Haematologica最新文献

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due, at least in part, to drug resistance of leukemia stem cells (LSC). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors can eradicate bpCML LSC. In this study, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with combinations of venetoclax/tyrosine kinase inhibitors. Transcriptional analysis of LSC exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to treatment with venetoclax/dasatinib. Pretreatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells to venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment did not affect normal stem cell function, suggesting a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is a LSC-selective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances the response to venetoclax/ dasatinib when targeting LSC, providing a rationale for exploring lysosomal disruption as an adjunctive therapeutic strategy to prolong disease remission.

Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/low-dose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to 5 years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (N=83) or non-HCT (N=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95% confidence interval [CI]: 18.9-30.1) in the HCT and 15.6 months (95% CI: 10.4-20.8) in the non-HCT arm (P=0.022) due to a decrease in cumulative relapse incidence from 91.1% (95% CI: 80.7-100.0) after non-HCT to 37.8% (95% CI: 27.2-48.4) after HCT (P<0.0001). The secondary endpoints RM-OS up to 5 years was 27.8 months (95% CI:22.3-33.2) in the HCT as compared to 28.6 months (95% CI: 22.2-35.0) in the non-HCT arm; non-relapse mortality at 5 years was 33.4% (95% CI: 23.0-43.9) with HCT and 0% without. In older patients with AML in CR1 5-year RM-LFS is better with HCT than with non-HCT consolidation treatment. The long-term RM-LFS benefit did not translate into a better RM-OS during the study period.

T-cell large granular lymphocyte clones that persist over time and that exhibit molecular and immunophenotypic features closely resembling those of T-cell large granular lymphocyte leukemia (T-LGLL) may be detectable in individuals who lack any clinical or laboratory features supporting a diagnosis of a T-cell malignancy. This condition represents a potential precursor state termed T-cell clones of uncertain significance (T-CUS). T-CUS represents the even more benign extreme of the wide spectrum of clonal T-large granular lymphocyte proliferations, emphasizing the need for an appropriate multiparametric diagnostic assessment that avoids misdiagnosis of T-cell neoplasia. This approach should overcome numerical cut-offs as the sole criteria to differentiate the benign condition from the related malignancies. In particular, genomic aberrancies might prospectively identify individuals who are at risk of progression to a full-blown T-cell malignancy. We herein discuss the significance of these T-cell clones in both healthy and disease states, suggesting molecular assays for tracking early steps of disease.

In diffuse large B-cell lymphoma (DLBCL) treatment response relies on imaging. We investigated the potential value of molecular measurable residual disease (MRD) on circulating tumor DNA (ctDNA) to predict patient outcomes. We retrospectively evaluated 73 patients. Analyses were conducted on 57 tumor biopsies, based on sample availability. At baseline, next-generation sequencing was used to detect clonal immunoglobulin (IG) gene rearrangements on tumor biopsies and ctDNA. MRD monitoring was applied by tracking the IG clones in ctDNA samples collected during treatment (interim) and at the end of treatment (EOT). MRD results were correlated with clinical data and radiologic disease assessment. Before treatment, clonal IG were found in 91.2% (52/57) of tumor biopsies and in 93.2% (68/73) of ctDNA samples. In paired samples, the same clonotype was found in 69.2% (36/52) of cases. At the interim analysis, ctDNA MRD was negative in 32/45 evaluable patients and positive in 13/45, correlating significantly with progression-free survival (PFS) (78.1% MRD- vs 30.8% MRD+; p.

Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non- Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat NHL and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.