Olverembatinib (HQP1351) is a potent third-generation (3G) tyrosine kinase inhibitor (TKI) that binds to both the active and inactive conformations of native ABL1 and mutant BCR::ABL1. It was developed as a potent inhibitor with activity against wild-type and mutated BCR::ABL1 for chronic myeloid leukemia (CML) patients. It is effective against the T315I mutation, which confers resistance to first and second generation TKIs. The results of clinical trials in China have led to olverembatinib approval by China's regulatory authority, National Medical Products Administration (NMPA), for adult patients with TKIresistant chronic phase (CP) or accelerated phase (AP) CML harboring the T315I mutation and for adult CP CML patients with resistance or intolerance to imatinib or 2G TKIs. Olverembatinib has also received breakthrough therapy designation by the NMPA in combination with low intensity chemotherapy for the first-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Global studies of olverembatinib are underway in CML and Ph +ALL, with the results of the US phase 1b study published in 2025. This review will summarize the safety, tolerability, and efficacy of olverembatinib in CML and Ph+ ALL in China and globally and discuss the role of olverembatinib among existing therapeutics and its future development.
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Oral decitabine/cedazuridine plus venetoclax offers a fully oral regimen for older or unfit patients with acute myeloid leukemia (AML). We previously reported outcomes from a phase II study; here we present extended follow-up of the frontline cohort. In this single-center phase II study, adults with AML ineligible for intensive induction received oral decitabine/cedazuridine (35 mg/100 mg, days 1-5) plus venetoclax in 28-day cycles. This analysis included newly diagnosed (ND) AML. Endpoints included overall response rate (ORR), overall survival (OS), relapse-free survival (RFS), duration of response (DOR) and safety. Outcomes were compared between de novo and secondary AML. Between March 2021, and January 2026, 68 patients were treated, including 32 de novo and 36 secondary AML; median age was 79 years. The cohort was high risk, with >50% ECOG ≥2, less favorable genomics and 16% prior hypomethylating agents exposure. ORR was 75% in de novo AML and 58% in secondary AML. Among responders, MRD negativity was 58% and 56%. With median follow-up of 32 months, median OS was 12.7 months (95% CI, 9.1-20.3) vs 7.2 months (95% CI, 3.6-29.9) (P = 0.61). Median RFS was 9.2 months vs 11.7 months (P = 0.56). No statistically significant differences were observed in survival, relapse or non-relapse mortality. Oral decitabine/cedazuridine plus venetoclax is an effective oral treatment for older or unfit patients with ND AML. Response rates were higher in de novo AML, while survival outcomes were not statistically significant. These findings highlight the need for improved therapeutic strategies particularly in secondary AML.
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Despite improvements in clinical outcomes for multiple myeloma (MM), some patients still experience short survival, and identifying high-risk (HR) MM patients early remains a substantial challenge. In this study, we collected recently published International Myeloma Society (IMS) / International Myeloma Working Group (IMWG) recommendation and four additional risk factors of diverse nature (APOBEC mutational activity, chromothripsis, EMC92 gene expression signature, proliferation index (PR)) and examined their predictive utility on CoMMpass data. All factors were highly associated with survival even when the treatment heterogeneity in CoMMpass data was adjusted. 27% of the patients harbored the IMS/IMWG lesion, but only 21% of them were implicated uniquely by it. As a whole, 68% of the patients harbored HR lesions, 62% of them with multiple lesions. "Multi-hit" effect was profound with median survival reduced drastically while the hazard ratio (HzR) increased sharply from single to quadruple-or-more HR factor inflicted groups compared with those without any HR lesions. The concordance, C-statistic, of patient's risk prediction starting from a baseline model with patient age and sex (C=0.63) increased slightly to C=0.65 with IMS/IMWG factor only but improved further to C=0.72 with additional HR factors. Interestingly, EMC92 turned out essential in the reliable prediction of a patient's risk of overall survival. Most functional high risk (FHR) patients also harbored additional HR lesions although a quarter of them were free of other lesions but still had very poor outcomes. These results provide a solid rationale for expanding HR factors beyond IMS/IMWG recommendation utilizing diverse genomic technologies.
von Willebrand disease (VWD) and hemophilia A (HA) are the most common inherited bleeding disorders, caused by quantitative or qualitative defects of von Willebrand factor (VWF) and coagulation factor VIII (FVIII). Over the past decades, both diseases have undergone a profound therapeutic transformation, evolving from supportive care to highly effective replacement, pharmacological, and prophylactic strategies. This perspective article compares the parallel but distinct trajectories of therapeutic developments in HA and VWD, highlighting shared milestones and disease-specific limitations. In HA, advances in recombinant technology, extended half-life factor concentrates, nonfactor therapies such as FVIII mimetics and emerging gene therapy approaches have established prophylaxis as the standard of care. VWD therapy has evolved more slowly, largely owing to the marked clinical and molecular heterogeneity of this disease, that often causes difficult and delayed diagnosis. Current management is based on desmopressin, plasma-derived products, and recombinant VWF, with limited prophylaxis implementation. Nevertheless, a rapidly expanding pipeline of novel therapies -- including VWF half-life extension strategies, VWF-independent coagulation rebalancing agents, antifibrinolytics, platelet-mimetic technologies, and gene-based approaches -- suggests an imminent shift in VWD management. Collectively, these developments indicate a transition toward more individualized and mechanism-driven therapy, with the potential to fill the therapeutic gap between VWD and HA and improve long-term outcomes and quality of life in patients with these inherited bleeding disorders.
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Many patients with chronic myeloid leukemia (CML) treated with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) experience persistent adverse events (AEs) that negatively impact daily living and the ability to remain on treatment. Asciminib, an allosteric inhibitor of BCR::ABL1, was designed to enhance efficacy and reduce off-target effects vs ATPcompetitive TKIs. The phase 3 randomized ASC4FIRST trial established the overall favorable safety profile of asciminib in patients with newly diagnosed CML in chronic phase (CP). This exploratory post hoc analysis of ASC4FIRST focused specifically on the tolerability of asciminib vs imatinib and asciminib vs second-generation [2G] TKIs. Analyses were conducted within each stratum to account for differences between strata; patients prerandomized to the imatinib stratum were older and had higher cardiovascular risk than those in the 2G stratum. Within both strata, patients receiving asciminib experienced fewer difficult-to-tolerate AEs (such as gastrointestinal toxicity, rash, and pleural effusion) and fewer AEs leading to dose modifications and discontinuations due to nonhematologic and hematologic AEs vs the investigator-selected (IS) TKI comparator, with a shorter median duration of dose modification. Additionally, median onset of AEs leading to dose modification occurred later in patients receiving asciminib vs ISTKIs. The safety and tolerability of asciminib observed in the ASC4FIRST trial demonstrate asciminib's excellent benefit-risk profile as a frontline therapy for a broad range of patients with newly diagnosed CML-CP.
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Hemophilic joint disease, or blood-induced joint disease (BIJD), a rises from recurrent or even subclinical hemarthroses that initiate a cascade of iron-driven synovial and cartilage pathology. When blood enters the joint, iron deposition triggers oxidative stress, generating IL-1β and TNF-α-mediated inflammation, synovial hyperplasia, and persistent angiogenesis. Foundational studies show that iron exposure activates oncogene-like programs in synovial fibroblasts, including c-MYC and MDM2, promoting proliferative and anti-apoptotic behavior that contributes to villous hypertrophy. Contemporary single-cell analyses reveal heterogeneous fibroblast, endothelial, and mast cell populations that orchestrate iron handling, inflammation, and vascular remodeling. Notably, endothelial cells exposed to repeated bleeding exhibit ferroptosis signatures, increased permeability, and signaling through ferritin light chain (FTL) to SCARA5-positive fibroblasts, forming an iron-responsive stromal circuit that may predispose joints to rebleeding. Macrophages propagate osteochondral injury through iRhom2/ADAM17-dependent TNF-α shedding, linking hemarthrosis to bone loss. Cartilage injury occurs rapidly: even short exposures to low concentrations of blood induce irreversible chondrocyte apoptosis, reduced proteoglycan synthesis, and matrix degradation driven by ROS and iron. Recent discoveries identify TNXB-AKT signaling as a critical cartilage-protective pathway lost in hemophilic arthropathy. Despite advances in systemic and non-factor therapies, joint bleeding and arthropathy persist, highlighting the need for mechanism-based interventions beyond hemostasis. Potential targets include iron/ROS modulation, endothelial ferroptosis inhibition, mast-cell stabilization, TNF-α pathway blockade, fibroblast state reprogramming, and activation of AKT-mediated cartilage survival pathways. An integrated model positions hemarthrosis as the initiating event and iron-centered inflammatory amplification as the driver of chronic joint degeneration, underscoring opportunities for joint-directed therapeutic innovation.
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CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces durable remissions in only 30-40% of patients with relapsed or refractory (R/R) B-cell non- Hodgkin lymphoma (B-NHL), highlighting a major need to improve outcomes. In dose-escalation studies, higher CAR T-cell doses improved tumor control but caused prohibitive toxicities. Having established the maximum tolerated JCAR014 dose in patients with B-NHL at 2 x 106 CAR+ cells/kg, we hypothesized that a second infusion at day 14 ("dose-dense") at the same dose and without repeat lymphodepletion, would be safe and enhance antitumor efficacy. We report outcomes from the pilot dose-dense cohort of a phase 1/2 trial (ClinicalTrials.gov identifier: NCT01865617) with 8-year follow-up. Two CAR T-cell products, each containing 2 x 106 CAR+ cells/kg, were manufactured for all 20 treated patients; 17 received both infusions. Any-grade cytokine release syndrome (CRS) and neurotoxicity (NT) occurred in 10 (59%) and 3 (18%) of dose-dense patients, respectively, and-except for one grade 2 CRS-events followed the first infusion only. Despite no additional lymphodepletion, CAR T-cell re-expansion after the second infusion occurred in 16 (94%) patients. By Lugano criteria, overall and complete response rates were 47% (8/17) and 41% (7/17), respectively. Among responders, the 8-year durationof- response rate was 63% (95% CI: 37-100), comparing favorably with the 26% (95% CI: 14-48) observed in patients treated with a single infusion. In conclusion, early redosing on day 14 was feasible, safe and led to durable responses in patients with R/R B-NHL.
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Assessing optimal anticoagulant duration in venous thromboembolism (VTE) requires balancing the risks of recurrent VTE and anticoagulant-associated bleeding with fixed-duration or indefinite anticoagulation. In unprovoked VTE, elevated on-treatment D-dimer level is a predictor of recurrent thromboembolism after anticoagulant cessation, but its impact on anticoagulant-associated bleeding is unknown. We performed a post-hoc pooled analysis of two prospective cohorts (BLEEDRISK and REVERSE-2 studies) that enrolled unprovoked VTE patients who continued anticoagulation after ≥3 months of initial treatment. We calculated incidence rates of major bleeding, intracranial hemorrhage and fatal bleeding by D-dimer quartiles, then determined hazard ratios with the lowest D-dimer quartile as reference. Among 3,337 participants, incidence rates of anticoagulant-associated major bleeding from the lowest to highest D-dimer quartile were 0.45, 0.91, 1.43 and 2.20 events per 100 person-years respectively. Accounting for age, sex and anticoagulant type, individuals in the highest D-dimer quartile had a 2.7-fold higher risk of anticoagulant-associated major bleeding compared to the lowest quartile (adjusted hazard ratio [aHR] 2.70, 95% CI 1.35 - 5.41, p=0.005). This association remained robust after additional adjustment for hemoglobin, creatinine and concurrent anti-platelet use in the BLEEDRISK cohort. We did not observe differences in risks of intracranial hemorrhage or fatal bleeding by D-dimer quartiles. Elevated on-treatment D-dimer levels predicted higher risks of major bleeding during indefinite anticoagulation. Given the established relationship between elevated on-treatment D-dimer levels and recurrent VTE after time-limited anticoagulation, our findings underscore the need for additional risk stratification tools in this population to personalize anticoagulant treatment that maximizes its net clinical benefit.
The bone marrow is a highly dynamic organ that undergoes continuous remodeling to maintain all different hematopoietic cell populations throughout life, adapting during development, aging, and disease. It serves as the primary site of both normal hematopoiesis and leukemic initiation and progression. While mesenchymal stromal cells have received substantial attention for their contribution to support acute leukemia, the bone marrow adipocyte lineage has remained largely overlooked. This has two main reasons: first, adipogenic progenitors are typically grouped under the broad mesenchymal stromal cell umbrella, obscuring the distinct contributions of specific stromal subsets; second, mature bone marrow adipocytes have traditionally been regarded as inert energy reservoirs rather than active components of the marrow microenvironment. Recent evidence challenges this view, demonstrating that different types of adipocyte lineage cells actively promote acute leukemia progression and chemotherapy resistance through distinct mechanisms. In this review, we summarize recent advances in defining subpopulations within the bone marrow adipocyte lineage and outline how leukemic cells exploit their functions. We further discuss how standard chemotherapy may inadvertently reshape leukemic-adipocyte lineage interactions, mediating resistance and facilitating the re-emergence of disease.
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