Annals of Hematology最新文献

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.

Talquetamab, a CD3/GPRC5D T-cell engager approved for triple class exposed myeloma patients, inducing deep and durable responses. Very few cases of relapsed/refractory (R/R) light chain (AL) amyloidosis patients treated with talquetamab, were reported to date. We report six heavily pretreated R/R AL amyloidosis patients with severe end-organ damage (five with cardiac involvement), treated with talquetamab. Talquetamab induced rapid and deep responses: Five patients achieved complete response. (including MRD negativity in all three evaluable patients). At data cut-off, three patients were alive and relapse-free at 8, 15 and 24 months, and three patients died, after 1, 1.5 and 5 months since initiation of treatment. Five patients were not evaluable for organ response: (Three due to end-organ kidney disease, and two who died before organ response assessment). One patient achieved cardiac response. Two patients were referred to kidney transplantation after achieving CR. Cytokine release syndrome occurred in four patients, all grade 1–2, and immune effector cell associated neurotoxicity syndrome (ICANS) was reported in one patient (grade 2). Infections occurred in two patients (one grade 3, one grade 5). Congestive heart failure exacerbation occurred in two patients (grades 3 and 4). Our results support talquetamab as an effective therapy for RRAL patients, although larger-scale studies are needed to optimize earlier timing and patient selection.

Historically, severe heart failure has been considered a contraindication for hematopoietic stem cell transplant (HSCT). Despite the growing use of the left ventricular assist device (LVAD), clinicians have avoided HSCT in patients with hematologic malignancies and an LVAD due to a multitude of potential complicating factors, including the use of cardiotoxic conditioning regimens and severe post-transplant thrombocytopenia requiring anticoagulation interruption. Currently, there are no published reports of a successful allogeneic HSCT in a patient with an LVAD. The case herein documents a 36-year-old man with acute myeloid leukemia (AML) and post-induction systolic heart failure necessitating LVAD (HeartMate 3) placement, who later successfully underwent allogeneic HSCT and is now in remission. We highlight preparative regimen considerations, the need to account for the effects of irradiation on the LVAD and external controller, and the importance of a multidisciplinary care team to demonstrate that the presence of an LVAD does not necessarily preclude patients with AML from potentially curative HSCT, particularly when managed with careful coordination and individualized risk-adapted strategies.

A 62-year-old female was referred to our hospital because of left pleural effusion. She had a history of primary large B-cell lymphoma (LBCL) of the CNS (PCNSL), which was treated with chemoradiotherapy 14 years ago. Imaging studies revealed no other lesions. Pathologically, large atypical lymphoid cells were present in the pleural fluid and positive for CD20 and CD79a, while EBV and HHV-8 were negative. She was diagnosed with HHV8-negative effusion-based lymphoma (EBL) and achieved complete response after two cycles of rituximab monotherapy. We performed targeted-capture sequencing of lymphoma-associated genes using tumor samples from EBL and PCNSL, and detected the identical mutations in eight genes including MYD88 and CD79B. Identical arm-level copy number changes and focal deletions involving HLA-B, HLA-C, and CDKN2A, were also observed, suggesting clonal association between EBL and PCNSL. On the other hand, there were several lymphoma subtype-specific alterations, such as CARD11 and KMT2D mutations in PCNSL as well as PIM1 and PRDM1 mutations in EBL. LBCLs involving specific extranodal sites, such as CNS, testis, and adrenal gland, tend to recur in CNS, and harbors characteristic driver alterations, such as mutations in MYD88 and CD79B, similar to the MCD subtype of diffuse large B-cell lymphoma. Our genetic analysis suggests that in this case (i) PCNSL recurred as EBL or (ii) EBL developed from a common founder clone with PCNSL after long-term remission, providing insights into genetic basis underlying extranodal LBCL with CNS tropism.

Cell division cycle 20 homologue (CDC20), a key regulator of mitosis, is frequently overexpressed in cancers and linked to tumor progression. However, its role in mantle cell lymphoma (MCL) remains unclear. This study explored the functional significance of CDC20 in MCL and its underlying mechanisms. CDC20 expression was analyzed in peripheral blood mononuclear cells (PBMCs), bone marrow mononuclear cells (BMNCs), clinical samples, and MCL cell lines (Z138, Mino, Rec1), followed by correlation with clinicopathological features. MCL cells were treated with the CDC20 inhibitor apcin or transduced with CDC20-knockdown lentivirus, and effects on proliferation, apoptosis, cell cycle, migration, and invasion were assessed. The anti-tumor effect of apcin was tested in the Z138-driven xenograft mouse model. RNA-seq was performed to identify signaling pathways altered upon CDC20 inhibition, and western blot (WB) analysis confirmed the dysregulation of key pathway components. Consequently, CDC20 was significantly upregulated in PBMCs, BMNCs, tumor tissues, and MCL cell lines compared to their respective controls. Apcin or CDC20 knockdown suppressed proliferation, migration, and invasion while inducing apoptosis and G2/M arrest in MCL cells. In vivo, apcin effectively and safely inhibited tumor growth. RNA-seq revealed differential genes were enriched in the PI3K/AKT signaling pathway. WB validated reduced PI3K/AKT phosphorylation levels after CDC20 inhibition, suggesting CDC20 promoted the malignant phenotype of MCL via PI3K/AKT signaling. Therefore, CDC20 plays a critical role in MCL pathogenesis. Targeting CDC20 and the PI3K/AKT pathway may offer a promising therapeutic strategy for MCL.