Expert Review of Hematology最新文献

Background: The pathophysiology of primary immune thrombocytopenia (ITP) is complicated and multifactorial, including platelet antibody formation and T cell imbalance. Emerging evidence has revealed differential miRNA expression in autoimmune disorders, including ITP. Nevertheless, the role of miR-106b-5p, miR-200c-3p, and miR-146a-5p in ITP remains unclear. Herein, we explored the potential role of these miRNAs in pediatric ITP and examined how their plasma levels influenced response to therapy.

Research design and methods: Three groups were recruited in this study: newly diagnosed ITP children (n = 25) in group I, chronic ITP children (n = 25) in group II, and normal controls (n = 25) in group III. Plasma levels of miR-106p-5p, miR-200c-3p, and miR-146a-5p were measured by polymerase chain reaction.

Results: MiR-106b-5p and miR-200c-3p were upregulated, whereas miR-146a-5p was downregulated in newly diagnosed and chronic ITP versus controls. MiR-200c-3p and miR-146a-5p were much higher in chronic ITP than newly diagnosed ITP. Lower miR-106b-5p levels were associated with complete response.

Conclusions: MiR-106b-5p and miR-200c-3p were elevated, while miR-146a-5p was suppressed in ITP versus controls. Reduced miR-106b-5p indicated a full response to therapy. These markers may be useful as diagnostic ITP biomarkers. Moreover, miR-106b-5p level can be used to monitor response to therapy and as a predictor for complete response.

Background: Hemophilia A and B are life-threatening congenital bleeding disorders traditionally managed with frequent factor replacement therapies, often complicated by breakthrough bleeds and inhibitor development. Marstacimab, a monoclonal antibody targeting TFPI, has emerged as a novel prophylactic treatment to reduce bleeding episodes in patients without inhibitors.

Methods: A systematic review was conducted following PRISMA guidelines. A comprehensive literature search was performed across multiple databases. Meta-analysis was conducted using R, applying a random-effects model.

Results: Nine manuscripts were included. Marstacimab significantly reduced the annualized bleeding rate (mean difference: -16.30; 95% CI: [-18.46, -14.15], p < 0.001) and showed a favorable safety profile with most adverse events being mild or moderate, and no thrombotic events reported. The use of a prefilled pen device further highlighted the therapeutic benefits and ease-of-use of Marstacimab.

Conclusions: This meta-analysis reinforces the efficacy and safety of Marstacimab in reducing bleeding rates in severe hemophilia A and B. The findings support its role as a promising, transformative alternative to conventional factor replacement therapies.

Registration: The study protocol for this systematic review was registered in the International Prospective Registry of Systematic Reviews (PROSPERO) database (www.crd.york.ac.uk/prospero/), and it was allocated the PROSPERO identification number CRD42024620215.

Introduction: The advent of immunotherapy has rapidly changed the treatment landscape of follicular lymphoma (FL).

Areas covered: Autologous CD19 chimeric antigen receptor T- cell (CAR-T) products show unprecedented efficacy in third-line FL but substantial rates of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Bispecific antibodies (BSAB) achieve deep and durable responses in heavily pretreated FL patients with less severe CRS and minimal neurological toxicity. BSAB have differing routes of administration, treatment duration and CRS prophylaxis. Checkpoint inhibitors show disappointing response rates in FL. Lenalidomide and tazametostat have modest single agent activity in FL, but synergize with other forms of immunotherapy.

Expert opinion: CAR-T offers a short duration of therapy with a potential plateau in progression free survival. Major disadvantages include cost, availability, requirement for lymphodepletion and toxicity. BSAB are available 'off the shelf,' have a comparably lower toxicity profile, and are ripe for combination. With both platforms, there are significant infectious risks. There are unanswered questions regarding when to use immunotherapy for FL, impact of disease burden, role of re-treatment and optimal sequencing/combinations. Moving forward, the field will need to develop new prognostic markers, reassess treatment indications, and focus on minimizing toxicity.

Background: Non-Hodgkin Lymphoma (NHL) is a group of hematological cancers with significant global mortality. Despite advances in treatment, mortality disparities persist across age, sex, region, and socioeconomic status, underscoring the need for a deeper understanding of global trends.

Research design and methods: Data from the Global Burden of Disease Study covering 204 countries between 1990 and 2021 were analyzed. The data were stratified by sex, age, and Socio-Demographic Index (SDI). Trends were assessed using the Estimated Annual Percentage Change (EAPC), and correlations with SDI were evaluated.

Results: From 1990 to 2021, global NHL deaths increased from 146,657 to 267,061, and death rates rose from 2.75 to 3.38 per 100,000 (EAPC: 0.51). Males and individuals aged 75 and older had higher mortality rates. High-SDI regions, including High-income North America (8.49 per 100,000) and High-income Asia Pacific (9.60 per 100,000), had the highest rates. Middle-SDI regions showed the most significant increases, while low-SDI regions experienced declines. Japan had a sharp rise in mortality (EAPC: 3.03), while Ethiopia had a decline (EAPC: -2.09).

Conclusion: NHL mortality increased globally from 1990 to 2021, with higher burdens in males and older adults. The fastest increases were observed in middle-SDI regions, reflecting healthcare disparities.

Introduction: Pyruvate kinase (PK) is an important glycolytic enzyme responsible for erythrocytic ATP production. PK allosteric activators have been shown to increase ATP and reduce 2,3-disphosphoglycerate among red blood cells leading to improved oxygen affinity, sickling, and hemolysis. In this systematic review, we aim to evaluate the efficacy and safety of PK activators in hemolytic anemias.

Methods: This study was conducted following the PRISMA guidelines. A literature search was conducted using relevant keywords over PubMed/Medline, Google Scholar, Cochrane Library, and clinicaltrial.gov, till 29 September 2024. Relevant data was extracted into a spreadsheet and synthesized qualitatively.

Results: The literature search yielded 7,153 results, with seven studies ultimately included in the review. These studies involved 206 patients, 166 of whom received mitapivat and the rest received placebo. Hemoglobin response was achieved by 38.0% to 80.0% of participants receiving mitapivat, with an average increase of 0.4 to 1.7 g/dL. Most studies reported improvements in bilirubin, lactate dehydrogenase, haptoglobin, and reticulocyte levels. Adverse events (AEs) were experienced by 93.2% of participants, with rates of 93.97% and 89.7% in the intervention and control groups, respectively. However, most AEs were mild and transient, and 23.4% were graded as 3 or higher.

Conclusions: In this study, PK activators, particularly mitapivat, demonstrated promising efficacy and safety profiles in managing hemolytic anemias. These agents significantly improved hemoglobin levels, markers of hemolysis, and hematopoietic response, offering a beneficial therapeutic option for various hemolytic conditions, including pyruvate kinase deficiency, sickle cell disease, and thalassemia.

Registration: A protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) before study initiation, CRD42024598980.

Background: Thrombosis is a major complication in polycythemia vera (PV), contributing to significant morbidity and mortality. This retrospective study aimed to develop a predictive model for thrombosis risk in PV patients using advanced statistical techniques.

Research design and methods: The study included 817 consecutive PV patients, with a median follow-up of 59 months. A Bayesian logistic regression model with sparsity-inducing R2D2 priors was used to predict thrombosis.

Results: Thrombotic events occurred in 13.2% of patients. The thrombosis group had significantly higher median neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), splenomegaly, cardiovascular risk factors, microvascular symptoms, pruritus, previous thrombosis, and Charlson Comorbidity Index (CCI) compared to the no-thrombosis group. Both groups were comparable in age. Multivariate regression analysis identified CCI, PLR, splenomegaly, and microvascular symptoms as key predictors of thrombosis. A clinical score, ThromboVera CS, was developed based on these predictors, classifying patients into low, moderate, or high-risk groups. In the low-risk group, 6.94% experienced thrombosis, compared to 15.76% in moderate-risk group and 48.78% in the high-risk group.

Conclusions: The ThromboVera CS score is a reliable, easy-to-use tool for predicting thrombosis in PV patients. It can help clinicians identify those at high risk, enabling early intervention that could significantly improve patient outcomes by targeting nearly 50% of high-risk patients.

Introduction: Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) continue to face poor outcomes despite recent advances in immunotherapy. The development of chimeric antigen receptor (CAR) T-cell therapies has transformed the treatment landscape, yet challenges such as severe cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and limited T-cell persistence have hindered their broader applicability. Obecabtagene autoleucel (obe-cel), a novel CD19-directed CAR T-cell therapy featuring a fast off-rate binding domain, represents a significant innovation aimed at optimizing the balance between efficacy and toxicity in this high-risk population.

Areas covered: This review examines the pharmacologic and clinical development of obe-cel, with a focus on the unique receptor design that mimics physiologic T-cell receptor interactions to mitigate overactivation and exhaustion. Data from early-phase and pivotal trials, particularly the FELIX phase Ib/II study, are discussed in detail, highlighting efficacy outcomes such as a 77% overall remission rate and favorable safety profile with low rates of grade 3 or higher CRS (2.4%) and ICANS (7.1%). A comprehensive literature search was conducted using PubMed and clinical trial databases to identify peer-reviewed publications, reports, ongoing studies, and regulatory updates relevant to obe-cel and comparable therapies in R/R B-ALL.

Expert opinion: Obe-cel represents an important conceptual advancement in CAR T-cell therapy, offering a promising alternative to existing high-affinity CD19 CARs. The integration of kinetic receptor engineering and split-dose administration appears to enhance both safety and durability of response, potentially redefining treatment goals in R/R B-ALL. As real-world experience and longer-term data accrue, obe-cel may emerge not only as a bridge to transplantation but also as a definitive therapy for select patients. The success of this approach may inform future CAR design across hematologic malignancies and support a paradigm shift toward receptor-tuned cellular immunotherapies.

Introduction: Chronic Lymphocytic Leukemia (CLL) is a disease marked by high infectious risk due to a combination of patient, disease and treatment-related factors. As a new landscape in the therapeutic panorama is emerging with the introduction of novel agents, it is essential to understand their impact on the incidence of infectious events and consequently what prevention and management strategies should be introduced.

Areas covered: We searched the PUBMED database considering peer-reviewed papers published between January 2013 and January 2025 that reported on at least 100 patients and provided detailed information on infectious complications. Retrospective studies, pooled analyses, and commentaries were excluded.

Expert opinion: Infections are a considerable adverse effect that can occur in CLL patients under treatment, with their incidence being influenced by intrinsic biology of the disease, the number of prior lines of therapy, and treatment duration. This being considered, the initiation of fixed duration therapy combined with the use of preventive measures, such as immunoglobulin replacement therapy and vaccination programs, should be preferred whenever feasible.

Background: Primary graft failure (PGF) is a life-threatening complication of allogeneic hematopoietic stem cell transplants (HSCT) and is associated with poor outcomes. Most clinical studies have focused on donor-specific anti-HLA antibodies (DSAs) against HLA-A, -B, and -DR molecules.

Research design and methods: We present the first reported case of PGF associated with a preformed high-level DSA against HLA-DQ alone. The 39-year-old patient was diagnosed with acute myeloid leukemia. She received a haploidentical graft from her son and suffered PGF. She had persistently high levels of DSAs against her son's HLA-DQA1 and HLA-DQB1 molecules after desensitization. No alternative donor was available.

Results: To circumvent the second graft failure, we adopted an approach of combining two units of unrelated cord blood (CB) and G-CSF-primed bone marrow (BM) and peripheral blood stem cells (PBSCs) from her son's transplants. The BM short tandem repeats (STRs) assay showed that one unit of the CB was fully engrafted, and the grafts from her son still failed to engraft.

Conclusions: We conclude that high levels of anti-HLA DQA1/DQB1 DSA could be associated with PGF in our case. Besides DSAs against HLA-A, -B, and -DR, attention should also be paid to DSAs against the HLA-DQ molecule.

Introduction: Von Willebrand factor (VWF) is a large multimeric protein present in the blood. Its most important and best characterized function is to control bleeding in primary hemostasis, which is triggered by different biophysical mechanisms and protein-receptor interactions involving different domains of VWF. Many different diseases related to VWF, most importantly von Willebrand disease comprising different types and sub-types, require diagnosis, laboratory analysis of concentration, and function of VWF.

Areas covered: As several different specific functions of VWF are physiologically relevant, several different assays are needed. The aim of this article is to provide a comprehensive overview of all relevant assays together with a description of how each assay is technically designed. Furthermore, guidance is given for choosing the right and validated assay methods.

Expert opinion: This information includes technical requirements, analytical performance data, references to relevant guidelines and other guidance documents, and reference standards. Also, information on availability and the type of the assay is provided, such as automated or manual, in vitro diagnostics or research use only. Relation to the clinical use of these assays, as well as performance, and result interpretation is covered in a second article in the same issue of this journal by the same authors.