Annals of Hematology最新文献

Ten-eleven translocation-2 (TET2) gene mutations are observed in 12–20% of adult patients with acute myeloid leukemia (AML). The prognostic impact of TET2 mutations in patients with AML and myelodysplastic syndromes has been reported in several studies; however, their results remain controversial. Therefore, we aimed to analyze the prevalence and significance of TET2 mutations in patients with AML. Data were obtained from 331 patients with AML according to the Hematologic Malignancies-SCREEN-Japan 01 and 02 studies, which were prospective multicenter genomic profiling analyses. We found a distinct type of TET2 mutations, with a particularly detrimental prognosis in the patients. Thirty-five patients with TET2 ‘significant’ mutations were identified (26 with frameshift mutations and nine with nonsense mutations). The proportion of patients with TET2 mutations was 31.7% (10.6% and 21.1% in the TET2 significant and non-significant mutation groups). The TET2 significant mutation group had a shorter OS than the TET2 non-significant mutation or wild-type TET2 group (median: 15.9 vs. 35.0 vs. 25.9 months). Regarding the response to chemotherapy according to TET2 status, the complete response (CR) or CR with incomplete count recovery rate was 37.1% in the TET2 significant mutation group and 46.6% in the non-significant mutation or wild-type group. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) improved patient prognosis in the TET2 non-significant mutation or wild-type TET2 group; however, allo-HSCT did not affect prognosis in the TET2 significant mutation group. This study indicates that certain TET2 mutations in patients with AML may have detrimental effects. 

The colony-stimulating factor 3 receptor (CSF3R) plays an essential role in differentiation, growth, and survival of granulocytes. Driver mutations in CSF3R gene represent a diagnostic marker of chronic neutrophilic leukemia (CNL). Less commonly, these mutations are observed in other myeloid neoplasms but their pathogenetic and prognostic role is still unclear. Here, we analyzed a large cohort of myeloid neoplasms to evaluate the incidence of CSF3R mutations and co-mutational profile. Mutational analysis was performed using targeted NGS myeloid panel in a consecutive cohort of 360 patients with myeloid neoplasms. Mutations in CSF3R were identified in 20/360 (5.6%) cases. A CSF3R gene mutation was present in 13/179 AML cases (7.3%), in 2/27 (7.4%) CMML cases, in 1/94 (1.1%) MDS cases and in 4/60 (6.7%) other myeloid neoplasms. The frequencies of patients with CSF3R mutations lowered to 2.8% in all cases and 3.4% in AML, excluding cases with variants of uncertain significance (VUS). A total of 23 mutations of CSF3R gene were detected, half localized in the extracellular domain, 5 in the transmembrane region (type I) and 6 mutations in the cytoplasmic domain (type II). In AML, CSF3R mutations were more frequent in patients harboring CBF alterations (25.0%) and CEBPA mutations (11.8%). Two cases with AML harboring pathogenic CSF3R variants were primary refractory to induction therapy. CMML cases with T618I variant showed a myeloproliferative phenotype. Overall, our findings support the notion that CSF3R variants, particularly type I and II pathogenic mutations, may modulate the phenotypic features of leukemic cells in myeloid neoplasia.

Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist analog with the potential risk to induce liver injury. This prospective registry study evaluated the prevalence and severity of hepatic injury in Chinese patients with severe aplastic anemia undergoing low-dose EPAG treatment (75 mg/day) in the context of standard immunosuppressive therapy (IST). The incidence of acute drug-induced liver injury was slightly higher in the IST + EPAG group than in the IST group at the 1st and 2nd month, but no statistically significant difference was observed: 10% vs 5% (p = 0.400), 9% vs 8% (p = 1.000). At the 1st month, the incidences of alanine aminotransferase, aspartate aminotransferase, and total bilirubin increased of grade 3 or higher in the IST + EPAG and the IST groups, were 5% vs 3% (p = 0.228), 2% vs 1% (p = 1.000), 2% vs 1% (p = 1.000), respectively. The logistic analysis indicated that serum ferritin level was associated with severe liver injury events. There was a slight increase in the incidence of severe hepatic injury events in the patients with SAA treated by EPAG, but it was insignificant.

The prefibrotic phase of primary myelofibrosis (pre-PMF) represents a distinct subentity within the spectrum of myeloproliferative neoplasms (MPNs), recognized by the World Health Organization (WHO) and the International Consensus Classification (ICC). Pre-PMF is characterized by unique morphological, clinical, and molecular features, distinguishing it from essential thrombocythemia (ET) and overt myelofibrosis (overt-PMF). The diagnostic process for pre-PMF relies on bone marrow histology, identification of molecular mutations and exclusion of other myeloid neoplasms. Misclassification remains a significant challenge due to overlapping phenotypes and the heterogeneity of clinical presentations, which range from asymptomatic cases to severe cytopenias and a high thrombotic risk. Management strategies for pre-PMF focus on mitigating symptom burden, reducing thromboembolic events, and preventing disease progression. Low-risk patients often benefit from observational approaches or low-dose aspirin, while cytoreductive therapies, such as hydroxyurea or interferon-alpha, are utilized in symptomatic or high-risk cases. JAK inhibitors like ruxolitinib have shown promise in addressing splenomegaly and systemic symptoms, although their role in pre-PMF requires further investigation. Advances in artificial intelligence are enhancing diagnostic precision by refining bone marrow histopathological analysis, paving the way for more accurate disease classification and tailored therapeutic strategies. This position paper integrates insights from a German expert panel discussion, underscoring the need for interdisciplinary collaboration, adherence to updated WHO/ICC diagnostic criteria, and personalized treatment approaches. By addressing diagnostic challenges and therapeutic nuances, it seeks to improve outcomes and quality of life for patients navigating the complexities of pre-PMF.