American Journal of Hematology最新文献

Lymphoma is one of the leading causes of cancer and cancer deaths and yet has not been amenable to population screening. The role of methylated DNA markers (MDMs) in the detection of lymphoma has not been extensively studied. We aimed to discover, validate, and test tissue-derived MDMs of lymphoma in archival plasma specimens. Reduced representation bisulfite sequencing (RRBS) was performed on a discovery set of frozen tissues. MDMs identified were converted to methylation-specific PCR assays and validated on independent formalin-fixed, paraffin-embedded (FFPE) tissues. Target enrichment long-probe quantitative-amplified signal (TELQAS) assays were developed and assayed in plasma-extracted, bisulfite-converted DNA from independent treatment-naïve lymphoma patients and healthy controls. Prediction of cancer status was modeled using random forest model with in silico cross-validation. After discovery and validation in tissue, 16 TELQAS assays (ZNF503, VWA5B1, HOXA9, GABRG3, ITGA5, MAX.chr17.7190, BNC1, CDK20, MAX.chr4.4069, TPBG, DNAH14, SYT6, CACNG8, FAM110B, ADRA1D, and NRN1) were selected for testing in plasma. These detected 78% (95% CI, 74%-82%) of lymphoma cases at 90% specificity. Excluding marginal zone and T-cell lymphomas, sensitivity increased to 84% (80%-88%). MDMs in plasma show promise to detect lymphoma and are candidates for inclusion in multi-cancer detection studies.

Sickle cell disease (SCD) is complicated by silent cerebral infarcts (SCIs), for which anemia is an important risk factor. Despite normal oxygen delivery (OD), cerebral vascular reserve (CVR), and cerebral metabolic rate of oxygen (CMRO₂) are diminished in SCD, possibly causing the formation of SCIs. Voxelotor inhibits polymerization by increasing the hemoglobin oxygen binding, ameliorating hemolytic anemia. Furthermore, anemia is related to cardiac complications. Our aims were to assess the effect of voxelotor on markers of cerebral perfusion, cerebral oxygen metabolism, and markers of cardiac stress in SCD patients. Cerebral hemodynamics and oxygen metabolism were measured with MRI before and after 3 months of voxelotor treatment (1500 mg/day) in 18 adults with SCD (HbSS/HbSβ⁰-thalassemia). Hemoglobin levels significantly increased (p = .001) and markers of hemolysis decreased (p < .05). OD increased from 6.5 (IQR, 6.0-7.1) mL O₂/100 g/min to 8.1 (IQR, 7.2-8.7) mL O₂/100 g/min (p = .001). CBF and CVR did not change. CMRO₂ decreased from 2.0 (IQR, 1.9-2.1) mL O₂/100 g/min to 1.9 (IQR, 1.6-2.1) mL O₂/100 g/min (p = .03). N-terminal pro-B type natriuretic peptide (NT-proBNP) levels decreased (p = .048) and maximum tricuspid regurgitation flow velocity (TRV_max) normalized in all but one patient with increased TRV_max. Voxelotor treatment in patients with severe SCD did not decrease CBF despite increased Hb levels. Cerebral oxygen metabolism slightly decreased, despite raised OD, most likely due to drug-induced increase in oxygen binding. Nonetheless, voxelotor improved clinically validated markers of cardiac stress.

We retrospectively evaluated the impacts of using granulocyte colony-stimulating factor (G-CSF) and its timing on posttransplant outcomes for 9766 adults with acute myeloid leukemia (AML) between 2013 and 2022 using a Japanese database. We separately evaluated three distinct cohorts based on graft type: 3248 received bone marrow transplantation (BMT), 3066 received peripheral blood stem cell transplantation (PBSCT), and 3452 received single-unit cord blood transplantation (CBT). Multivariate analysis showed that G-CSF administration significantly accelerated neutrophil recovery after BMT, PBSCT, and CBT. However, it was associated with a higher risk of grades II-IV acute graft-versus-host disease (GVHD) across all graft types. Moreover, an increased incidence of overall chronic GVHD was observed with G-CSF administration in BMT and CBT patients, but not in PBSCT patients. G-CSF administration significantly improved overall survival (OS) and leukemia-free survival (LFS) only following CBT. Regarding the timing of G-CSF, in comparison with late initiation of G-CSF (Days 5-10), early initiation (Days 0-4) did not provide benefits for hematopoietic recovery regardless of graft type. In contrast, late initiation was significantly associated with a lower risk of grades II-IV acute GVHD and better OS and LFS in CBT patients. These data demonstrated that G-CSF administration accelerated neutrophil recovery and increased the risk of grades II-IV acute GVHD across all graft types, but significantly improved survival outcomes but only following CBT. Therefore, routine use of G-CSF should be considered for CBT in adult patients with AML.

Fanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in FANCD2 (mainly hypomorphic mutations) than for patients with biallelic mutations in FANCA and FANCG, with the lack of the mutant protein in patients with biallelic mutations in FANCG contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA. Clinical Trial Registration number: NCT06490510.

PIEZO1 encodes a mechanoreceptor, a cation channel activated by mechanical stimuli. Gain-of-function (GoF) variants in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS), or xerocytosis, a pleiotropic syndrome characterized by anemia and iron overload. DHS patients develop hepatic iron overload independent of the degree of anemia and transfusion regimen. PIEZO1-GoF variants suppress hepcidin expression in both hepatic cellular model and constitutive/macrophage-specific Piezo1-GoF mice model. Therefore, PIEZO1-GoF variants regulate hepcidin expression by a crosstalk between hepatocytes (HCs) and macrophages with a still unknown mechanism. Transcriptomic and proteomics analysis in the human hepatic Hep3B cells engineered for the PIEZO1-R2456H variant (PIEZO1-KI) revealed alterations in the actin cytoskeleton regulation, MAPK cascade, and RAS signaling. These changes mainly occur through a novel key regulator, RRAS, whose protein and mRNA levels are regulated by PIEZO1 activation and inhibition. This regulation was further confirmed in C57BL/6 mouse primary HCs treated with Yoda-1 and/or GsMTx-4. Indeed, PIEZO1-KI cells exhibited hyper-activated RAS-GTPase activity that is rescued by PIEZO1 inhibition, restoring expression of the hepcidin gene HAMP. A negative correlation between RAS signaling and HAMP regulation was confirmed by inhibiting RAS-GTPase and MEK1-2 activity. Conversely, rescued HAMP gene expression requires downregulation of RRAS, confirming negative feedback between RAS-MAPK and BMP/SMADs pathways in HAMP regulation. We demonstrated that PIEZO1-GoF variants influence the actin cytoskeleton organization by activating the hepatic RAS signaling system. Understanding the role of RAS signaling in regulating iron metabolism could pave the way for new therapeutic strategies in DHS and other conditions characterized by iron overload.

Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) represents a rare entity that has been categorized as a disease-defining recurring cytogenetic abnormality with adverse risk in the 2022 European LeukemiaNet classification. This rating was mainly based on a retrospective analysis comprising patients from several large clinical trials, which, however, included only 21 patients treated with allogeneic stem cell transplantation (alloSCT). Therefore, the European Society for Blood and Marrow Transplantation performed a registry study on a larger cohort to evaluate the role of alloSCT in t(8;16) AML. Sixty transplant recipients with t(8;16) AML were identified. Two-year overall and leukemia-free survival (OS/LFS) was 43/39%. Patients transplanted in first complete remission (CR1, n = 44) achieved a 2-year OS/LFS of 48%/48%. Following alloSCT in CR1, the multivariable analysis identified a complex karyotype (CK) as a major risk factor for relapse (HR 4.17, p = .016), lower LFS (HR 3.38, p = .01), and lower OS (HR 3.08, p = .017). Two-year OS/LFS of patients with CK was 19%/19%, in contrast to 67%/67% in patients with t(8;16) outside a CK. Other factors for inferior outcomes were older age and secondary AML. In summary, alloSCT could mitigate the adverse risk of patients with t(8;16) AML not harboring a CK, particularly when performed in CR1.

According to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate-dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini-consolidations (idarubicin 8 mg/m² day 1, cytarabine 50 mg/m²/12 h, day 1-5) and IDAC. Inclusion criteria were newly diagnosed AML, age > 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini-consolidations and 474 patients received IDAC. Mini-consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini-consolidation group (4 vs. 2; p < .0001). Median relapse-free survival was 18 months with mini-consolidations and 12 months with IDAC (p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (p = .004). Median OS was 36 versus 31 months with mini-consolidations or IDAC, respectively (p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (p = .43). In older AML patients, post-remission therapy with mini-consolidations represents an alternative to IDAC.