Hematology最新文献

Objectives: The aim of this study was to characterize the clinical features and outcomes of patients with JAK2 V617F- and CALR-unmutated essential thrombocythemia (ET) and to identify potential driver mutations through whole-exome sequencing (WES).

Methods: This was a cross-sectional study including patients diagnosed with ET between 2007 and 2024. Clinical characteristics and outcomes were compared between patients with and without JAK2V617F and CALR mutations. WES was analyzed in JAK2V617F- and CALR-unmutated ET patients.

Results: Thirty-nine out of 162 ET patients (24%) were JAK2V617F- and CALR-unmutated. This group was younger than patients in the JAK2V617F mutated group (mean age 53.7 vs. 61.1 years, p = 0.012) and had lower incidence of thrombotic events (5.1% vs. 9.1%, p = 0.327). The median overall survival was 13.51 years compared to 12.61 years in patients with JAK2V617F or CALR mutations (p = 0.63). There were no statistically significant differences in clinical symptoms, incidence of thrombosis, bleeding, myelofibrosis, or leukemic transformation. WES was analyzed in 15 patients. Uncommon MPL mutations were identified, including MPLL265F, MPLP70L, and MPLR321Q. Potential novel CALR mutations were detected in exon 5 (c.540C > T, N180 = ) and exon 6 (c.703-3del). Non-driver gene mutations were detected, including RUNX1 (57.1%), ASXL1, DNMT3A, SETBP1, and MSH6.

Discussion and conclusions: Patients with JAK2V617F- and CALR-unmutated ET tend to present at a younger age and exhibit a lower incidence of thrombosis compared to those with JAK2V617F-mutated ET. The application of WES enabled the detection of uncommon and potential driver mutations in JAK2V617F- and CALR-unmutated ET.

Objectives: Limited published data exist on switching therapy from pegcetacoplan to iptacopan in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Methods: Three patient cases were collected from the Mayo Clinic, Cleveland Clinic, and Levine Cancer Institute.

Results: Patient 1 is a 57-year-old woman with PNH. She experienced extravascular hemolysis (EVH) while on C5 inhibitors and breakthrough hemolysis (BTH) after switching to pegcetacoplan. Patient 2 is a 37-year-old woman seeking care for PNH, who was initiated on C5 inhibitor therapy and switched to pegcetacoplan. EVH and BTH were observed while she was on C5 inhibitor therapy, and transfusions were required with both C5 inhibitor and pegcetacoplan therapy. Patient 3 is a 58-year-old man with aplastic anemia and PNH who was initiated on C5 inhibitor therapy, then switched to pegcetacoplan. He experienced both EVH and BTH.

Discussion: All three patients switched from pegcetacoplan to iptacopan, and none experienced EVH or BTH while on iptacopan. After switching to iptacopan, all three patients improved hemoglobin levels and abating transfusion requirements.

Conclusion: In this case series, three patients with PNH were successfully transitioned from pegcetacoplan to iptacopan monotherapy. No patients exhibited laboratory evidence of BTH, EVH, or intravascular hemolysis after switching to iptacopan.

Objectives: Our study integrates SNP array and metaphase cytogenetics (MC) to decode clonal architecture in myelodysplastic syndromes (MDS) and related disorders.

Methods: We retrospectively analyzed chromosomal aberrations in 33 patients diagnosed with MDS and related disorders by both SNP array and MC, of whom ten were detected with chromosomal copy number variations (CNVs) by MC. SNP array was used to quantify the clonal burden of CNVs using the metric median copy number state.

Results: We found that SNP array-derived median copy number state was associated with the abnormal/total ratio by MC, implying the utility of the SNP array derived indicator for detecting the clonal burden of chromosomal CNVs in MDS and related disorders. In our cohort, patients with isolated trisomy 8 clones showed relatively low clonal burden and more stable outcomes compared with those having trisomy 8 in complex karyotypes, whereas +1/1q + clones, even as sole lesions, were associated with aggressive progression. The higher clonal burden of trisomy 8 (elevated median copy number deviations compared to other lesions) was found in patients with complex karyotypes and poor prognosis, which further supported the staged evolution theory and provided a new perspective for studying the development of chromosomal abnormalities in myelodysplastic neoplasms.

Conclusion: The SNP array may serve as a novel tool for precision disease management, enabling early identification of high-risk clones and refinement of prognostic assessment in myelodysplastic neoplasms.

Objectives: Numerous observational research avenues have identified a possible correlation between aplastic anemia and autoimmune diseases, rooted in analogous dysfunctional immune responses. Nevertheless, causal link between autoimmune diseases and aplastic anemia remains elusive. The study aims to investigate the causal association of autoimmune diseases and aplastic anemia.

Methods: This study leveraged summary data from genome-wide association studies pertaining to six prevalent autoimmune diseases: ulcerative colitis, Crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, celiac disease, and type 1 diabetes mellitus, procured from expansive, public genome-wide association studies meta-analysis databases. Aplastic anemia - related genetic information was extracted from the UK Biobank. Utilizing single nucleotide polymorphisms as genetic instruments - meeting criteria P < 5 × 10^-8 and linkage disequilibrium [LD] r² < 0.001 - the study employed Cochran's Q test, the MR-Egger intercept test, and leave-one-out analysis to gauge the sensitivity concerning the impact of autoimmune diseases on aplastic anemia.

Results: The findings underscore a definitive causal relationship between systemic lupus erythematosus and aplastic anemia, as evidenced by the statistics (OR_IVW = 1.193, 95% CI 1.013-1.404, P = 0.035). Duplicate SLE GWAS from the FinnGen database demonstrated that patients with SLE are more susceptible to AA (OR_IVW = 1.193, 95% CI 1.013-1.404, P = 0.035). Additionally, the Mendelian randomization analysis reported no evidence of horizontal or directional pleiotropy.

Conclusions: In summary, the study suggests that systemic lupus erythematosus could serve as a potential risk factor contributing to the onset of aplastic anemia. To substantiate this hypothesis, ensuing studies encompassing larger sample sizes are warranted.

Purpose: Platinum-based chemotherapy is considered as salvage therapy to relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients. However, treatment failure due to drug resistance occurs in some patients, particularly those with Exportin 1 (XPO1) overexpression. This study investigates whether XPO1 inhibition enhances platinum sensitivity in DLBCL subtypes.

Methods: XPO1 expression in DLBCL was predicted using online datasets. Cell lines representing DLBCL subtypes were treated with varying concentrations of the XPO1 inhibitor selinexor (XPO1i), cisplatin (CDDP), and oxaliplatin (OXA), alone or in combination. Cellular viability was assessed via CCK-8 assay, while apoptosis rates and reactive oxygen species (ROS) levels were measured by flow cytometry. Protein levels of XPO1 and pro-apoptotic cytokines were evaluated using Western blotting.

Results: Bioinformatic analysis revealed elevated XPO1 expression in DLBCL. Both XPO1i and platinum-based therapy inhibited cellular viability and promoted apoptosis across DLBCL subtypes in a dose-dependent fashion. The combination of XPO1i at its IC50 and CDDP synergistically suppressed cell viability across both activated B-cell-like- and germinal-center B-cell-like (GCB)-DLBCL subtypes compared to CDDP monotherapy. The combination of XPO1i at its IC30 and OXA synergistically led to a greater reduction in cell viability, along with enhanced induction of apoptosis and ROS accumulation in GCB-DLBCL cells. In OCI-Ly8 and OCI-Ly1 cells, OXA alone inhibited phosphorylation of AKT and mTOR while increasing phosphorylation of JNK, ATM, and p53, and expression of γH2AX; these effects were potentiated by the combination of XPO1i and OXA.

Conclusion: XPO1 inhibition enhances platinum-induced cytotoxicity in GCB-DLBCL, supporting clinical evaluation of XPO1i-platinum combinations as salvage therapy.

Objectives: This study investigated outcomes and response to pegcetacoplan in complement inhibitor naïve (CI_naïve) and experienced (CI_exp) PNH patients.

Methods: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross-sectional survey of physicians and their patients in Canada, France, Germany, Italy, Spain, and the UK between December 2023 and April 2024. Physicians reported patient characteristics and clinical outcomes, which were used to define pegcetacoplan response. Results were stratified by prior CI prescription. Analyses were descriptive.

Results: Forty-eight physicians reported on 63 patients (CI_naïve:11; CI_exp:52). Median (IQR) age was 45.0 (33.0-55.0) years, 60.3% were male. At treatment initiation versus at survey for CI_naïve and CI_exp, respectively, median (IQR) haemoglobin levels (g/dL) were 8.0 (5.0-9.0) versus 12.0 (11.2-12.3), and 9.0 (8.0-9.2) versus 11.0 (10.2-12.0); lactate dehydrogenase levels (U/L) were 500 (350-1625) versus 250 (175-525), and 470 (290-588) versus 265 (190-379); absolute reticulocyte counts (x10⁹ /L) were 220 (151-250) versus 110 (95-140), and 212 (134-281) versus 120 (105-228). At pegcetacoplan initiation, 4.4% of patients met criteria of good-to-complete response versus 79.5% at survey.

Conclusions: Pegcetacoplan proved effective for CI_naïve and CI_exp patients in a real-world setting, with numerically improved clinical outcomes and high response rate.

Objective: This study aimed to investigate the therapeutic potential of sovleplenib, a selective SYK inhibitor, in aplastic anemia (AA), focusing on its effects on immune modulation and the cGAS-STING-NF-κB inflammatory axis.

Methods: An immune-mediated AA mouse model was established and treated with sovleplenib. Hematopoietic function was assessed via peripheral blood counts and bone marrow mononuclear cell (BMNC) counts. Immune cell profiles were analyzed by flow cytometry. Cytokine levels were measured by ELISA. Underlying mechanisms were explored through proteomics and Western blotting.

Results: Sovleplenib treatment significantly improved peripheral blood counts (HGB, WBC, PLT) and BMNCs, and reduced bone marrow fat vacuolation. It corrected immune imbalance by increasing the CD4⁺/CD8⁺ T-cell ratio and decreasing the M1/M2 macrophage ratio, promoting an M2 phenotype. Concurrently, it elevated Arg-1 level while suppressing ROS, TNF-α, and IFN-β. Mechanistically, sovleplenib inhibited the activation of key pathway components (cGAS, STING, p-TBK1, p-p65).

Discussion: The results demonstrate sovleplenib's dual role in promoting hematopoiesis and immunomodulation. Its efficacy is mechanistically linked to the suppression of the overactivated cGAS-STING-NF-κB pathway, a key driver of inflammation in AA.

Conclusion: Sovleplenib represents a promising targeted therapy for AA.

Background: Hypoplastic myelodysplastic syndrome (hMDS) is an uncommon MDS subtype, accounting for approximately 10-15% of cases, characterized by bone marrow hypocellularity, severe cytopenias, and features of immune dysregulation. Its clinical course overlaps with aplastic anemia, yet optimal management for lower-risk patients remains undefined, particularly in Asian populations.

Methods: We retrospectively analyzed 48 patients with lower-risk hMDS (IPSS-R very low/low/intermediate) treated at Tianjin Medical University General Hospital from 2013 to 2021. Patients received cyclosporine A (CsA, n = 16), hypomethylating agents (HMAs, n = 10), low-dose HMAs (LD-HMAs, n = 11), or best supportive care (BSC, n = 11). Responses were assessed by modified IWG criteria, and survival was evaluated by Kaplan-Meier and Cox regression analyses.

Results: Median age was 61 years (range 16-84), with 60.4% male. Somatic mutations were present in 64.6%, and PNH clones in 29.2%. Six-month overall response rates were 75.0% for CsA, 70.0% for HMAs, 54.5% for LD-HMAs, and 36.4% for BSC (p = 0.220). CsA achieved significantly longer complete remission (median 75 months) and hematologic improvement durations (p < 0.05). Median overall survival (OS)/progression-free survival (PFS) for CsA were 78.0/76.0 months, compared with 17.0/6.8 for HMAs, 31.0/15.0 for LD-HMAs, and 36.0/15.0 for BSC (p < 0.01). HMAs were associated with increased grade 3-4 infections.

Conclusion: CsA provides superior response durability, survival outcomes, and safety compared with other approaches, supporting its use as first-line therapy in lower-risk hMDS. Integration of immune and molecular profiling may refine individualized treatment strategies.

Objective: This review aims to summarize current progress in targeted therapy for acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar). This subtype of AML often shows resistance to chemotherapy and has a poor prognosis. The purpose is to emphasize potential therapeutic strategies and explore drugs currently under clinical development. Methods: We reviewed studies on the molecular characteristics of KMT2Ar AML and examined targeted drugs that can block key genetic and epigenetic mechanisms. Information on drug mechanisms, preclinical findings, and clinical trials was collected and analyzed.

Results: Several new agents targeting KMT2A-related pathways are being explored. Menin inhibitors show encouraging clinical activity, while other inhibitors, such as those targeting DOT1L, BET, and EZH2, have produced promising preclinical results. Early data suggest that combination therapy may be more effective in overcoming drug resistance than monotherapy.

Discussion: Providing a new therapeutic direction for the abnormal molecular networks in KMT2Ar AML offers a promising approach. However, most therapies are still in the early stages and clinical translation is limited. Further research is needed to improve the safety and long-term efficacy of the treatment.

Conclusion: There is an urgent need for effective targeted drugs for KMT2Ar AML. Continuous research and clinical trials will be key to improving patient prognosis and advancing precise treatment for this challenging leukemia subtype.

Objectives: To investigate the clinical significance of Fluorescence in situ hybridization (FISH) in detecting aberration of chromosome 5, 7, or 17 in newly diagnosed acute myeloid leukemia (AML) patients.

Methods: We retrospectively evaluated the clinical features and outcomes of 77 adult newly diagnosed AML patients with 5/5q, 7/7q, or 17/17p loss detected by either FISH or conventional karyotype.

Results: Among 77 patients, all (100%) were identified by FISH, while only 47 (61%) were positive with conventional karyotype. Patients with FISH-positive displayed similar age at onset, gender, WBC, and gene mutation spectrum with those identified by karyotype. In FISH-positive but karyotype-negative group, the 3-year OS and EFS were 28.9% and 23.9%, respectively, which were similar to 29.1% and 21% with FISH-positive and karyotype-positive (P = 0.59 and 0.48). When comparing the outcomes of patients with or without hematopoietic stem cell transplantation (HSCT), both groups of patients with and without HSCT showed similar outcomes. Patients underwent HSCT with 3-year OS at 76.2% in FISH and 64.3% in FISH-positive and karyotype-positive group (P = 0.66), while patients without HSCT had 3-year OS at 33.3% and 39% (P = 0.63), respectively.

Conclusion: Overall, patients with 5, 7, or 17 chromosomal abnormalities identified by either FISH or karyotype have similar clinical characteristics and outcomes. FISH could supplement to conventional karyotype for detecting aberration of chromosome 5, 7, or 17 in newly diagnosed AML.