Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening condition. Caplacizumab substantially shortens the time to clinical response, yet delayed platelet count recovery is occasionally observed, raising concerns about iTTP refractoriness. This retrospective multicenter study analyzed 204 acute iTTP episodes reported to the German REACT-2020 and Austrian ATMAR registries, all treated with caplacizumab. Refractoriness was assessed using the 2017 International Working Group criteria and the more stringent definition by the French Reference Center for Thrombotic Microangiopathies. We evaluated time to platelet recovery and presence of confounding clinical conditions, potentially accounting for persistent thrombocytopenia, in all episodes. By day 5 after caplacizumab initiation, 83.8% of patients (171/204) achieved a clinical response, and the remaining 16.2% (33/204) showed at least a doubling of the platelet count. Only three patients (1.5%) met laboratory criteria for refractoriness. In all cases, plausible alternative causes were present (e.g., missed doses, infection). No patient was refractory without a confounding factor. In 8/204 patients (3.9%) we observed a markedly prolonged thrombocytopenia (≥10 days) and identified confounding conditions in all cases. In the stratified Cox model, the presence of alternative causes of thrombocytopenia was the only independent determinant of delayed platelet count normalization (HR 0.16, 95% CI 0.09-0.28, p < 0.001), whereas baseline parameters were not predictive. In the context of caplacizumab-based therapy, true refractoriness is rare. Delayed platelet count recovery is predominantly attributable to concomitant clinical conditions. Careful clinical assessment and context-sensitive interpretation of treatment response before escalating iTTP-specific therapy may avoid unnecessary treatment intensification and associated risks.

Acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is a primary cause of early transplant mortality after bone marrow transplantation (BMT), driven by local antigen presentation and T-cell expansion. We sought to clarify the role of various donor dendritic cell (DC) subsets in this process in order to define therapeutic strategies to prevent gut GVHD. Donor plasmacytoid DC (pDC) were prominent in the ileum of BMT recipients without GVHD but were largely absent in gut during GVHD. In contrast, donor XCR1+ conventional DC (cDC) were dramatically increased in the mesenteric lymph nodes (mLN) of BMT recipients with GVHD. We utilized Xcr1-DTR mice and Clec4c-DTR mice to enable highly efficient XCR1+ cDC versus pDC depletion. Donor XCR1+ cDC but not pDC deletion attenuated lethal GVHD, depleting most cDC presenting alloantigen, which inhibited α4β7 and the expansion of alloantigen-specific donor Th1 cells in the gut. Aldehyde dehydrogenase 1A (ALDH1A) expression by cDC is known to modulate GVHD and we thus examined the effect of a pan-ALDH1 inhibitor, WIN18,446, on this axis. WIN18,446 administration improved survival and these effects were ALDH1A1-specific but mediated by inhibition of CD11b+ rather than XCR1+ cDC, inhibiting alloantigen-specific Th17 cell differentiation in the gut. These findings highlight the limited role of pDC in the induction of gut GVHD and identify differential and dominant roles for XCR1+ and CD11b+ donor cDC in controlling Th1 and Th17 mediated gut aGVHD. The targeting of donor cDC subsets represents an effective strategy to prevent lethal gut GVHD.

The Phase 1/2 Intergroup study E4412 (NCT01896999; ClinicalTrials.gov) investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) in relapsed/refractory (R/R) classic Hodgkin lymphoma (HL) while concurrently targeting CD30+ Hodgkin Reed Sternberg cells with the antibody-drug conjugate brentuximab vedotin (BV). 147 patients ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients are included in primary efficacy analysis. The primary endpoint, complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (one-sided p=0.29). The median survival follow-up is 38.0 months (interquartile range 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the two arms (HR=0.78, CI 0.39-1.57, one-sided p=0.24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, was similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared to BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned post-hoc comparison; 58 patients received SCT; 36-month PFS (from SCT) was greater than 90% for both arms. Sixty-six patients were alive and progression free after the first scan (disease evaluation) and did not undergo SCT. The 36-month PFS (from first scan) was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared to 45.8% (26.3, 63.4) for BV/Nivo (HR=0.45, CI 0.19-1.08, one-sided p=0.03). The study did not meet its primary endpoint of superior CR rate for the triplet, but it supports the use of checkpoint-ADC induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT for the triplet of BV/Ipi/Nivo.

Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor (ct)DNA sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling timepoints, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista - a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma - to samples obtained from the GHSG HD21 trial following two cycles of treatment (MRD-2) using a case-cohort-design. Patients with positive MRD-2 were at higher risk for relapse, progression or death compared with MRD-2 negative patients (4-year progression-free survival (PFS): 36.7% vs. 82.2%; HR 5.3, 95%CI 2.0-13.8; p = 0.0008). Following inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 had 4-year PFS rates of 72.2% vs. 95.3%. By combining MRD-2 with PET-2, patients were stratified into three distinct groups regarding risk of relapse: low (MRD-2 negative and PET-2 negative), intermediate (MRD-2 positive or PET-2 positive), and high (MRD-2 positive and PET-2 positive). In summary, these results suggest that assessment of MRD-2 by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

In hepatocytes, transferrin receptor 1 (Tfr1) plays a limited role in iron acquisition but negatively regulates signaling to the iron hormone hepcidin (Hamp) through its interaction with the hemochromatosis protein Hfe. Its homologue transferrin receptor 2 (Tfr2), operates as an iron sensor and direct positive regulator of hepcidin expression. We generated TfrcAlb-Cre;Tfr2Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study their effects on iron homeostasis. These animals are viable and develop systemic iron overload, recapitulating a key feature of Tfr2Alb-Cremice, albeit with milder hepatic iron accumulation and relatively higher residual hepcidin expression, presumably driven by "liberated" Hfe. Only Tfr1-expressing primary hepatocytes from Tfrcfl/fl;Tfr2fl/fl and Tfr2Alb-Cre mice internalized fluorescent holo-transferrin (AF647-Tf), arguing against a significant contribution of Tfr2 or other receptors in transferrin-bound iron uptake. Under dietary iron restriction, Hamp mRNA suppression and hepatic iron depletion were comparable in Tfr2-deficient livers from TfrcAlb-Cre;Tfr2Alb-Cre and Tfr2Alb-Cre mice, despite compensatory Tfr1 upregulation in the latter, which likely sequesters Hfe. Conversely, Tfr1-deficient but Tfr2-expressing livers from TfrcAlb-Cre mice displayed relatively elevated Hamp mRNA, as expected. Following an acute dietary iron challenge, HampmRNA induction and Smad1,5,9 phosphorylation occurred only in the liver of Tfr2-expressing TfrcAlb-Cre but not in TfrcAlb-Cre;Tfr2Alb-Cre mice, indicating that "liberated" Hfe requires Tfr2 to become functionally active. Collectively, these findings demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, and that Tfr2 and Hfe exhibit non-redundant functions under chronic iron loading, but act cooperatively to induce hepcidin in response to an acute iron challenge.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk, single cell (sc) TCR, and scRNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T-cells. We identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN- and RNA-seq that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in HDACi-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely utilized for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

NXT007 is a next-generation, activated factor VIII (FVIIIa)-mimetic bispecific antibody under investigation in the phase 1/2 NXTAGE trial (jRCT2080224835). Here, we report the primary analysis of the multiple-ascending-dose Part B in people with hemophilia A (PwHA). Eligible participants were men with severe HA without FVIII inhibitors. Four dose cohorts (B1-B4) were planned, with NXT007 administered subcutaneously at maintenance doses of 0.072 mg/kg, 0.28 mg/kg, 0.70 mg/kg, and 1.08 mg/kg, respectively, every 4 weeks. Primary endpoints were safety (adverse events [AEs] and serious AEs [SAEs]), tolerability, pharmacokinetics, pharmacodynamics, and efficacy; secondary endpoints included incidence of anti-NXT007 antibodies (ADAs). Participants in cohorts B1 (n=10), B2 (n=6), B3 (n=6), and B4 (n=8) had received NXT007 for a median (minimum-maximum) of 114.1 (29-140), 96.4 (88-112), 58.1 (52-72), and 22.2 (4-28) weeks, respectively. Two participants discontinued treatment: NXT007-unrelated AE (n=1) and complete loss of NXT007 exposure due to ADAs (n=1). Participants' plasma NXT007 concentration showed a dose-dependent increase, and predicted FVIII-equivalent activity reached a non-hemophilic level (≥40 IU/dL) in B2 onwards. NXT007 had a favorable safety profile at all doses. Most AEs were mild/moderate and all three SAEs were considered unrelated to NXT007. Mean annualized treated bleed rates were 1.48 (B1), 0.28 (B2), 0.00 (B3), and 0.00 (B4). Pharmacokinetics-affecting NXT007 ADAs were observed in two participants, including the participant in B1 who discontinued. NXTAGE Part B demonstrates that NXT007 could provide non-hemophilic coagulation activity in PwHA, with a less burdensome dose regimen than currently available therapies.

In a real-world analysis of brexucabtagene autoleucel (brexu-cel) recipients with relapsed/refractory B-ALL (n = 278), lack of response to prior blinatumomab correlates with significantly worse post CAR-T outcomes.

VCAR33, a donor-derived CD33-directed chimeric antigen receptor (CAR) T cell product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe pre-clinical characterization of the VCAR33 construct, which was optimized for long-term anti-tumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in Arm A (bone marrow blasts ≥ 5%) at dose level 1 (DL1; 1 x 106 CAR+ T cells/kg) and 8 patients in Arm B (bone marrow blasts < 5%) at DL1 (n=5) and DL2 (3 x 106 CAR+ T cells/kg; n=3). The study ended for non-safety reasons before escalation to DL3 (1 x 107 CAR+ T cells/kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all < grade 3). Four patients (26.7%) experienced immune cell-associated neurotoxicity syndrome (1 ≥ grade 3) and 1 patient (6.7%) had grade III acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in Arm A and 1 Arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary anti-leukemic activity. ClinicalTrials.gov: NCT05984199.

Immune thrombocytopenia (ITP) is associated with a variable and unpredictable clinical course in children, including a spectrum of bleeding and systemic symptoms in the months following diagnosis. Although many children will have spontaneous resolution of disease prior to 1 year, up to 30% will go on to develop chronic disease. Known predictors for developing chronic ITP are limited, making clinical management and guidance during this early course of disease very challenging. Additionally, the pathophysiology of immune dysregulation in ITP is complex, with multiple variables likely contributing to the development of chronic disease. We aimed to create a statistical model to predict development of chronic ITP. Utilizing a retrospective training cohort of 611 children with ITP from two institutions and two validation cohorts comprised of 161 children, we developed and validated a multivariable logistic regression model and found that age, sex, IgG, IgA, IgM, presenting platelet count, presenting lymphocyte count, known secondary cause at diagnosis, and DAT positivity were useful in predicting chronic ITP. The external validations demonstrated consistent discriminative performance and clinical utility. The model is available for use at https://opal.shinyapps.io/citp-rm/. A chronicity prediction tool to use at the time of ITP diagnosis will better equip hematologists to counsel patients and families and engage in appropriate treatment strategies for individual patients earlier in their course.

We found that PSMD1, a key subunit of the 19S proteasome regulatory particle, was overexpressed and correlated with poor prognosis in multiple myeloma (MM). Genetic depletion of PSMD1 decreased cancer cell viability, induced polyubiquitinated protein accumulation, and promoted apoptosis. Proteomic analysis revealed the activation of immune-related pathways, suggesting the potential for immune modulation. Targeting PSMD1 with siRNA, delivered via lipid nanoparticles (LNPs), reduced tumor growth in MM cell lines and primary patient samples while sparing normal cells. It also overcame proteasome inhibitor resistance and the protective effects of the bone marrow milieu. In MM xenograft mouse models, PSMD1 siRNA LNPs significantly reduced tumor growth and prolonged survival. In addition, PSMD1 depletion had similar effects on other types of cancer cell lines. These findings position PSMD1 as a critical target in cancer therapy, with broad implications for overcoming drug resistance, improving therapeutic outcomes, and potentially impacting immune responses across various cancers. These findings provide a foundation for the clinical development of PSMD1-targeted therapies in myeloma and other malignancies.

Caring for individuals with hematological disorders is increasingly complex, and with medical complexity often comes ethical complexity. Prognostic uncertainty, stakeholder conflicts, and myriad other ethical challenges often contribute to situations that can benefit from ethics support. Through the presentation of three vignettes focusing on ethical dilemmas arising from hematology cases, we review the four phases of clinical ethics consultation: consult triage; ethics consult intake; stakeholder meeting(s) and additional data collection; and ethics analysis and recommendations. In tandem, we review some of the most common ethical framework/approaches used to inform hematology ethics consultation support services. We conclude that ethics consult services can be a valuable resource in providing care for patients with blood disorders and are a vital resource to enhance patient care, support clinicians, and ensure that difficult choices are navigated with clarity, compassion, and integrity.