Patients with cancer-associated thrombosis (CAT) are commonly treated with low-molecular-weight heparin (LMWH), but whether dose capping is needed in patients over 90 kg is unclear. We conducted the WAVe study, a multicenter prospective cohort study in adult patients (≥ 18 years) with acute CAT and a weight of over 90 kg starting anticoagulation. Patients received weight-adjusted dalteparin at 200 IU/kg per day (up to 33 000 IU) for 30 (± 4) days, after which anticoagulation was continued per clinician discretion and followed for 6 months. The primary outcome was major bleeding (MB) at 30 days. Secondary outcomes included objectively confirmed recurrent venous thromboembolism (VTE) at 30 days and trough anti-Xa levels. The cumulative incidences of outcomes were estimated by time-to-event analysis, with death as a competing risk. The study stopped early due to recruitment challenges after 91 patients. Median weight and daily dose of dalteparin were 107.5 kg and 22 500 IU, respectively. Three patients had a MB episode for a cumulative incidence of 5.3% (95% CI 1.1%-14.8%) at 30 days. One patient had recurrent VTE for a cumulative incidence of 1.2% (95% CI 0.1%-5.7%) at 30 days. No significant bioaccumulation noted up to Day 30 based on trough anti-Xa levels. The median Day 7 trough anti-Xa levels were higher in those with bleeding events within 30 days compared to those without (0.6 vs. 0.2 IU/mL, p = 0.01). Our results suggest that weight-adjusted dosing of dalteparin in patients over 90 kg is associated with acceptable rates of bleeding and thrombosis. Trial Registration: NCT03297359.

Gilteritinib is a selective FLT3 inhibitor approved for the treatment of relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) following ≥ 1 prior line of therapy. However, data on its effectiveness in later-line settings is limited. We conducted a multicenter, retrospective study including 171 adult patients with R/R FLT3-mutated AML who received gilteritinib as third-line or beyond between August 2017 and March 2024 across centers in Italy, Spain, the United Kingdom, and Turkey. The primary endpoint was overall survival (OS). Secondary endpoints included overall response rate (ORR), composite complete remission (cCR), duration of response. Among the 171 patients, 84% carried FLT3-ITD mutations and 26% had received ≥ 3 prior lines of therapy. The cCR rate was 28%, and ORR was 47%. Patients who were younger and presented with relapsed (vs. refractory) disease had better outcomes. Prior exposure to venetoclax or allogeneic hematopoietic stem cell transplantation (HSCT) was associated with inferior response. Gilteritinib enabled HSCT in 12% of patients. Median OS was 7.1 months (95% CI, 5.9-10.1), and in Cox-regression analysis was significantly improved among responders and those who underwent HSCT (median OS: 21.5 months; 95% CI, 12.8-NR). Prior venetoclax exposure was associated with shorter survival (5.7 months; 95% CI, 5.1-8.8). On multivariate analysis, previous exposure to venetoclax and FLT3 inhibitors was the strongest predictor of reduced response rates. Despite heavy pretreatment, gilteritinib retained clinically relevant activity in later-line R/R FLT3-mutated AML. Its use beyond second-line may serve as a bridge to HSCT in selected patients. Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.

Polyfunctional cytomegalovirus (CMV)-specific T cells are critical for antiviral immunity in allogeneic hematopoietic cell transplantation (HCT) recipients. However, gaps remain in managing refractory CMV and optimizing virus-specific cellular therapy (VST). We conducted a comparative analysis of how timing and dosing of immunosuppressive agents, including post-transplant cyclophosphamide (PT-Cy), corticosteroids, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs), shape CMV-specific T-cell polyfunctionality. CD4 and CD8 T-cell responses (IFN-γ plus ≥ 1 functional marker) were assessed following pp65 stimulation within 100 days post-HCT in the pre- and post-letermovir era. Among 243 patients, 31% exhibited polyfunctional CD4 and CD8 responses. PT-Cy did not significantly impair T-cell functionality. Cyclosporine was associated with higher frequencies of polyfunctional T cells compared to tacrolimus, even at concentrations above the therapeutic range. Intermediate (≥ 0.5 mg/kg) and high-dose (≥ 1 mg/kg) corticosteroids, especially within 2-4 weeks before testing, significantly suppressed T-cell responses, though rapid tapering preserved function. Prolonged administration of MMF (≥ 2000 mg) diminished T-cell polyfunctionality. These findings provide novel insights into the importance of timing and dosing of the immunosuppressive effects of PT-Cy, corticosteroids, MMF and CNIs on CMV-specific immunity. Adjusting immunosuppression in specific time windows may improve the management of refractory CMV infections and optimize VST in HCT recipients.

Chronic kidney disease (CKD) is common and a major contributor to increased morbidity and early mortality in people with sickle cell anemia (SCA). Urine albumin-to-creatinine ratio (uACR) is recommended to identify patients with SCA-related CKD but its utility in predicting long-term kidney dysfunction remains unclear in this patient population. In two independent, longitudinal cohorts of patients with hemoglobin SS or Sβ-thalassemia (USA: n = 268, median follow-up 6 years; France: n = 310, median follow-up 8.2 years) we investigated the utility of uACR, as well as other clinical and modifiable risk factors, for predicting a decline in kidney function as determined by the rate of estimated glomerular filtration rate (eGFR) decline. Using linear mixed-effects models, a higher baseline uACR independently predicted a faster rate of eGFR decline as well as a more rapid annual eGFR decline, defined as ≥ 3 mL/min/1.73m (p ≤ 0.009). Furthermore, baseline uACR of ≥ 100 mg/g creatinine was independently associated with the rate of eGFR decline and rapid annual eGFR decline in both cohorts. Tobacco smoking was also associated with a faster rate of eGFR decline and was congruous between the two cohorts. In conclusion, we demonstrate that uACR is an important clinical tool that predicts a more rapid decline in kidney function and should be routinely monitored in people with SCA. Our data also support preventative care to reduce tobacco smoking for mitigating the risk of CKD progression in this high-risk population.

In our study, we identified a novel, ruxolitinib-sensitive, CCDC6::JAK2 fusion gene as a driver of atypical JAK2-unmutated MPN with a polycythemic phenotype. The CCDC6::JAK2 chimeric protein retains the CCDC6 coiled-coil domain and the JAK2 kinase domain. Dimerization of chimeric proteins through coiled-coil domains promotes JAK2 autophosphorylation leading to constitutive activation of the JAK/STAT signaling pathway.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for secondary acute myeloid leukemia (sAML). This study compared haploidentical donor (Haplo), matched sibling donor (MSD), and matched unrelated donor (MUD) HSCT in patients with sAML in first complete remission (CR1). Data from 3862 patients (Haplo = 643, MSD = 715, MUD = 2504) transplanted between 2010 and 2022 were analyzed, with a median follow-up of 3.3 years. Groups differed in patient and donor age, conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prophylaxis. Multivariate analysis showed that MSD-HSCT had a higher relapse risk than Haplo-HSCT (hazard ratio [HR]: 1.64) but lower non-relapse mortality (NRM, HR: 0.32) and acute GVHD risk (HR: 0.54 for grade II-IV), leading to an overall survival (OS) benefit (HR: 0.76). MUD-HSCT had lower NRM than Haplo-HSCT (HR: 0.63) but there were no significant differences in OS or GVHD risk. Donor type did not impact leukemia-free survival (LFS) or GVHD-free and relapse-free survival (GRFS). Adverse cytogenetics and reduced-intensity conditioning were associated with increased relapse risk, while lower Karnofsky scores, older age, and adverse cytogenetics independently predicted worse NRM, LFS, OS, and GRFS outcomes. Female-to-male donor-recipient pairs had an increased risk of chronic GVHD. In this registry-based analysis, MSD offered the best outcomes for sAML in CR1. Haplo-HSCT was comparable to MUD-HSCT, despite a higher NRM, and achieved long-term disease control in 60% of patients due to a low relapse incidence. In the absence of an MSD, both Haplo and MUD are viable alternatives.

Diamond-Blackfan Anemia Syndrome (DBAS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by impaired erythropoiesis and significant genetic heterogeneity. Diagnosis can be challenging due to clinical variability and the lack of sensitive and specific biomarkers. We investigated the evidence for a DNA methylation (DNAm) episignature in a cohort of 80 DBAS patients with causative variants in various ribosomal protein genes: DBA1 (RPS19, n = 30), DBA4 (RPS17, n = 6), DBA5 (RPL35A, n = 8), DBA6 (RPL5, n = 15), DBA7 (RPL11, n = 13), DBA10 (RPS26, n = 8). We identified a distinct and highly accurate episignature biomarker for DBAS, clearly differentiating it from both Fanconi anemia and a broad spectrum of other episignature-positive disorders. Furthermore, we developed a specific DNAm classifier for the clinically similar DBA6 and DBA7 subtypes. Applying the DBAS episignature analysis to six molecularly uncharacterized cases, three exhibited the DBAS pattern. Subsequent genome sequencing identified causative genetic variants in two (RPL5: c.325-380A>G:p.?; RPL26: c.-6 + 3_-6 + 25del:p.?), validating the test robustness. Methylation profiles from two revertant cases (RPS19:P47L and RPS17 full gene deletion) exhibited the DBAS episignature, suggesting it to be a stable epigenetic mark associated with the underlying genetic mutation, likely established early in development. In conclusion, we propose DNAm profiling as a robust diagnostic tool for DBAS, providing a biomarker applicable to all patients with clinical suspicion of the disease and critically aiding in the resolution of variants of uncertain significance and molecularly uncharacterized cases.

Compared to historical reports, both aGVHD and cGVHD appeared to have decreased in the recent transplant era, possibly due to the extension of T-cell depletion, the availability of effective second-line approaches in SR/D GVHD and improved anti-infectious prophylaxis and treatments.