Expert Review of Hematology最新文献

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.

Background: People with von Willebrand disease (VWD) experience increased bleeding and decreased quality of life; those with a severe bleeding phenotype may benefit from prophylactic treatment. This retrospective chart review evaluated real-world effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) in all subtypes of VWD.

Research design and methods: People aged ≥12 years with a confirmed VWD diagnosis from US health care centers who received either routine or intermittent (for menorrhagia) prophylactic rVWF treatment were included. Eligibility criteria included availability of medical records ≥ 6 months pre- (baseline period) and post-rVWF initiation (rVWF treatment period). Annualized bleed rate (ABR), healthcare resource utilization (HCRU), and treatment patterns were the main outcomes of interest and were compared between both periods.

Results: Of 30 participants across 11 sites, 23 (76.7%) received routine rVWF prophylaxis for a mean duration of 2.9 years. Treatment is ongoing in most participants. ABR and total and bleed-related inpatient visits and number of surgeries decreased during the rVWF treatment period versus the baseline period.

Conclusions: Participants receiving routine rVWF prophylaxis in this study experienced reduced ABR and HCRU versus the baseline period, indicating that rVWF prophylaxis may result in improved outcomes in people with VWD across all subtypes.

Background: Elevated blood counts in polycythemia vera (PV) are associated with increased thrombotic risk, which contributes to morbidity and mortality.

Research design and methods: This retrospective study describes treatment patterns and blood count control in patients with PV managed at community oncology practices (January 2014-February 2023; Integra Precision Q database).

Results: Of a total 10,112 patients, most received phlebotomy (68.1%) or hydroxyurea (HU; 28.2%) as initial treatment, with median follow-up of 32.1 (IQR, 13.5-58.5) months and 31.5 (IQR, 16.8-54.9) months, respectively. Changing treatment was less common than remaining on initial treatment despite 67.8% of patients on phlebotomy and 30.4% on HU having elevated hematocrit (≥45%) after 1 year of treatment. In contrast, 85.4% of patients who switched to ruxolitinib from HU achieved hematocrit < 45% after 1 year, and fewer required phlebotomy during ruxolitinib treatment than with HU treatment (RUX, 29.3%; HU, 53.5%). Additionally, 54.2% of patients who switched to ruxolitinib achieved white blood cell counts < 11 × 10⁹/L, and 57.5% achieved platelet counts ≤ 400 × 10⁹/L after 1 year of ruxolitinib treatment.

Conclusions: This real-world evidence highlights the importance of considering alternative therapies for patients whose initial treatment regimen does not provide adequate clinical benefit.

Background: Extended half-life (EHL) products have changed the treatment landscape of patients with hemophilia as patients maintain protective FVIII levels with minimal occurrence of spontaneous bleeding.

Research design and methods: Two independent datasets from the multi-country patient record form (PRF)-based study and PicnicHealth/Komodo Health study were analyzed to understand the real-world use of EHL products for patients with hemophilia A (HA).

Results: Most patients receiving EHL prophylaxis were on per-label dosing. Those receiving individualized dosing had moderate to severe disease. EHL dose adjustment occurred in 20% of patients of which 14.3% experienced a second dose adjustment. Treatment efficacy was mainly monitored via annualized bleeding rate (ABR) with quality of life, tolerability, and treatment efficacy being the primary considerations for Healthcare Personnel when selecting treatment. Switching to a different EHL or standard half-life (SHL) product did not significantly reduce median ABR while switching to non-factor therapy significantly reduced median ABR from 5.2 to 0.94, p < 0.0001. Patients on individualized dosing had higher ABRs than those on per-label dosing both before index EHL treatment and while on EHL treatment, whereas individualization via dose adjustment was associated with significant median ABR reduction (p < 0.0001).

Conclusions: Individualization may support improved outcomes in patients unable to achieve satisfactory outcomes on a per-label dosing regimen.