Annals of Hematology最新文献

Venetoclax-obinutuzumab therapy successfully induced remission of acquired von Willebrand syndrome (AVWS) in a 72-year-old patient with chronic lymphocytic leukemia (CLL). Initially diagnosed with CLL, the patient later experienced severe bleeding due to AVWS, as evidenced by reduced factor VIII (FVIII) and von Willebrand factor (VWF) levels. Despite initial treatment with VWF/FVIII concentrates and tranexamic acid, persistent bleeding prompted the initiation of venetoclax-obinutuzumab. This regimen resulted in normalization of coagulation parameters and undetectable minimal residual disease, indicating effective CLL control and subsequent AVWS remission. This case highlights the potential of targeted CLL therapies in the management of rare associated hematologic complications.

AML is an aggressive haematological malignancy characterised by uncontrolled proliferation and differentiation arrest of myeloid progenitor/stem cells. Conventional treatment methods principally entail chemotherapy and haematopoietic stem cell transplantation; however, the efficacy of these treatments is constrained by the occurrence of relapses and treatment-related toxicity. In recent years, research into molecular mechanisms has driven the development of targeted therapies against specific gene mutations and advanced multiple immunotherapy strategies. Among these, C-type lectin-like molecule 1 (CLL-1) has emerged as a promising new immunotherapy target due to its specific expression in AML blast cells and leukemia stem cells. CLL-1-targeted therapies have been shown to have the potential to alleviate drug resistance, reduce non-specific toxicity, and address issues of immune escape. This review provides a comprehensive summary of the latest research advances in CLL-1-targeted therapies for AML, with the aim of providing novel insights and directions for clinical treatment.

Interstitial pneumonia (IP) is an important pulmonary complication in children with acute lymphoblastic leukemia (ALL), yet its incidence, clinical characteristics, and predictors remain insufficiently defined. We conducted a single-center retrospective study including 484 children diagnosed with ALL and treated at the First Affiliated Hospital of Sun Yat-sen University between February 2002 and January 2022. Among 484 patients, 33 (6.82%) developed IP. The incidence was higher in boys than girls (8.92% vs. 2.94%) and significantly elevated in high-risk versus non–high-risk ALL (16.67% vs. 3.78%, P < 0.001). IP occurred more frequently during maintenance therapy than intensive chemotherapy (75.75% vs. 24.25%, P = 0.047), with a median onset of 122 days after maintenance initiation. Common symptoms included dyspnea (100%), fever (87.87%), and cough (75.75%). Imaging commonly demonstrated diffuse ground-glass opacities and interstitial changes. Management involved antibacterial therapy (84.84%), antifungals (75.75%), antivirals (72.72%), corticosteroids (87.87%), and oxygen therapy (93.93%). Twenty-six patients improved, whereas seven died, predominantly due to respiratory failure. In high-risk patients during maintenance therapy, lower absolute lymphocyte counts and changes in absolute neutrophil count/white blood cell ratio (ANC/WBC) and absolute lymphocyte count/white blood cell ratio (ALC/WBC) were significantly associated with IP onset, suggesting their potential predictive value. No variables were significantly associated with mortality. Early recognition and timely initiation of corticosteroids and supportive care are essential. Hematologic indices may help identify children at heightened risk, supporting improved surveillance and risk-adapted management.

Acute promyelocytic leukemia (APL) is characterized by the presence of PML::RARA fusion gene, and a favorable response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) administration. Here, we studied the leukemogenic properties of a novel fusion gene, ETV6::RARA t(12;17)(p13;q21), identified in an APL patient lacking the PML::RARA rearrangement. The ETV6-RARA fusion protein was over-expressed via lentiviral transfection in leukemia cells and its effects on cell growth were evaluated with cell counting kit 8 (CCK8) assay and on apoptosis and cellular differentiation with flow cytometry. The expression features induced by ETV6-RARA were studied by whole transcriptomic RNA sequencing analysis. ETV6-RARA over-expression enhanced the differentiation of U937 and HL60 cells to ATRA administration. ATRA, but not ATO, decreased the in-vitro levels of ETV6-RARA protein. ETV6-RARA significantly reduced the proliferation rates of U937 cells as compared to the control. Apoptosis in U937 ETV6-RARA+ cells was induced with combined ATRA and ATO administration. Differential gene expression analysis showed significant up-regulation of RARA in U937 ETV6-RARA+ cells, and gene set enrichment analysis revealed similarity between cells with ETV6::RARA and patients with PML::RARA based on their total RNA expression profiles. Furthermore, the expression profiles of U937 ETV6-RARA+ cells presented the activated enrichment of HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION, and inhibited enrichment of HALLMARK_E2F_TARGETS pathways compared to the control cells. ETV6::RARA is an ATRA/ATO sensitive fusion gene.

Chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved overall survival (OS) in relapsed or refractory large B-cell lymphomas (R/R LBCL). However, factors associated with outcomes of CAR-T cell therapy in patients with R/R LBCL have not been fully elucidated. And limited evidence supports the use of early endpoints to evaluate the efficacy and long-term survival. Progression-free survival (PFS) at 6 months (PFS6) was defined as being alive and free of relapse or progression within 6 months of CAR-T cell infusion. We aimed to assessed OS stratified by PFS6 by analyzing data from 71 R/R LBCL patients treated with CAR-T therapy across 2 hospitals. Subsequent OS was defined from the time of PFS6 or progression within 6 months to death. Among them, 58% reached PFS6. Compared with patients failed to achieve PFS6, 1-year OS was 91.3% vs. 40.2% and 2-year OS was 91.3% vs. 32.1%, respectively. Patients achieving PFS6 had excellent outcome, whereas patients exhibiting earlier progression had a poor survival. Key predictors of PFS failure included older age (> 60) (P = 0.040, OR:3.40, 95%CI:1.06–10.93), lower pretransfusion hemoglobin level (P = 0.019 OR:0.27, 95%CI:0.09–0.81), and higher IFN-ʏ level (P = 0.022, OR:2.00, 95% CI:1.66–4.08). This insight could aid in risk stratification and support the use of PFS6 as a surrogate endpoint in clinical trials.

Until the early 2020s, standard mantle cell lymphoma (MCL) treatment in Germany primarily included chemoimmunotherapy, autologous stem cell transplantation (autoSCT) for eligible patients in first line, and covalent Bruton tyrosine kinase inhibitors (cBTKis; ibrutinib at the time) for relapsed/refractory disease. However, real-world data on MCL treatment patterns and outcomes in Germany remain scarce. This retrospective observational study analyzed administrative claims data between 2015 and 2020. Annual incidence and prevalence, treatment patterns, healthcare visits, and overall survival (OS) were evaluated. Extrapolated to the German statutory health insurance population, annual MCL prevalence and incidence rates (per 100,000 individuals) ranged from 6.64 to 10.02 and from 1.28 to 2.06, respectively, showing an upward trend. Among 369 patients with MCL in the database (2015–2020) receiving at least one anti-cancer treatment, median age at diagnosis was 71 years and average Charlson Comorbidity Index was 2.9. In first-line, patients mainly received chemoimmunotherapy (77.2%; n = 285); 13.8% (n = 51) underwent autoSCT, and 30.9% (n = 114) received rituximab maintenance; in second-line (n = 193), 45.6% received chemoimmunotherapy and 22.3% a cBTKi. Median OS from diagnosis was 6.3 years. In cBTKi-treated patients (n = 82), median OS from first cBTKi therapy initiation (> 75% of the patients received cBTKi in second or third line) was 11.2 months, decreasing to 3.0 months from cBTKi discontinuation (n = 45). This study presents the first comprehensive analysis of MCL epidemiology, treatment patterns, and survival outcomes in Germany using claims data. Findings indicate rising MCL incidence and prevalence, a high treatment burden and poor survival outcomes, underscoring the need for treatment advancements.

Background

Molecular profiling has transformed risk stratification in myelodysplastic neoplasms (MDS). However, the independent prognostic value of specific genomic alterations beyond comprehensive molecular scoring remains unclear. We investigated whether CUX1 copy-number loss (haploinsufficiency) adds prognostic value and its association with other mutations. Given its correlation with chromosome 7 abnormality, we examined its independent significance within the current MDS molecular framework.

Methods

A cohort of 501 MDS patients with available CUX1 copy-number data (CNACS gene-level calls) and complete clinical follow-up was analyzed from cBioPortal. We assessed associations with clinical characteristics, co-occurring alterations, and survival. Cox proportional hazards models evaluated independence adjusting for IPSS-R and IPSS-M.

Results

CUX1 loss occurred in 129/501 patients (26%), nearly always with − 7/del(7q) (98%). Patients with CUX1 loss had higher marrow blasts (median 7% vs. 4%, P < 0.001), IPSS-R scores (6.9 vs. 4.6), and IPSS-M scores (2.33 vs. 0.79). CUX1 loss strongly associated with EZH2 alterations (OR 223.8) and complex karyotype (60%). In univariable analysis, CUX1 loss predicted inferior overall survival (OS; median 11.8 vs. 27.1 months; HR 2.39, 95%CI 1.85–3.08, P < 0.001) and leukemia-free survival (LFS; HR 2.30, 95%CI 1.78–2.98, P < 0.001). After IPSS-M adjustment, associations were non-significant (OS HR 1.27, P = 0.11; LFS HR 1.23, P = 0.15) with negligible incremental discrimination. Within the − 7/del(7q) subgroup, no survival difference was detected (OS P = 0.41; LFS P = 0.31).

Conclusion

CUX1 loss identifies high-risk MDS with − 7/del(7q) and EZH2 co-alterations but provides no independent prognostic information beyond IPSS-M. Isolated CUX1 deletions are rare. CUX1 loss reflects − 7/del(7q) biology rather than independent prognostic significance.

This study analyzed the correlation among serum cystatin C (CysC) levels, hypermethotrexemia, and kidney damage following high-dose methotrexate (HD-MTX) chemotherapy in children with acute lymphoblastic leukemia (ALL) to aid early prediction, diagnosis, and treatment. Clinical data from 103 children diagnosed with ALL were collected, totaling 412 HD-MTX chemotherapy sessions. The association between 20-h serum CysC levels, 44-h MTX blood concentrations, and 44-h serum creatinine levels was analyzed. Forty-four patients in the low-risk group received 3 g/m² of HD-MTX, while 59 patients in the intermediate-risk group received 5 g/m² of HD-MTX. Some patients experienced a 20% dose reduction due to high 44-h MTX concentrations in previous cycles; however, no dose increases were observed. In the high MTX concentration group, 31.4% (27/86) of patients had elevated 20-h serum CysC levels, significantly higher than the 2.8% (9/324) in the low-concentration group (P < 0.001). However, baseline serum CysC levels did not differ significantly (P = 0.377). Among the 36 cycles with elevated 20-h serum CysC levels, 19.4% (7/36) of patients progressed to elevated serum creatinine levels at 44 h. In contrast, only one patient in the normal serum CysC group showed such progression (P < 0.001). Furthermore, the 20-h serum CysC levels positively correlated with 44-h MTX concentrations and serum creatinine levels. Our findings indicate that 20-h serum CysC levels can predict hyperammonemia and kidney injury.