infused cell dose. In this cohort, 61% of grafts were cryopreserved, and nearly half (45%) identified as racial/ethnic groups other than non-Hispanic White.At 1 year, OS was 86% (95% CI, 76–92) for <7/8 vs 79% (72–84) for 7/8. Relapse was 23% (14–33) vs 17% (12–23); NRM 8% (4–16) vs 14% (9–19); and GRFS 55% (43–65) vs 51% (44–58) in <7/8 and 7/8, respectively. At 6 months, grade II–IV acute GVHD occurred in 34% (24–44) vs 39% (32–46), and grade III–IV in 7% (3–14) vs 8% (5–13) in <7/8 and 7/8, respectively. At 1 year, moderate/severe chronic GVHD was 8% (3–15) vs 11% (7–16). Primary graft failure occurred only after RIC/NMA: 8% (3–18) with <7/8 vs 3% (1–8) with 7/8.In <7/8 recipients, 1-year OS was 91% with MAC and 84% with RIC/NMA; relapse 32% vs 20%; GRFS 53% vs 55%; and NRM 9% vs 8%, respectively. Conclusions PTCy-based GVHD prophylaxis results in excellent outcomes following <7/8 MMUD HCT, with OS >80% and low NRM and GVHD, comparable to 7/8. Extending donor criteria to 4–6/8 mismatches should broaden equitable donor access while permitting optimization of non-HLA factors.

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.

Human leukocyte antigen (HLA)-mismatched unrelated donor (MMUD) hematopoietic cell transplantation (HCT) has emerged as an effective therapy for adult patients with hematologic malignancies. The MMUD ACCESS Trial (NCT04904588), which incorporated post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis, demonstrated combined overall survival of 81% in enrolled patients, 59% who were ethnically diverse. Given PTCy is also associated with significant bacterial and viral infections, we defined infection burden in the full adult cohort (N=268) using infections graded according to an international standard (CTCAE, Common Terminology Criteria for Adverse Events, version 5.0). Infection density (number of infections per 100 days at risk), cumulative incidence of infection, and frequency of pathogen types were categorized by post-HCT time, conditioning intensity, level of donor HLA mismatch, and presence of acute GvHD. Of 465 recorded CTCAE grade 2-5 infections recorded in 183 (68%) adults, 176 (38%) infections were significant or life-threatening and most infections (296, 64%) occurred within the first 100 days. Infection density at Days 0-30 was significantly higher than at other times and was similar by conditioning and level of HLA mismatch as were pathogen types and isolates. Multivariable analysis showed that acute GvHD is significantly associated with infection. Lastly, 21 (7.8%) patients died from infection. Results show significant infection burden using standard dose PTCy in the MMUD HCT setting, irrespective of conditioning and level of donor HLA mismatch, and will serve as a benchmark for trials investigating reducing infection burden following MMUD HCT.

The importance of HLA mismatch in haploidentical hematopoietic cell transplantation (HaploHCT) with post-transplant cyclophosphamide (PTCy) is debated. If HLA mismatch does impact outcomes, a molecular mismatch model could predict transplant outcomes more effectively than allele mismatch. In this retrospective study, we quantified molecular HLA disparity using eplet mismatch for 265 patient-donor pairs undergoing HaploHCT with PTCy for hematologic malignancy. We discovered an interaction among eplet mismatch (EpMM), HLA class, and mismatch vector that was associated with clinical outcomes. This interaction was termed Class-wise HLA Imbalance of Mismatched Eplets (CHIME), which comprised risk scores of 0, 1, and 2. The CHIME score retained association with non-relapse mortality (CHIME 1 vs. 0, HR 2.85 (1.10-7.37); CHIME 2 vs. 0, HR 3.63 (1.36-9.68), adjusted p = 0.046) and severe aGvHD grade III-IV (CHIME 1 HR 7.82 (1.03-59.22); CHIME 2 HR 8.08 (1.01-64.63), adjusted p = 0.046) after adjustment for transplant-related variables. The CHIME score, when combined with CD3 cell dose, correlated with higher rates of cytokine release syndrome (CRS). The CHIME model may improve clinical outcome prediction over HLA antigen or allele mismatch.

Transplant-related morbidity remains a major barrier to broader application of allogeneic hematopoietic cell transplantation (HCT) in older adults. The frequency and importance of physical disabilities early after HCT have not been well-characterized. We sought to characterize the incidence and prognostic impact of physical disability complicating HCT in patients ≥60 years of age. We retrospectively analyzed 699 consecutive patients ≥60 years who underwent HCT at our institution. Physical disability post-HCT was defined as one or more of the following: (1) mobility dependence (requiring a person to assist walking); (2) delirium with loss of instrumental activities of daily living; (3) fall; or (4) intensive care unit admission. Disability-free Survival (DiFS) failure events included any of these disability events or death. The median age was 66 years; 20% were age ≥70 years. Melphalan-based conditioning was used in 85%, and 77% had matched donors. By day 30, 38% developed mobility dependence, 25% experienced delirium, 15% required intensive care unit care, and 5% experienced a fall. Day 30 DiFS was 57.2%, with a disability event preceding every death by day 30. One-year NRM landmarked at day 30 was 31.6% for patients with prior disability, versus 9.8% without (P < .001). In multivariable analysis, disability was independently associated with increased landmark NRM (Hazard Ratio [HR] = 2.70, 95% confidence interval [CI]: 2:03 to 3.60) and worse landmark overall survival (HR = 1.86, CI: 1.49 to 2.33), independent of acute graft-versus-host disease by day 30. Disability frequently complicates HCT in older adults and independently predicts higher NRM risk. Day 30 DiFS is a novel endpoint to quantify HCT morbidity and a potential target for trials to circumvent HCT-related complications.

Patients with adverse/intermediate risk acute leukemia/MDS have poor overall survival (OS) after allogenic hematopoietic cell transplant (HCT) due to high relapse rates after standard conditioning regimen. Previously, we showed TMLI combined with fludarabine/melphalan (Flu/Mel) conditioning prior to PBSC HCT is safe and promising, however Graft-versus-Host disease (GVHD) rates remain high when the regimen is combined with CNI-based GVHD prophylaxis (Al Malki et al EBMT 2024). Orca-T is an investigational T cell immunotherapy composed of highly purified regulatory T cells, hematopoietic stem cells, and conventional T cells from a suitable donor. We hypothesized that combining TMLI with Orca-T is feasible and safe in older patients with promising 1-year GVHD/relapse-free survival.This study is open to accrual (NCT06195891) and consists of 1) Dose finding phase to identify the recommended phase 2 dose (RP2D) of TMLI [12, 14, or 16 Gy] at each dose level (DL)] combined with Orca-T, and 2) an expansion cohort of 12 patients treated at the RP2D. Secondary objectives are incidence of acute and chronic GVHD, relapse, non-relapse mortality (NRM) rates and rates of OS and event-free survival at 1 and 2 years post-HCT. Eligible patients are ≥60 years old with intermediate/adverse risk AML, ALL (CR1, active disease or MRD+), or MDS with a matched (related/unrelated) or haploidentical donor. All patients received Flu (30 mg/m2 x 3 days) and Mel (100 mg/m2 x 1 day). GVHD prophylaxis was single agent tacrolimus from day +3 post-HCT.At abstract submission, 6 AML patients have been treated (3 at DL1 [12Gy] and 3 at DL2 [14Gy]) with mean follow up duration of 226 days (range 16-380); and 4 patients proceeding 180 days. Median age at HCT was 64 years (range 60-71), 66% were female, 50% Hispanic, and 83% Caucasian. Pre-HCT, all but 1 patient were in morphologic CR, MRD+ by flow was seen in 83.3% (n=5) of patients, and 60% had adverse risk per ELN2022. Five patients received HLA matched PBSC graft from sibling donor and one patient at DL2 received a haploidentical graft. Five patients have completed the 30-day dose-limiting toxicity (DLT) period with no reported DLTs; the 6th patient is currently within the DLT period. The most common G3+ non-hematologic adverse events were febrile neutropenia (n=4) hypertension (n=4), diarrhea (n=2) and anorexia (n=1). All patients engrafted with a median time to ANC and PLT engraftment of 11 and 16 days, respectively. UPN001 relapsed at 11 months and died at 12 months; the remaining 5 are alive and in follow-up. No NRM was observed by day +100. Acute GVHD occurred in 2 patients: one Grade 2 at DL2 and one Grade 3 at DL1 (per MAGIC criteria). No chronic GVHD has been reported so far.In conclusion, TMLI-based conditioning combined with Orca-T is feasible and safe at 12 and 14 Gy TMLI. Enrollment is ongoing to determine the RP2D. No unexpected safety signals have been observed in patients treated to date.

CIBMTR registry data shows that allogeneic HCT is being performed with increasing frequency in older patients. In this population, selecting a conditioning regimen that balances disease control while reducing non-relapse mortality (NRM) is critical to improving overall survival (OS). We retrospectively evaluated outcomes of 48 consecutive patients with AML, aged ≥ 70 years, who underwent allogeneic HCT at our center (2009 to 2019) using Flu/Mel conditioning and Tac/Siro-based GVHD prophylaxis. The primary objective of this retrospective analysis was to assess 5-year OS and identify clinical factors associated with survival.The median age at HCT was 71 years (range 70-78). Patients were transplanted in CR1 (62%), CR-2 (19%), or active disease (19%). Donor types were 8/8 HLA matched related (23%) or unrelated (77%). The median donor age was 31 years (range 19-77), and 17% of HCTs were from female donor to male recipient. A high/very-high Disease Risk Index (DRI) score was seen in 33% of patients, 44% of patients had an HCT-CI >2 and 21% had adverse risk features by ELN 2022 criteria. Peripheral blood stem cells were used as the graft source in all patients, and 75% of patients received a melphalan dose of 140 mg/m2.With a median follow-up duration of 7.0 years (range 5.1-10.7) among survivors, the 2 and 5-year OS rates were 77% (95% CI: 62-87%) and 65% (95% CI: 49-76%), respectively. Leukemia-free survival (LFS) at 2 and 5 years were 73% (95% CI: 58-83%) and 62% (95% CI: 47-74%), respectively. The relapse rate at 2 and 5 years were 10% (95% CI: 4-21%) at both time-points, and non-relapse mortality (NRM) was 10% (95% CI: 4-21%) at day 100 and 27% (95% CI: 15-40%) at 5 years. The cumulative incidence of Grade 2-4 and 3-4 acute GVHD at day +100 was 27% (95% CI: 15-40%) and 15% (95% CI: 6-26%), respectively. Cumulative incidence of chronic GVHD at 2 years was 65% (95% CI: 49-76%). Bone marrow CD3 chimerism > 95% at Day 30 was seen in 85% of patients.On Univariate analysis, 5-year was significantly corelated with remission status CR 1/2 versus active disease (70% vs 44%; p=0.014), secondary AML (80% vs 42%; p=0.027), prior Venetoclax use (72% vs 25%; p=0.003), and melphalan dose 140 mg/m2 vs 100 mg/m2 (75% vs 33%; p=0.018). These factors also showed significant differences in LFS and NRM, but not in relapse rate.In conclusion, our data suggests that allogeneic HCT using Flu/Mel conditioning and Tac/Siro GVHD prophylaxis in patients with AML results in promising 5-year OS with low relapse rates. This reduced intensity regimen remains an effective strategy for older AML patients undergoing allogeneic HCT from a matched donor.

Introduction Early detection of relapses in patients undergoing allogeneic hematopoietic cell transplantation (HCT) may enable early intervention. The ACROBAT study (NCT04635384) evaluates the use of AlloHeme, a next-generation sequencing (NGS)-based, ultra-sensitive monitoring test for relapse prediction in post-HCT patients. Methods Post-HCT acute myeloid leukemia (AML) and or myelodysplastic syndrome (MDS) patients enrolled in ACROBAT were included in this analysis. Testing was performed at 14 post-HCT time points over 2 years, as outlined in the study protocol. An increase of ≥0.2% in recipient chimerism between two consecutive time points was defined as increasing mixed chimerism (iMC) and an AlloHeme test positive. Treating physicians determined relapses per the Center for International Blood & Marrow Transplant Research criteria. Here we describe the findings of the 18-month interim analysis with the intent of presenting the final study readout for all subjects at Tandem Meetings 2026. Results Table 1 presents the demographics and disease characteristics of 227 enrolled AML and MDS patients. Out of the 227 enrolled patients, 32 subjects were excluded from the analysis due to events (non-relapse mortality (NRM), study withdrawal, and relapses) that occurred before the two tests used to determine iMC. Among the remaining 195 subjects with 18+ months of follow-up (median, 23.4 months; range, 1.8-24), 37 subjects (19%) experienced relapse, and 26 (13.3%) subjects had non-relapse mortality (NRM). AlloHeme had an AUC of 86% for relapse prediction based on sensitivity (88%), specificity (85%), PPV (60%), and NPV (97%). In comparison, modeling at the STR-PCR threshold of 1% iMC and site-reported multi-flow cytometry measurable residual disease (MFC-MRD) demonstrated lower sensitivity to predict relapse (Table 2). A time-varying risk model showed that the relapse risk for patients with an iMC is 54.0 times (95% CI = 22.4, 142.8; p < 0.001) higher than that of non-iMC patients. 3- and 6-month landmark analyses demonstrated significantly higher relapse incidence in subjects with iMC compared with non-iMC (p-values < 0.05) (Figure 1). Among subjects who were iMC positive before or at the time of the relapse event, the test provided a median lead time of 36 days to clinical relapse (IQR: 18–72 days), with 47% of relapses identified at least 45 days before the relapse.Further optimizing the performance for risk prediction by incorporating additional AlloHeme cell subtype analytes into an algorithm improved specificity to >92% and PPV to >74% without affecting sensitivity and NPV. Conclusion ACROBAT interim results demonstrate that AlloHeme monitoring for post-HCT AML and MDS patients can identify relapses with a significant lead time compared to traditional methods of relapse detection, which could enable timely interventions.

The MAGIC Algorithm probability (MAP), based on serum ST2 and REG3α, predicts acute GVHD-related non-relapse mortality (NRM) as early as 7 days after HCT (Hartwell et al. JCI Insight 2017). We retrospectively analyzed day 7 MAP in 721 patients transplanted in 2021-2024 at City of Hope (Park et al. ASH Abstract 2464, 2025). Among them, 164 (23%) were high-risk (HR) and 557 (77%) were low-risk (LR) with detailed characteristics shown in Table 1. With a median follow-up of 18 months among survivors (n=539), HR patients had higher NRM compared to LR (29.8% vs. 9.5% at 1 year, p<0.001), higher NRM without prior acute GVHD (17.4% vs. 3.7% at 1 year, p<0.001), and lower overall survival (63.8% vs. 84.0% at 1 year, p<0.001), with no difference in relapse or acute GVHD incidence. In multivariable analysis, MAP remained independently associated with NRM (HR 3.4, 95% CI 2.4-5.0, p<0.001). Cause-specific mortality analysis demonstrated higher GVHD-related and non-GVHD-related deaths (primarily infection and organ dysfunction) among HR patients, supporting day 7 MAP as a marker of systemic tissue injury rather than GVHD alone.To identify clinical determinants of HR MAP, we further evaluated patient and HCT variables. Age, HCT-CI, KPS, disease type, conditioning regimen, donor type, and GVHD prophylaxis were significant in univariable analysis. In multivariable models, older age (each year: HR: 1.012 [1.000 - 1.024), p=0.047), HCT-CI ≥3 (HR: 1.941 [1.332 - 2.829], p<0.001), and unrelated donor (vs matched related) (HR: 2.246 [1.400 - 3.605], p=0.004) remained independently associated with HR MAP (Table 2). Regarding GVHD prophylaxis, PTCy or CNI+MTX, compared with tacrolimus/sirolimus (T/S), was not associated with higher HR MAP incidence, while ruxolitinib with T/S (mainly used in MF/MPN) and abatacept (primarily used in pediatric patients) were independently associated with lower incidence of HR MAP (HR: 0.232 [0.079 - 0.687], p=0.037). Because pre- HCT gut dysbiosis is associated with poor HCT outcomes, we examined pre-HCT broad-spectrum antibiotic exposure as a surrogate, which showed no association with HR MAP or clinical outcomes (NRM, acute GVHD).In summary, day 7 MAP is a strong, independent predictor of NRM irrespective of the development of acute GVHD. Our data suggest that the tissue vulnerability and resiliency in the organ function (represented by HCT-CI and age) and the magnitude of the initial allo-immune response as seen in matched unrelated donor compared with matched related donor, are key drivers of HR MAP. These findings provide insight into the complex nature of post-transplant NRM and warrant further effort to develop biomarker-guided preemptive strategies to mitigate the risk of GVHD-related NRM as well as non-GVHD-related NRM.

The success of allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (aGVHD). We have previously reported that neutrophils can exacerbate tissue damage caused by conditioning regimens. Pegtarazimod is a synthetic peptide, derived from the capsid protein of human astrovirus serotype 1, that was shown to reduce neutrophil effector functions. Therefore, we evaluated the therapeutic activity of pegtarazimod against aGVHD. Pegtarazimod significantly reduced aGVHD-related mortality, histological aGVHD severity, and pro-inflammatory cytokines in multiple in vivo mouse models, while maintaining the anti-leukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase (NOX2) in the bone marrow. In addition to the anti-inflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase-2 clinical trial AURORA, pegtarazimod treatment was well-tolerated in patients with corticosteroid-refractory (SR) aGVHD (NCT06343792) with an overall response rate (ORR) of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity. The clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.

The use of systemic corticosteroids is recommended only for grades II to IV acute graft-versus-host disease (GVHD), but many patients are often treated at the onset of grade I in real-world practice. We retrospectively analyzed outcomes of 1143 patients with grade I GVHD from 24 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers. Approximately half received "up-front" systemic steroids, whereas the remainder received topical steroids alone; GVHD progressed to grade II to IV in only one-third of these patients. Up-front steroids decreased the risk for grade II to IV GVHD but not grade III to IV acute GVHD or the need for a second line of treatment. Systemic steroids were equally effective at treating grade I or II GVHD; however, up-front therapy exposed 3 times more patients to systemic steroids, with a corresponding threefold increase in GVHD that required additional therapy and a threefold rise in infection-related deaths. In multivariable analyses, up-front steroids were significantly associated with higher nonrelapse mortality (NRM; P = .026). MAGIC biomarkers identified most patients with grade I GVHD as low risk and unlikely to progress to severe GVHD regardless of treatment. Nevertheless, low-risk patients who received up-front steroids experienced a threefold increase in infectious deaths compared with those treated topically. This study supports the consensus recommendation of topical therapy for patients with low-risk grade I GVHD, a strategy that can be supported by biomarkers to avoid unnecessary steroid exposure and increased NRM.

ABSTRACT:Posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is now standard for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT). Previous studies comparing MUD and haploidentical donor HCT using PTCy were limited in size and follow-up. We therefore performed a registry-based analysis examining the impact of donor type on HCT with PTCy. Adult patients (n = 5873) receiving MUD (n = 1973) or haploidentical (n = 3900) HCT with PTCy for acute leukemia (74.2%) or myelodysplastic syndrome (MDS; 25.8%) reported to the Center for International Blood and Marrow Transplant Research between 2017 and 2021 were included. Primary end points were 3-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS). Cox regression and sensitivity analyses were performed through adjustment of propensity scores. Haploidentical HCT had worse OS (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.04-1.27; P = .005) and GRFS (HR, 1.19; 95% CI, 1.10-1.29; P < .001) versus MUD HCT. Donor age was the only other donor factor associated with survival. Results were confirmed in sensitivity analysis. When restricted to reduced intensity conditioning or donors <30 years, OS did not differ between groups. Haploidentical HCT was associated with higher primary graft failure (HR, 1.67; P = .002), increased grade 3/4 acute GVHD (HR, 1.28; P = .039), higher moderate/severe chronic GVHD (HR, 1.47; P < .001), and nonrelapse mortality (HR, 1.34; P < .001). Grade 2 to 4 acute GVHD and relapse risk did not differ. This large analysis showed that in adults with acute leukemia or MDS, MUD HCT was associated with improved outcomes versus haploidentical HCT with PTCy-based GVHD prophylaxis.

The JAK-STAT signaling pathway regulates cytokine and growth factor production and signaling, hence, influencing immune recovery after allogeneic HCT. We have previously reported results of our phase 2a clinical trial (NCT04339101) showing that peri-HCT administration of Itacitinib (Ita), a selective JAK1 inhibitor, in combination with tacrolimus (Tac) / sirolimus (Siro) GVHD prophylaxis in matched donor reduced intensity HCT setting, is safe and associated with 100% engraftment, a low cumulative incidence of GVHD, and promising 1-year GVHD-free relapse-free survival of 54% [Ali et al, Blood (2024) 144 (Supplement 1)]. Here, we report the pharmacokinetics/pharmacodynamics of Ita and its impact on immune reconstitution in patients enrolled in this trial.GVHD prophylaxis was Ita (200 mg/day – from day -3 pre-HCT until day +100), with Tac/Siro (target levels: 5-10ng/ml for both). Ita exposure was assessed from day -3 to day +5. T cell subsets were monitored on days +35 and +100. Serum cytokine level was measured at pre-HCT, days +14 and +28.Ita at 200 mg/day dose resulted in variable systemic exposure, with average trough concentration of 12.5 nM (IQR: 7.3-23.0) (Fig 1A) and AUC0-12 at 2145 nM*h (IQR: 1440-2926). The average trough concentrations for Tac and Siro were less variable mainly due to therapeutic drug monitoring (TDM): 8.83 ng/ml (IQR: 7.65-10.2) and 7.06 ng/ml (IQR: 5.15-8.5), respectively (Fig 1B). When stratified by Ita trough levels, patients with higher-than-median Ita concentrations (24.5 nM; IQR: 16.8–33.7) also exhibited higher Siro trough levels (Fig 1C), likely due to shared metabolic pathway involving Cytochrome P450 3A4.The absolute number of T cell subsets on day +35 averaged 61.6/µL (IQR: 30.8–131) for CD4⁺, 21.3/µL (IQR: 10.1–39.7) for CD8⁺, increasing by day +100 to 94.5/µL (IQR: 51.9–153) and 37.8/µL (IQR: 21.5–75.9), respectively. Regulatory T cells (Treg) counts were 3.91/µL (IQR: 1.95–7.54) on day +35 and 3.31/µL (IQR: 1.74–6.42) on day +100.Patients who developed grade 2–4 acute GVHD had Treg counts of 1.22/µL (IQR: 1.1–2.3) at day +35 and 5.7/µL (IQR: 2.1–7.0) at day +100 (Fig 1D). Ita trough levels and AUC demonstrated a negative correlation with Treg counts (Fig 1E). These patients also had modest elevations in GVHD biomarkers (HGF, Reg3A, TNF-R1) on day 14 but not on day 28 (Fig 1F). While Ita trough centration did not significantly correlate with GVHD biomarkers (Fig 1G), Ita AUC showed a positive correlation with HGF, IL-6, and ST2 levels.In conclusion, oral administration of Ita during the peri-HCT period showed substantial interindividual variability in drug exposure and possible interaction with Siro. Interestingly, the higher Ita levels (trough and/or AUC) were associated with lower number of Treg and higher levels of GVHD biomarkers, suggesting that further optimization of Ita dosing and TDM may lead to further improvement of HCT outcomes.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14-28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.