European Journal of Haematology最新文献

Multiple myeloma (MM) is a hematologic malignancy manifested by proliferation of clonal plasma cells leading to end-organ damage. Despite significant advancements in therapeutics, it remains incurable. Cellular therapies such as chimeric antigen receptor (CAR-T) therapy and T-cell engager (TCE) therapies have delivered high overall response rates, but almost all patients relapse and subsequent options are limited particularly in view of the increasing prevalence of prior exposure to anti-BCMA agents and immunomodulator (IMiD) therapies. Our retrospective review of 12 patients between January 2024 and December 2025 who received a combination of talquetamab, elranatamab, or teclistamab with pomalidomide found that 11 of 12 had an overall response, of whom 6 had very good partial response or better at median follow-up of 9.9 months. All 12 patients were prior exposed to pomalidomide, of whom 10 had been exposed to prior CAR-T with a median of 7 prior lines of therapy. Safety profiles were favorable: 6 patients experienced Grade 1 CRS, 7 experienced Grade III neutropenia, and 7 of 8 patients receiving talquetamab experienced on-target, off-tumor side effects like dysgeusia and skin dryness.

The GAIA-CLL13 trial showed that venetoclax-obinutuzumab (Ven-O) based regimens, with or without ibrutinib, offer superior efficacy compared to chemoimmunotherapy (CIT) with regards to progression free survival (PFS) in fit, treatment-naïve (TN) CLL patients. However, their higher costs warrant a cost-effectiveness evaluation. This study assessed the cost-effectiveness of Ven-O versus venetoclax with rituximab (Ven-R), venetoclax-obinutuzumab-ibrutinib (Ven-O-I), and CIT in fit, TN CLL patients without TP53 aberrations across the Netherlands, Norway, and Denmark. A state-transition Markov model including later line treatment was applied to estimate costs, life years (LYs), and quality-adjusted life years (QALYs) over a 38-year horizon. Results were sensitive to long-term OS assumptions. In the base-case analysis, extrapolating OS and PFS for each treatment separately, all venetoclax-based treatments appeared cost-effective compared to CIT in all three countries. ICERs for Ven-R, Ven-O, and Ven-O-I versus CIT were €35 840, €32 513, €30 331 for the Netherlands, €39 881, €38 099, €26 381 for Norway, and €34 010, €37 804, €33 215 for Denmark. In the sensitivity analyses, however, cost-effectiveness was lost when only allowing separate OS and PFS extrapolations for statistically significant differences at 60-month follow-up. Furthermore, cost-effectiveness results were sensitive to varying assumptions about national willingness-to-pay (WTP) thresholds, IGHV-status, and time horizon. In conclusion, venetoclax-based treatments may be considered a cost-effective treatment option for fit, TN CLL patients without TP53 aberrations in the Netherlands, Norway, and Denmark, but the pricing process for targeted agents should take the uncertainty about cost-effectiveness into account when negotiating pricing of medication. Longer follow-up data is needed to address the uncertainties.

Extramedullary disease (EMD) of multiple myeloma (MM) is a critical indicator of disease progression, with a complex pathophysiology involving tumor microenvironment dysregulation, chromosomal abnormalities, and aberrant signaling pathway activation. Advances in detection technologies have significantly improved EMD diagnosis rates in recent years, but clinical treatment still faces challenges such as high drug resistance rates and difficulties in managing lesions at specific sites. This article systematically reviews the definition, classification, biological characteristics, pathophysiological mechanisms, diagnostic methods, current treatment strategies, and emerging therapeutic challenges of EMD. It emphasizes the interactions between different pathogenic factors and the heterogeneous therapeutic responses of various EMD subtypes, aiming to provide a comprehensive reference for clinical practice and research directions.

Myelodysplastic syndromes/neoplasms (MDS) constitute a very heterogeneous group of clonal myeloid neoplasms characterized by a variable clinical course and recurrent genetic abnormalities. Their treatment relies on risk classification as lower or higher-risk categories by the original International Prognostic Scoring System (IPSS) or the current revised (IPSS-R) or molecular IPSS-M. Higher-risk MDS (HR-MDS) are clonal hematopoietic disorders characterized by significant cytopenias, dysplastic changes, and a high propensity for progression to acute myeloid leukemia (AML). Up to 40% of them usually progress to AML within two years of diagnosis. Allogeneic stem cell transplantation (HSCT) remains the only potential cure and standard of care for eligible patients. Despite standard treatments such as Allo-HSCT and hypomethylating agents (HMAs), outcomes remain suboptimal. Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies.

Acalabrutinib, a second-generation Bruton's tyrosine kinase inhibitor (BTKi), is characterized by enhanced specificity and selectivity for BTK with minimal off-target effects, offering a significant evolution in the treatment of chronic lymphocytic leukemia (CLL). Its mechanism of action, a covalent binding to Cys481 within the BTK active site, ensures potent and sustained blockade of B cell receptor signaling, leading to disruption of key survival and proliferation pathways in malignant B cells. Long-term data from pivotal phase III trials confirmed the high efficacy of acalabrutinib-containing regimens in both treatment-naïve and relapsed/refractory CLL, showing durable progression-free survival, favorable overall survival rates, and low incidence of serious adverse events such as atrial fibrillation and hypertension, likely attributable to its improved selectivity, with limited immunosuppression and better tolerability leading to lower discontinuation rates compared to first-generation BTKi. Fixed-duration combination with acalabrutinib plus venetoclax, with or without obinutuzumab, has recently emerged as a highly efficacious strategy, providing sustained minimal residual disease (MRD) negativity with manageable toxicity, further supporting the clinical utility of acalabrutinib regimens. The demonstrated efficacy, robust safety, and flexibility of acalabrutinib in both continuous and fixed-duration regimens make it a cornerstone for individualized CLL management, enabling tailored treatment approaches based on patient- and disease-specific factors.

Background: Extended-duration anticoagulation reduces recurrent venous thromboembolism (VTE) in cancer and non-cancer patients. Reduced-dose direct oral anticoagulants (DOACs) may be safer if they match efficacy with less bleeding risk. We conducted a systematic review and meta-analysis of trials comparing reduced-dose and extended-dose DOACs.

Methods: Randomized controlled trials comparing reduced-dose with extended-dose anticoagulation for secondary VTE prevention were systematically reviewed. Primary outcomes included recurrent symptomatic VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT). Secondary outcomes included bleeding, adverse events, and all-cause mortality. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Subgroup and leave-one-out sensitivity analyses explored heterogeneity and robustness. All analyses were conducted in R (version 4.3.1).

Results: Six RCTs (n = 9382) were included. Reduced-dose anticoagulation showed no statistically significant difference in recurrent VTE (RR 0.98, 95% CI 0.72-1.33), PE (RR 0.96, 95% CI 0.61-1.50), or DVT (RR 0.86, 95% CI 0.56-1.32) compared with extended-dose therapy. Major bleeding was significantly reduced (RR 0.68, 95% CI 0.48-0.98), as were clinically relevant non-major bleeding and any bleeding. All-cause mortality did not differ significantly. Heterogeneity was low to moderate across outcomes, and sensitivity analyses confirmed the stability of results.

Conclusion: Reduced-dose anticoagulation demonstrated similar efficacy with improved safety compared with extended-dose therapy. These findings support individualized dose reduction strategies after extended anticoagulation.

Trial registration: ClinicalTrials.gov identifier: CRD420251081952.

Background: Individuals with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) face transformation risks to acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). While older age is linked to increased risk, it remains unclear whether risk increases with age or with disease duration.

Objectives: To examine how age and disease duration affect AML and MDS transformation in MPN.

Methods: We used Swedish nationwide register data to model transformation rates as continuous functions of age and disease duration for each subtype and outcome. Cumulative incidences were estimated accounting for competing risk of death.

Results: This study included 7156 patients with PV, 6810 with ET, and 1080 with PMF diagnosed in 2001-2021. In PV and ET, AML rates increased with disease duration. In PMF, AML rates were highest soon after diagnosis and declined over time. The 10-year cumulative incidence of AML at diagnosis age 70 was 3.5% in PV, 4.7% in ET, and 18.2% in PMF; for MDS, it was 1.7%, 3.1%, and 10.7%, respectively.

Conclusion: AML and MDS transformation risks vary by MPN subtype and depend on age and disease duration, with disease duration elevating AML risk in PV and ET; incorporating both factors is essential for individualized risk assessment.