Introduction Systemic inflammation is increasingly recognized as a driver of immune dysfunction and therapeutic resistance. We evaluated InflaMix, a classifier of maladaptive inflammatory activation recently validated in CAR-T recipients (Raj, Nat Med 2025), in adults with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (alloHCT). Objective Determine whether pre-alloHCT InflaMix independently predicts progression-free survival (PFS), overall survival (OS) and non-relapse mortality (NRM) in AML after adjustment for clinical covariates and TP53 status. Methods We conducted a single-center observational study of 667 patients who underwent first alloHCT for AML (2014-2024). Using InflaMix, a validated probabilistic classifier trained on 14 laboratory and cytokine parameters collected within 2 weeks pre-alloHCT (including IL-6, IL-10, TNFa, albumin, LDH, hemoglobin, AST, alkaline phosphatase and CRP), we assigned patients to inflammatory versus non-inflammatory clusters. Outcomes included PFS, OS and NRM. Multivariable Cox regression models for PFS/OS and a Fine-Gray subdistribution model for NRM were adjusted for age, conditioning intensity, donor match, graft-versus-host disease (GVHD) prophylaxis, graft source, and TP53 mutation status. Secondary analyses included acute GVHD incidence and time to neutrophil engraftment. Results At baseline, InflaMix assigned 901 (90%) patients to the non-inflammatory group and 66 (10%) to the inflammatory group (Table 1). Inflammatory assignment was an independent predictor of inferior outcomes, including PFS (hazard ratio [HR] 1.61, 95% CI 1.36–1.91, p<0.001) and OS (HR 1.69 (HR 1.77, 95% CI 1.49–2.11, p<0.001). Inflammation conferred worse survival across both mutant TP53 (TP53mut) and wild-type (TP53wt), with the largest effect observed in TP53mut patients (Figure 1). Inflammation emerged as a strong predictor of NRM, with over a twofold increase in NRM (HR 2.38, 95% CI 1.55-3.66, p<0.001) (Figure 2). Inflammatory status was not associated with acute GVHD or differences in time to neutrophil engraftment, indicating that this signature reflects a distinct, non-alloimmune axis of immune dysregulation. Conclusion Baseline inflammation, as defined by InflaMix, independently predicts post-alloHCT relapse and mortality in AML. Among TP53mut patients, InflaMix further discriminated outcomes across inflammatory clusters, adding prognostic value for this high-risk subgroup. The reproducibility of this inflammatory signature across cellular therapy settings suggests a shared maladaptive immune axis, positioning InflaMix as a practical, point-of-care tool to refine risk stratification and inform inflammation-targeted strategies, particularly in TP53mutAML.

Acute graft-versus-host disease (aGvHD) remains a substantial cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Limited studies explore the association between specific major histocompatibility complex (MHC) alleles and aGvHD or transplant-related mortality (TRM). After a noted clinical trend of higher TRM among a series of patients with aGvHD and MHC class I HLA- A   ∗ 01:01, we retrospectively evaluated transplant outcomes of 404 adult allo-HCT patients who underwent unmodified allografts between 03/2010 and 02/2017. HLA- A   ∗ 01:01 was expressed by 104 (25.7%) patients. In a univariate analysis, patients who underwent unmodified transplants and expressed HLA- A   ∗ 01:01 had a higher risk of TRM (HR 1.63 [95% CI: 1.05-2.53], p = 0.035). In a multivariate cause-specific Cox model, HLA- A   ∗ 01:01 was significantly associated with TRM after adjusting for grade II-IV aGvHD, conditioning regimen intensity, and age at transplant (HR 1.59 (95% CI: 1.02-2.48) p = 0.039). There were no significant differences in overall survival (OS), aGvHD, or chronic GvHD based on HLA- A   ∗ 01:01 expression. With confirmation in a larger cohort, these findings have potential implications for the selection of allograft type, conditioning regimen, and post-transplant monitoring for this high-risk population.

Myeloid malignancies with TP53 alterations are characterized by genomic instability, chemotherapy resistance, and very poor outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). Hypomethylating agents (HMAs), small molecule targeted therapies, and donor lymphocyte infusion (DLI) are often used post-transplant to mitigate relapse risk in high-risk myeloid malignancies, but their impact on survival in TP53-mutated disease remains uncertain. To evaluate the impact of post-transplant interventions and graft-versus-host disease (GVHD) on relapse and survival outcomes in patients with TP53-mutated or chromosomal 17p-deleted myeloid malignancies. This is a single-center retrospective study of adult patients with TP53-mutated and/or chromosomal 17p-deleted myeloid malignancies who underwent first allo-HCT between 2014 and 2023. Survival outcomes were assessed using the Kaplan-Meier method. Univariable Cox proportional hazards regression was used to assess associations of baseline characteristics with outcomes. Analyses of post-HCT interventions (maintenance/preemptive HMAs, targeted therapies, and/or DLI) and the development of chronic GVHD (classic chronic or acute/chronic overlap) were landmarked at 60 and 180 days, respectively, and both exposures were treated as time-dependent covariates. Cause-specific multivariable Cox proportional hazards regression models adjusted for baseline covariates were fitted to assess associations of outcomes with the time-dependent exposures. Prespecified subgroup analyses were performed for the ultra-high-risk group, defined as complex karyotype and/or ≥2 TP53/17p alterations. Among 158 patients (median age 65 years, IQR: 57- 70), acute myeloid leukemia (54%) and myelodysplastic syndromes (40%) were the most common myeloid malignancies. Complex karyotypes were present in 68%, and ultra-high-risk features were present in 73%. Reduced-intensity conditioning was used in 59%. Approximately 49% of patients received post-HCT interventions; 68% of these were administered before relapse (preemptively or as prophylaxis/maintenance). In a landmark analysis at day 60 post-HCT (N = 145), prerelapse HMA, targeted therapies, and/or DLI was not associated with improved overall survival (OS) (HR: .95; 95% CI: .56, 1.62; P = .80), progression free survival (PFS) (HR: .95; 95% CI: .49, 1.30; P = .40), or cumulative incidence of relapse (CIR) (HR: 1.05; 95% CI: .60, 1.85; P = .90) after adjusting for key baseline characteristics. Similarly, in a landmark analysis at day 180 post-HCT (N = 100), the occurrence of chronic GVHD was not associated with OS (HR: .78; 95% CI: .24, 2.61; P = .70), PFS (HR: .67; 95% CI: .20, 2.23; P = .50), or CIR (HR: .34; 95% CI: .05, 2.54; P = .30). Findings were similar in the ultra-high-risk subgroup (N = 115) where post-HCT interventions showed no association with OS (HR: .81; 95% CI: .45, 1.45; P = .50), PFS (HR: .72; 95% CI: .42, 1.24; P = .20), or CIR (HR: .87; 95% CI: .46, 1.62; P = .70). In this single center study, preemptive or prophylactic post-HCT interventions did not significantly improve survival or reduce relapse risk in patients with TP53-altered myeloid malignancies, including those with ultra-high-risk features. While the study was limited by its small sample size and heterogeneous interventions, these findings highlight the urgent need to develop novel therapeutic strategies for this high-risk population.

Double-unit cord blood transplantation (dCBT) has been associated with high rates of progression-free survival (PFS) in adults with hematologic malignancies but also with relatively high rates of acute graft-versus-host disease (aGVHD). We conducted a single-arm, phase 2 clinical trial that investigated the addition of tocilizumab, an interleukin-6 receptor blocker, to cyclosporine-A (CSA) and mycophenolate mofetil (MMF) for aGVHD prophylaxis after intermediate-intensity dCBT. A total of 45 patients (median age, 47 years; range, 27-60 years; 80% acute leukemia; median hematopoietic cell transplant-comorbidity index, 2) were enrolled from March 2018 to March 2021. Transplant outcomes were compared with 39 previous CSA and MMF dCBT controls with similar inclusion criteria. Tocilizumab recipients had less pre-engraftment syndrome (38%; 95% confidence interval [CI], 24-52 vs 72%; 95% CI, 54-84; P < .001) but inferior day 45 neutrophil engraftment (93%; median, 25.5 days vs 97%; median, 22 days; P = .009]. The primary end point of day 100 grade 2 to 4 aGVHD was no different between groups (71%; 95% CI, 55-82 with tocilizumab vs 82%; 95% CI, 65-91; P = .11). However, there was a trend toward a lower day 100 incidence of stage 1 to 4 lower gastrointestinal aGVHD with tocilizumab (16%; 95% CI, 7-28 vs 33%; 95% CI, 19-48; P = .059). There were no significant differences in the 3-year incidences of relapse, transplant-related mortality, PFS, or overall survival between the groups. Tocilizumab recipients exhibited a distinct pattern of gut microbiome disruption. In summary, tocilizumab-based GVHD prophylaxis delayed neutrophil recovery without a significant reduction in aGVHD and had no survival benefit after dCBT. Investigation of alternative strategies to prevent severe aGVHD after dCBT is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03434730.

Study representation of underserved communities

Abstract Purpose: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating MM-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (autoHCT). Patients and Methods: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared to control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of MM-specific immunity at 1-year post-transplant. Results: The study enrolled 203 patients, with 140 randomized post-transplantation. Vaccine production was successful in 63/68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control) (p=0.37, 80% CI 44.5%, 61.3% and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control) (p=0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control) (p=0.4). Vaccination induced a statistically significant expansion of MM-reactive T cells at 1 year as compared to prior to vaccination (p=0.024) and in contrast to the non-vaccine arm (p=0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year post-transplant. Conclusions: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1-year post-transplant but was associated with a significant increase in circulating MM-reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study.

Supplemental Figure 1: (A) Progression Free Survival Kaplan Meier Curve. (B) Overall Survival Kaplan Meier Curve.

TG101348 and ruxolitinib inhibit JAK2 mediated STAT5 and STAT3 phosphorylation.

moDC stimulated NK cells retain surface expression of the gamma chain receptor despite the presence of JAK inhibitors.

All the enriched pathways in various analyses.

Previous studies evaluating weight bearing of distal radius fractures treated through dorsal spanning bridge plates used extra-articular fracture models, and have not evaluated the role of supplementary fixation. We hypothesized that supplementary fixation with a spanning dorsal bridge plate for an intra-articular wrist fracture would decrease the displacement of individual articular pieces with cyclic axial loading and allow for walker or crutch weight bearing.Thirty cadaveric forearms were matched into 3 cohorts, controlling for age, sex, and bone mineral density. An intra-articular fracture model was fixed with the following 3 techniques: (1) cohort A with a dorsal bridge plate, (2) cohort B with a dorsal bridge plate and two 1.6-mm k-wires, and (3) cohort C with a dorsal bridge plate and a radial pin plate. Specimens were axially loaded cyclically with escalating weights consistent with walker and crutch weight-bearing with failure defined as 2-mm displacement.No specimens failed at 2- or 5-kg weights, but cohort A had significantly more displacement at these weights compared with cohort B. Cohort A had significantly more failure than cohort C. Both cohort A and cohort B had significantly more displacement at crutch weight bearing compared with cohort C. The supplementary fixation group had significantly lower displacement at crutch weight-bearing compared with cohort A in all gaps. Survival curves demonstrated the fixation cohort to survive higher loads than the nonfixation group.There was significantly less displacement and less failure of intra-articular distal radius fractures treated with a spanning dorsal bridge plate and supplementary fixation. Our model showed that either type of fixation was superior to the nonfixation group.When considering early weight-bearing for intra-articular distal radius fractures treated with a spanning dorsal bridge plate, supplementary fixation may be considered as an augmentation to prevent fracture displacement.

Numbers and ratios of dendritic cells and T cells migrated from skin explants

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Although alternative donors extend transplant access, whether recipient ancestry affects the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 adult patients with acute myelogenous leukemia (AML) who underwent transplantation. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% vs 24%). Overall, the median time from transplant indication to allograft was 127 days (range, 57-1683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication to transplant time >180 days owing to significant delays in indication to consult >90 days and consult to transplant >120 days. Compared with recipients of HLA-matched unrelated donors (URDs), HLA-mismatched adult donor recipients were at an increased risk of delayed indication to transplant, whereas HLA-identical sibling and cord blood recipients were at a lower risk. Subanalysis showed more indication to transplant delays >180 days in non-European (44%) vs European (19%) 8/8 URD recipients. Finally, the pandemic further exacerbated delays for non-Europeans. In summary, although non-European patients with AML are less likely to receive 8/8 URDs as expected, if they do, their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry, whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and use all alternative donor sources are critical to ensure timely transplantation for patients with AML.

Sections show morphologic and immunohistochemical findings of MF lesion

Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and >= 4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning. Comorbidities are common in patients with haematologic malignancies and may increase the risk of non-relapse mortality (NRM) after allogeneic haematopoietic cell transplantation (allo-HCT). We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities including liver, pulmonary, renal and cardiac dysfunction as well as older age. In this study, we validated the SCI in a cohort of patients treated with a HLA-matched allo-HCT following reduced-intensity conditioning. Higher SCI scores were strongly associated with increasing NRM and reduced overall survival. These findings suggest that the SCI is a reliable tool for risk stratification of allo-HCT candidates.image

Supplementary Figures S1-S3.

Supplemental Figure 1: (A) Progression Free Survival Kaplan Meier Curve. (B) Overall Survival Kaplan Meier Curve.

Induction of NKG2A and KIR expression is dependent on duration of coculture, but not on proliferation. Flow cytometric contour plots illustrating NKG2A (A) and KIR (B) surface expression on initially KIRnegNKG2Aneg NK cells at baseline and following three days (d+3) and six days (d+6) coculture with poly(I:C) matured moDCs. (C-D) KIRnegNKG2Aneg NK cells, stimulated by an equal combination of allogeneic LCcyto and moDCpoly at 10:1 NK:DC ratio were harvested after six days coculture (d+6) and restimulated using freshly matured DCs from the same donors for a further six days (d+12). Stimulated KIRnegNKG2Aneg NK cells were stained for KIR, NKG2A and CD16 expression at both time points. (C) Flow cytometric contour plots illustrating KIR and NKG2A surface expression at d+6 and d+12. (D) Flow cytometric histogram depicting FcgammaRIII (CD16) surface expression at d+6 (dashed line) and d+12 (solid line).

Study representation of underserved communities