Expert Review of Hematology最新文献

Introduction: Numerous risk staging systems exist for newly diagnosed multiple myeloma (NDMM), from older models which rely purely on markers of 'tumor burden' to modern scores which incorporate tumor genetics. While the 2025 IMS-IMWG high-risk criteria, based on specific cytogenetic analyses and the β2-microglobulin titer, represent a major push to harmonize NDMM risk stratification, multiple barriers to successful, comprehensive implementation in standard practice remain. There also exists substantial heterogeneity in how therapeutic trials quantify risk.

Areas covered: We herein summarize the novel 2025 IMS-IMWG criteria. We then provide a brief overview of the current state of NDMM risk stratification in standard practice, as well as the variability in 'high-risk' disease definitions in NDMM trials. Finally, we discuss ways in which such variation in 'high-risk' definition is being addressed.

Expert opinion: Attempts to improve prognostication and potentially demonstrate outcome prediction in NDMM have been confounded by variable performance of risk stratification in standard clinical practice and substantial heterogeneity of 'high-risk' definitions in clinical trials. If implemented comprehensively, the 2025 IMS-IMWG criteria will allow for apples-to-apples comparison across trials via meta-analysis and thus harmonize risk assessment in myeloma, setting the stage for investigation of risk-adapted treatment deescalation and intensification.

Background: The recent discontinuation of antihemophilic factor Method M, monoclonally purified (AHF-M) and recombinant antihemophilic factor (rAHF) requires evaluation of hemophilia A treatment strategies for some patients. This post-hoc analysis characterized the safety and efficacy of third-generation recombinant factor VIII (FVIII) products (antihemophilic factor [recombinant], plasma/albumin-free method [rAHF-PFM] and PEGylated rAHF [rAHF-PEG]) after switching from plasma-derived AHF-M or first-generation rAHF.

Research design and methods: Previously treated patients from three trials (rAHF-PFM: two; rAHF-PEG: one) whose last recorded FVIII replacement therapy was either AHF-M or rAHF were included. Bleeding outcomes, consumption, hemostatic efficacy, safety, and immunogenicity were evaluated.

Results: Of 114 participants, 19 were previously treated with AHF-M and 95 with rAHF; 97 participants transitioned to rAHF-PFM and 17 to rAHF-PEG. Participants switching to rAHF-PEG prophylaxis achieved lower bleeding rates compared with previous prophylaxis. Most bleeding events were treated with one to two infusions of rAHF-PFM or rAHF-PEG with good or excellent hemostatic efficacy ratings. No participants developed inhibitors to rAHF-PFM or rAHF-PEG.

Conclusions: Results from this post-hoc analysis demonstrated improvements in bleeding outcomes in participants switching to rAHF-PEG and were consistent with the original trial results, supporting the feasibility of transitioning from the older- to newer-generation Takeda FVIII replacement therapies.

Introduction: Undetectable minimal residual disease (uMRD) has emerged as a critical prognostic and potentially predictive biomarker in chronic lymphocytic leukemia (CLL), particularly in venetoclax-based time-limited regimens.

Areas covered: Clinical trials such as MURANO, CLL-14, and CLL-13 have shown that uMRD at the end of treatment correlates with prolonged progression-free survival (PFS) and overall survival (OS), irrespective of disease biology. MRD-adapted strategies in BTK inhibitor + venetoclax combinations have also been explored, with studies suggesting that MRD-adapted therapy results in durable remissions and potential for reduced toxicity. Recent studies have begun to explore MRD-guided therapy duration for venetoclax + anti-CD20 monoclonal antibody regimens, allowing for tailored treatment based on the depth of response. In this review, we highlight that the predictive value of MRD appears to be regimen- and biology-specific, with differing implications for patients with mutated versus unmutated IGHV.

Expert opinion: While fixed-duration therapy simplifies treatment, MRD-guided approaches offer a more individualized strategy that may optimize outcomes while minimizing overtreatment. Ongoing trials will further define the role of MRD-adapted therapy duration in first-line CLL treatment. Overall, MRD is a powerful tool to move beyond one-size-fits-all regimens and may become integral in personalizing CLL management across diverse therapeutic regimens.

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only available curative treatment option for hematologic manifestations of Fanconi Anemia (FA), which include bone marrow failure and hematological malignancies. Outcomes after allo-HCT have improved significantly over the last 30 years by optimizing preparative regimens, graft-versus-host-disease (GvHD) prophylaxis and supportive care. Nevertheless, indications for transplant should be carefully weighed, based on a thorough evaluation of risks and benefits, as this procedure has intrinsic morbidity and mortality and may increase the risk and accelerate the onset of late malignancies and FA related complications.This review, following a thorough Medline search of the pertinent published studies, reports the most recent data on HCT in FA, focusing on HCT strategies, post-transplant follow-up, and impact of allo-HCT on FA-associated late effects.

Expert opinion: While we continue to generate evidence to determine the optimal candidates, timing and strategies for HCT in FA patients, we must also consider the implications for future treatment modalities like gene therapy/gene editing. The primary objective of all strategies must be to mitigate - or at the very least, not exacerbate - the risk of long-term complications that remain a leading cause of the unacceptably high mortality rate in FA.

Background: Lymphoma poses a significant public health challenge with complex subtypes. While obesity and adipokines have been linked to lymphoma, causal relationships remain unclear. This study uses Mendelian randomization (MR) to systematically assess these associations.

Research design and methods: Two-sample MR analyzed genetic data from genome-wide association studies to evaluate causal links between obesity, adipokines (adiponectin, leptin, and resistin), and lymphoma subtypes (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin lymphoma, and other unspecified types of non-Hodgkin lymphoma). Primary analysis used inverse variance weighted (IVW), supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses (MR-Egger regression, Cochran's Q test, MR-PRESSO, leave-one-out) and linkage disequilibrium score regression (LDSC) ensured robustness.

Results: IVW revealed obesity positively associated with follicular lymphoma (OR = 1.352, 95% CI: 1.095-1.670, p = 0.005) and other unspecified types of non-Hodgkin lymphoma (OR = 1.297, 95% CI: 1.050-1.603, p = 0.016). No significant links were found between adipokines and lymphoma. Sensitivity analyses confirmed no heterogeneity or pleiotropy.

Conclusions: Obesity may independently increase lymphoma risk, unrelated to adipokines. These findings highlight new risk factors, urging further research into pathological mechanisms and biomarkers.

Introduction: Immune thrombocytopenia (ITP) is an autoimmune-bleeding disorder; its management is shifting from empiricimmunosuppression and splenectomy to targeted, pathway-specific drugs that raise platelet counts with fewer long-term toxicities.

Areas covered: This review critically appraises evidence behind six mechanistic drug classes poised to reshape ITP care: thrombopoietin receptor agonists, spleen tyrosine kinase inhibitors, reversible Brutontyrosine kinase inhibitors, neonatal Fc-receptor antagonists, proximal complementblockers, and plasma-cell or BAFF-directed therapies. We interrogated PubMed, ClinicalTrials.gov, and hematology-conference abstracts (January 2010-May2025), retrieving synthesizing phase 2-3 trials and key observational studies. Throughout, we contrast these agents with steroids, intravenous immunoglobulin, and rituximab, highlighting shared immunomodulatory nodes and unique points of divergence that may inform rational sequencing or combination.

Expert opinion: Mechanism-focused agents already enable steroid-sparing outpatient regimens and personalized care, yet durable remission and predictive biomarkers remain elusive. FcRn and reversible BTK inhibitors are closest to regulatory approval; complement blockade delivers24-hour platelet rescue, while plasma-cell or BAFF inhibition may consolidate sustained disease control. Research priorities include biomarker-guided pathway selection, optimal positioning with thrombopoietin receptor agonists, long-termpharmacovigilance, and cost-effectiveness analyses to ensure equitable global access.

Background: Genetic factors associated with familial multiple myeloma (MM) have been studied, yet the somatic engagement of germline predisposition genes remains underexplored. This study aims to systematically analyze somatic variants in previously reported germline familial myeloma predisposition genes.

Research design and methods: A systematic literature search identified 179 genes associated with familial MM. Somatic variants and associated demographic data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study, which includes non-selected myeloma patients (5.3% with a first-degree family history of hematological malignancy) were analyzed.

Results: 1863 somatic variants across the 179 predisposition genes were detected, with substitutions being the most common variant type (95.7%) and missense variants the most frequent consequence (40.6%). Notably mutated genes with pathogenic potential included DIS3, LRP1B, EP300, SAMHD1, ARID1A, DNAH2, MUC17, BIRC6, MYH14, DSP, and DCHS1. Pathogenic variants did not show significant demographic associations. Moreover, variant types, consequences, and associated demographics revealed similar rates in young myeloma patients (≤50 years) and patients with a first-degree family history of hematological malignancy.

Conclusions: This study highlights a significant rate of pathogenic somatic variants in germline predisposition genes of familial myeloma, suggesting candidate genes to be investigated in myelomagenesis.

Background: Adherence to iron chelation therapy (ICT) is essential for preventing iron overload complications and optimizing health outcomes in transfusion-dependent thalassemia (TDT) patients. This study evaluates the cost-effectiveness of ICT adherence in Malaysia.

Research design and methods: A cross-sectional analysis was conducted at a tertiary hospital. Adherence was measured using the Malaysia Medication Adherence Assessment Tool, and health utility values were assessed with SF-6D. Based on the societal perspective, costs and quality-adjusted life years (QALYs) were compared between adherent and non-adherent patients, with incremental cost-effectiveness ratio (ICER) calculations and sensitivity analyses.

Results: One hundred and sixty-two adult TDT patients were recruited. Adherent patients (n = 76) achieved higher QALYs (0.783 vs. 0.733) but incurred slightly higher annual costs ($7,773.26 vs. $7,643.33). The ICER of $2,598.90 per QALY remained below Malaysia's willingness-to-pay threshold ($5,441.16), confirming cost-effectiveness. Sensitivity analyses indicated that cost variations significantly influenced the ICER, while utility values had minimal impact.

Conclusions: The findings underscore the economic and clinical benefits of ICT adherence, advocating for targeted strategies to enhance compliance. Future research should explore long-term cost implications and intervention strategies to improve adherence, ensuring sustainable thalassemia management.