European Journal of Haematology最新文献

Objectives: CAR-T cell therapies such as lisocabtagene maraleucel (liso-cel) have transformed the treatment of patients with second line primary refractory or early relapsed ≤ 12 months (R/R) large B-cell lymphoma (LBCL). The objective of this study was to assess the cost-effectiveness of liso-cel compared to standard of care (SOC) to treat R/R LBCL in France.

Methods: A 3-health-state model was developed to compare liso-cel to SOC over 20 years in France. Efficacy and safety were extrapolated from the TRANSFORM trial (NCT03575351), or DESCAR-T (registry of patients treated with a CAR-T in France). Costs were calculated using French-specific sources. Outcomes were quality-adjusted life years (QALY), life-years (LY), total costs, incremental cost-utility and cost-effectiveness ratios (ICUR, ICER). Probabilistic sensitivity analysis (PSA) was conducted to assess the robustness of the results.

Results: Liso-cel generated 5.7 QALY (6.4 LY) for a €265 907. SOC generated 4.4 QALY (5.1 LY) for €233 903. ICUR and ICER were estimated at €24 580/QALY and €23 464/LY gained versus SOC. PSA showed that liso-cel was more effective and more costly in 92% of the simulations.

Conclusions: Liso-cel is cost-effective versus SOC to treat R/R LBCL patients in France. Generation of long-term real-world data is needed in order to validate these findings.

Objectives: Our aim was to gain deeper insight into the genetic susceptibility of iron deficiency anemia (IDA).

Methods: We performed the first multi-ancestry meta-analysis of genome-wide association study (GWAS), which included 113 055 IDA cases and 1 783 936 healthy controls.

Results: Through multi-ancestry meta-analysis, 31 risk loci were identified, alongside 703 candidate genes indicated and 47 genes prioritized for IDA. Heritability analyses demonstrated that the liability scale heritability was 3.1% ± 0.2%, whereas an estimated 43.92 million effective sample size would be required to explain 90% of the phenotypic variance. Gene enrichment analysis, gene-set analyses, and genetic correlation studies revealed that IDA-related genes were enriched in whole blood, influenced the role of HFE (hemochromatosis gene) in regulating systemic iron homeostasis, and showed positive correlations with inflammatory diseases, psychological diseases, and cardiovascular diseases. Finally, gene-based prioritized analysis and gene-drug interaction analysis identified some potential targets (e.g., BLK), while drug repurposing approaches highlighted exploratory drug candidates (e.g., folic acid) for IDA.

Conclusion: We identified 31 novel risk loci for IDA and further characterized its genetic architecture.

Diffuse large B-cell lymphoma (DLBCL) remains the most common aggressive lymphoma, representing a biologically heterogeneous disease with diverse clinical behaviors. For more than two decades, R-CHOP has been the cornerstone of frontline treatment, curing approximately two-thirds of patients. Despite this success, a substantial subset-particularly those with high-risk biology, double-hit genetics, activated B-cell-like (ABC) subtype, or adverse clinical features-still experience relapse or refractory disease. Recent advances in lymphoma biology, immunotherapy, and targeted therapy have stimulated intense interest in improving frontline outcomes. Strategies include optimizing cytotoxic backbone regimens, incorporating antibody-drug conjugates (ADCs), immunomodulatory agents (IMiDs), bispecific antibodies, and exploring the feasibility of frontline CAR-T cell therapy. This review provides a comprehensive and discursive synthesis of the biological rationale, clinical evidence, trial results, and practical considerations shaping contemporary frontline treatment. We highlight the emerging role of molecular subtyping, the tumor microenvironment, and high-risk biomarkers, while discussing ongoing challenges and opportunities in integrating novel modalities into standard practice. Although R-CHOP remains the universal backbone, the therapeutic landscape is entering a transformative era, with polatuzumab-based regimens, bispecific combinations, and precision-guided approaches positioned to redefine frontline care for selected subgroups.

Venous thromboembolism presents a critical complication in hematologic malignancies, profoundly affecting patient outcomes. Traditional anticoagulant options, low-molecular-weight heparin and vitamin K antagonists, encounter significant limitations, especially concerning bleeding risks exacerbated by chemotherapy-induced thrombocytopenia. Direct oral anticoagulants (DOACs), including factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and thrombin inhibitors (dabigatran), have emerged as appealing alternatives due to their ease of use, predictable pharmacokinetics, and reduced monitoring requirements. However, their safety and optimal use remain uncertain in hematologic malignancies due to underrepresentation in clinical trials and specific bleeding risks. This review comprehensively summarizes current evidence regarding DOAC safety, efficacy, and clinical management considerations in leukemia, lymphoma, multiple myeloma, and myeloproliferative neoplasms. It emphasizes individualized anticoagulation strategies, highlights existing evidence gaps, and outlines future research priorities, particularly the safe application of DOACs in severe thrombocytopenia and interactions with targeted therapies. Ultimately, tailored anticoagulant approaches are essential to optimizing patient outcomes in this complex patient population.

Importance: Blood type has been proposed as a potential factor in cancer susceptibility; however, its role in childhood leukemia remains unclear. Prior studies have yielded conflicting results, and data from pediatric populations are limited.

Objective: This study examines whether ABO/Rh blood types are differentially distributed across acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML) subtypes in children.

Design: A retrospective cohort study was conducted that included 540 children aged 0-18 years diagnosed with leukemia between January 2010 and December 2023. Statistical associations were tested using χ² tests and ANOVA (R v4.1.3).

Setting: Database was collected from the national electronic health records from Clalit Health Services, Israel's largest healthcare provider.

Participants: A total of 540 pediatric oncologic patients were identified. Leukemia subtypes were distributed as acute lymphoblastic leukemia, acute myeloid leukemia, or chronic myeloid leukemia. Other data collected included blood type with its Rh type, age, sex, ethnicity, and disease outcome.

Results: No statistically significant association was found between blood type and leukemia subtypes (χ² = 6.3, p = 0.600). This remained true after adjusting for age, sex, and ethnicity (p values > 0.05). Survival status (alive/dead as of December 31, 2023) did not differ significantly by blood type (p = 0.774), although O^- patients showed the highest survival rate (94.1%) and AB⁺ the lowest (82.9%). No differences were observed in blood type distribution by sex (p = 0.892) or ethnicity (p = 0.910). Subgroup analyses revealed slight numerical trends, such as a higher proportion of O⁺ among AML cases (44.1%), but these lacked statistical power due to small sample sizes (AML n = 34, CML n = 10). Multivariable logistic regression showed no significant associations (all adjusted ORs 0.65-1.10; 95% CIs crossing 1.0).

Conclusion: In this cohort of pediatric leukemia patients, ABO/Rh blood types were not significantly associated with specific leukemia subtypes or survival outcomes. Because this study lacks a control group from the general population, it does not assess whether blood type influences the risk of developing leukemia; rather, it evaluates whether blood type is differentially distributed across leukemia subtypes among diagnosed cases. Our study contributes important evidence from a region with distinct blood type demographics and supports the need for future larger, multi-center studies to explore subtle associations in rare subtypes and blood groups.

Objectives: The WIL-31 study demonstrated efficacy and safety of prophylaxis with the plasma-derived von Willebrand factor/factor VIII concentrate wilate in von Willebrand disease (VWD) of all types and was the only prospective study with an on-demand run-in study as an intra-individual comparator. This subgroup analysis examines the efficacy of wilate prophylaxis in patients with type 3 VWD in WIL-31.

Methods: Patients received 20-40 IU/kg wilate prophylaxis 2-3 times weekly for 12 months.

Results: Twenty-two patients in WIL-31 had type 3 VWD. Mean total annualized bleeding rate (ABRs) during on-demand versus prophylaxis was 37.1 versus 5.2 (86% reduction). During prophylaxis, 115 bleeds occurred, most (95%) of which were minor; the most common bleeding site was the nose (40% of bleeds). Mean overall spontaneous ABRs during on-demand versus prophylaxis were 26.5 versus 2.8 (89% reduction); mean treated spontaneous ABRs were 20.3 versus 1.4, respectively (93% reduction). ABRs were reduced further during the second 6 months of prophylaxis versus the first 6 months. Results were consistent in subgroups by age. No serious adverse events related to study treatment and no thrombotic events were observed.

Conclusions: Prophylaxis with wilate was effective and well tolerated in patients with type 3 VWD, in all age groups.

Trial registration: NCT04052698; https://clinicaltrials.gov/study/NCT04052698.

Background: Long-term central venous catheters (CVCs) play a critical role in the management of pediatric patients with chronic illnesses, particularly in oncology. These devices provide reliable vascular access for the administration of chemotherapy, total parenteral nutrition, antibiotics, blood products, and frequent blood sampling.

Objective: Review the etiology, complications, and management of retained long-term central venous catheters in children.

Methods: This review analyzes existing literature and clinical experience to highlight mechanisms of catheter adherence and embolization, with a focus on pediatric-specific challenges.

Results: Prolonged catheterization may lead to endothelial injury and fibrotic adherence of the catheter to the vessel wall. Catheter fracture with embolization is a rare but serious complication. Management includes surgical, endovascular, and conservative approaches. Pediatric-specific ethical considerations are vital when fragments are left in situ.

Conclusion: Awareness of risk factors and timely intervention strategies can mitigate complications from retained CVCs. Further research is needed to understand the long-term effects and improve clinical guidelines.

Although chimeric antigen receptor (CAR)-T cells targeting B-cell maturation antigen (BCMA) have significantly advanced multiple myeloma (MM) therapy, many patients eventually progress, prompting the search for the most effective salvage regimens. To address this demand, we performed a random-effects meta-analysis evaluating response rates to salvage treatments after anti-BCMA CAR-T failure. We identified 36 eligible studies comprising 476 patients and seven distinct interventions through systematic database screening. Among them, bispecific antibodies (bsAbs) were the most common choice, followed by anti-BCMA CAR-T cells. We separately assessed response rates to both first- and any subsequent (combined)-line salvage interventions. In the first-line setting, selinexor-based regimens yielded the highest overall response rates (ORR) of 67% (95% CI: 38%-91%), followed by bsAbs (60%; 95% CI: 43%-76%). In the combined setting, anti-GPRC5D CAR-T cells achieved the highest ORR (88%; 95% CI: 65%-100%), followed by anti-BCMA CAR-T cells (75%; 95% CI: 42%-98%). Belantamab mafodotin demonstrated the lowest efficacy (0%; 95% CI: 0%-17%). Complete response rates remained low across all interventions (range: 0%-40%). Heterogeneity investigations revealed superior responses with human/humanized anti-BCMA CAR-T constructs compared with the animal-based receptors. In summary, our meta-analysis suggested that CAR-T cells and bsAbs are suitable for salvage use after anti-BCMA CAR-T failure in MM. Trial Registration: PROSPERO number: CRD42024621077.

The interplay between the commensal microbiota and the mammalian immune system may influence the outcomes of T cell-driven cancer immunotherapies. However, clinical studies supporting microbiota-based interventions in chimeric antigen receptor T-cell (CAR-T) therapy remain scarce. This study included 30 adult patients with B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel) or 4-1BB investigational product. Shotgun metagenomics sequencing (SMS) of fecal samples, collected before lymphodepletion and 1 month post infusion, enabled species-level resolution. We also trained 25 microbiome-based machine-learning (ML) models for response prediction. Neither prior "high-risk" antibiotics exposure nor alpha diversity influenced toxicity, response, or survival. However, dysbiosis was observed between 11 healthy controls and patients, particularly in those treated with axi-cel. SMS identified species associated with clinical outcomes. Increased abundance of Alistipes senegalensis and Alistipes onderdonkii correlated with lower neurotoxicity and improved survival, respectively. Bifidobacterium longum was associated with reduced cytokine release syndrome, whereas Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium breve correlated with poorer survival. ML models demonstrated strong predictive performance, with some identifying non-responders using only six species selected by the Boruta method (Bacteroides xylanisolvens, Bifidobacterium bifidum, Bifidobacterium breve, Eubacteriaceae bacterium Marseille-Q4139, Negativibacillus massiliensis, and Sellimonas intestinalis). These findings deepen current knowledge and support prospective microbiota-based strategies in CAR-T therapy.