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Expert Opinion on Emerging Drugs Dec 2020: Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder with heterogenous prognosis, but with no curative therapies with exception of allogeneic... (Review)
Review
: Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder with heterogenous prognosis, but with no curative therapies with exception of allogeneic transplant. Therapeutic options for patients with CMML are limited, and although hypomethylating agents such as azacitidine and decitabine are the standard of care, only 40% of patients achieve a response, and most responses are transient. Over the last 5 years, significant advances have been made in the understanding of the clonal landscape of CMML, some of the mechanisms associated to resistance to HMA, and other key biological processes involved in disease pathogenesis. : The current article reviews the most relevant emerging therapies currently undergoing clinical trials for the treatment of previously untreated or relapsed CMML. : The presence of recurrent somatic mutations in CMML represents therapeutic opportunities to utilize specific small molecule inhibitors such as IDH, FLT3, MEK/ERK, PLK1, or splicing inhibitors and modulators. In addition, other novel agents such as immune therapies, BCL2 or MCL1 inhibitors and other monoclonal antibodies could lead to therapeutic advances. Identifying specific patient populations likely to benefit from some of these interventions, and development of optimal combinations will remain the challenge when determining their role in therapy.
Topics: Animals; Antineoplastic Agents; Drug Design; Drug Resistance, Neoplasm; Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Prognosis
PubMed: 33280448
DOI: 10.1080/14728214.2020.1854224 -
Best Practice & Research. Clinical... Jun 2020Chronic myelomonocytic leukemia (CMML) is defined by myelodysplasia, pathologic accumulation of monocytes and a substantial risk to transform to secondary acute myeloid... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is defined by myelodysplasia, pathologic accumulation of monocytes and a substantial risk to transform to secondary acute myeloid leukemia (sAML). In recent years, minimal diagnostic criteria for classical CMML and CMML-variants were proposed. Moreover, potential pre-stages of CMML and interface conditions have been postulated. Oligomonocytic CMML is a condition where the absolute peripheral blood monocyte count does not reach a diagnostic level but all other criteria for CMML are fulfilled. Among potential pre-stages of CMML, clonal and non-clonal conditions have been described, including idiopathic monocytosis (IMUS) and clonal monocytosis of unknown significance (CMUS). Patients with myelodysplastic syndromes (MDS), clonal cytopenia of unknown significance (CCUS), clonal hematopoiesis of indeterminate potential (CHIP) and idiopathic cytopenia of undetermined significance (ICUS) may also progress to CMML. The current article provides an overview of pre-CMML conditions and oligomonocytic CMML, with special reference to diagnostic criteria, differential diagnoses, clinical outcomes and management.
Topics: Clonal Hematopoiesis; Diagnosis, Differential; Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Myelodysplastic Syndromes; Prognosis
PubMed: 32460976
DOI: 10.1016/j.beha.2019.101137 -
Blood Mar 2023Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem...
Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem cells (HSCs). Hypomethylating agents (HMAs) can modify the clinical course of MDS and CMML. Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated HSCs. However, in patients with established disease it is unclear whether (1) HSCs with multiple mutations progress through differentiation with comparable frequency to their less mutated counterparts or (2) improvements in peripheral blood counts following HMA therapy are driven by residual wild-type HSCs or by clones with particular combinations of mutations. To address these questions, the somatic mutations of individual stem cells, progenitors (common myeloid progenitors, granulocyte monocyte progenitors, and megakaryocyte erythroid progenitors), and matched circulating hematopoietic cells (monocytes, neutrophils, and naïve B cells) in MDS and CMML were characterized via high-throughput single-cell genotyping, followed by bulk analysis in immature and mature cells before and after AZA treatment. The mutational burden was similar throughout differentiation, with even the most mutated stem and progenitor clones maintaining their capacity to differentiate to mature cell types in vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Hematopoietic Stem Cells; Monocytes; Clone Cells
PubMed: 36493342
DOI: 10.1182/blood.2022018602 -
British Journal of Haematology Mar 2023In this article, we describe three broad pathologic presentations of plasmacytoid dendritic cells (pDCs) that may be encountered in clinical practice, in which an... (Review)
Review
In this article, we describe three broad pathologic presentations of plasmacytoid dendritic cells (pDCs) that may be encountered in clinical practice, in which an association between pDCs and myeloid neoplasms is identified: (1) myeloid neoplasms with mature pDC expansion, most commonly seen in chronic myelomonocytic leukaemia (CMML); (2) myeloid neoplasms with pDC differentiation, in which pDCs show a spectrum of maturation from early immature pDCs to mature forms, most commonly seen in acute myeloid leukaemia (AML); (3) myeloid neoplasms associated with blastic plasmacytoid dendritic cell neoplasm (BPDCN), either stemming from the same precursor or representing an independent clonal process. Additionally, we also discuss AML with pDC-like phenotype, in which myeloblasts show immunophenotypic features that may mimic those seen in pDCs. Using these presentations, we provide a diagnostic algorithm for appropriate pathologic classification, while attempting to clarify and homogenize nomenclatures pertaining to different biologic states of pDCs.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Phenotype; Cell Differentiation; Myeloproliferative Disorders; Dendritic Cells
PubMed: 36606610
DOI: 10.1111/bjh.18632 -
American Journal of Medical Genetics.... Oct 2021Noonan syndrome (NS) is one of the common RASopathies. While the clinical phenotype in NS is variable, it is typically characterized by distinctive craniofacial...
Noonan syndrome (NS) is one of the common RASopathies. While the clinical phenotype in NS is variable, it is typically characterized by distinctive craniofacial features, cardiac defects, reduced growth, bleeding disorders, learning issues, and an increased risk of cancer. Several different genes cause NS, all of which are involved in the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. Juvenile xanthogranuloma (JXG) is an uncommon, proliferative, self-limited cutaneous disorder that affects young individuals and may be overlooked or misdiagnosed due to its transient nature. A RASopathy that is known to be associated with JXG is neurofibromatosis type 1 (NF1). JXG in NF1 has also been reported in association with a juvenile myelomonocytic leukemia (JMML). As RASopathies, both NS and NF1 have an increased incidence of JMML. We report a 10-month-old female with NS who has a PTPN11 pathogenic variant resulting in a heterozygous SHP2 p.Y62D missense mutation. She was found to have numerous, small, yellow-pink smooth papules that were histopathologically confirmed to be JXG. In understanding the common underlying pathogenetic dysregulation of the Ras/MAPK pathway in both NS and NF1, this report suggests a possible molecular association for why NS individuals may be predisposed to JXG.
Topics: Female; Genetic Predisposition to Disease; Humans; Infant; Leukemia, Myelomonocytic, Juvenile; Mutation, Missense; Neurofibromin 1; Noonan Syndrome; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Xanthogranuloma, Juvenile; ras Proteins
PubMed: 34032360
DOI: 10.1002/ajmg.a.62353 -
Current Hematologic Malignancy Reports Jun 2021For decades, the management of chronic myelomonocytic leukemia (CMML) or juvenile myelomonocytic leukemia (JMML) has been largely inextricable from myelodysplastic... (Review)
Review
PURPOSE OF REVIEW
For decades, the management of chronic myelomonocytic leukemia (CMML) or juvenile myelomonocytic leukemia (JMML) has been largely inextricable from myelodysplastic syndromes (MDS), myeloproliferative neoplasms, and acute myeloid leukemia. Hallmarks of these diseases have been the emergence of unique genomic signatures and discouraging responses to available therapies. Here, we will critically examine the current options for management and review the rapidly developing opportunities based on advances in CMML and JMML disease biology.
RECENT FINDINGS
Few clinical trials have exclusively been done in CMML, and in JMML, the rarity of the disease limits wide scale participation. Recent case series in JMML suggest that hypomethylating agents (HMAs) are a viable option for bridging to curative intent with allogeneic hematopoietic stem cell transplant or as posttransplant maintenance. Emerging evidence has demonstrated targeting the RAS-pathway via MEK inhibition may also be considered. In CMML, treatment with HMAs is largely derived from data inclusive of MDS patients, including a small number of patients with dysplastic CMML variants. Based on CMML disease biology, additional therapeutic targets being investigated include inhibitors of splicing, CD123/dendritic cell axis, inherent GM-CSF progenitor cell hypersensitivity, and targeting the JAK/STAT pathway. Current evidence is also expanding for oral HMAs. The management of CMML and JMML is rapidly evolving and clinicians must be aware of the genetic landscape and expanding treatment options to ensure these rare populations are afforded therapeutic interventions best suited to their needs.
Topics: Age Factors; Biomarkers; Combined Modality Therapy; Disease Management; Disease Susceptibility; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Targeted Therapy
PubMed: 33728588
DOI: 10.1007/s11899-021-00622-8 -
Current Hematologic Malignancy Reports Jun 2020Knowledge of both somatic mutations and copy number aberrations are important for the understanding of cancer pathogenesis and management of myeloid neoplasms. The... (Review)
Review
PURPOSE OF REVIEW
Knowledge of both somatic mutations and copy number aberrations are important for the understanding of cancer pathogenesis and management of myeloid neoplasms. The currently available standard of care technologies for copy number assessment such as conventional karyotype and FISH are either limited by low resolution or restriction to targeted assessment.
RECENT FINDINGS
Chromosomal microarray (CMA) is effective in characterization of chromosomal and gene aberrations of diagnostic, prognostic, and therapeutic significance at a higher resolution than conventional karyotyping. These results are complementary to NGS mutation studies. Copy-neutral loss of heterozygosity (CN-LOH), which is prognostic in AML, is currently only identified by CMA. Yet, despite the widespread availability, CMA testing is not routinely performed in diagnostic laboratories due to lack of knowledge on best-testing practices for clinical work-up of myeloid neoplasms. In this review, we provide an overview of the clinical significance of CMA in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). We will also elaborate the specific clinical scenarios where CMA can provide additional information essential for management and could potentially alter treatment. Chromosomal microarray (CMA) is an effective technology for characterizing chromosomal copy number changes and copy-neutral loss of heterozygosity of diagnostic, prognostic, and therapeutic significance at a high resolution in myeloid malignancies.
Topics: Chromosome Aberrations; Chromosomes, Human; Comparative Genomic Hybridization; DNA Copy Number Variations; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Loss of Heterozygosity; Microarray Analysis; Myelodysplastic Syndromes; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Reproducibility of Results
PubMed: 32382988
DOI: 10.1007/s11899-020-00578-1 -
Biochemical Pharmacology Jul 2023Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a hematopoietic malignancy with poor response to cytotoxic...
Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a hematopoietic malignancy with poor response to cytotoxic chemotherapy. Novel therapeutic strategies are urgently needed for patients with JMML. Previously, we established a novel cell model of JMML with HCD-57, a murine erythroleukemia cell line that depends on EPO for survival. SHP2-D61Y or -E76K drove the survival and proliferation of HCD-57 in absence of EPO. In this study, we identified sunitinib as a potent compound to inhibit SHP2-mutant cells by screening a kinase inhibitor library with our model. We used cell viability assay, colony formation assay, flow cytometry, immunoblotting, and a xenograft model to evaluate the effect of sunitinib against SHP2-mutant leukemia cells in vitro and in vivo. The treatment of sunitinib selectively induced apoptosis and cell cycle arrest in mutant SHP2-transformed HCD-57, but not parental cells. It also inhibited cell viability and colony formation of primary JMML cells with mutant SHP2, but not bone marrow mononuclear cells from healthy donors. Immunoblotting showed that the treatment of sunitinib blocked the aberrantly activated signals of mutant SHP2 with deceased phosphorylation levels of SHP2, ERK, and AKT. Furthermore, sunitinib effectively reduced tumor burdens of immune-deficient mice engrafted with mutant-SHP2 transformed HCD-57. Our data demonstrated that sunitinib selectively inhibited SHP2-mutant leukemia cells, which could serve as an effective therapeutic strategy for SHP2-mutant JMML in the future.
Topics: Animals; Humans; Mice; Leukemia, Myelomonocytic, Juvenile; Sunitinib; Signal Transduction; Mutation; Antineoplastic Agents; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 37187274
DOI: 10.1016/j.bcp.2023.115588 -
Bulletin Du Cancer Nov 2023Systemic inflammatory or autoimmune diseases (SIAD) are observed in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia... (Review)
Review
Systemic inflammatory or autoimmune diseases (SIAD) are observed in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML), with a broad clinical spectrum including asymptomatic biological abnormalities, isolated inflammatory clinical manifestations (recurrent fever, arthralgia, neutrophilic dermatoses…) or identified systemic diseases (giant cell arteritis, recurrent polychondritis…). Recent advances in molecular biology have shed new light on the pathophysiological mechanisms that link inflammatory manifestations and myeloid hemopathies, particularly in VEXAS syndrome following the identification of somatic mutations in the UBA1 gene, or in neutrophilic dermatoses with the concept of myelodysplasia cutis. Although the presence of SIAD does not seem to affect overall survival or the risk of transformation into acute myeloid leukemia, their treatment remains a challenge given the frequent high level of corticosteroid dependence as well as the poor efficacy and tolerance (cytopenias, infections) of conventional immunosuppressive agents. Recent prospective data supports the interest of a therapeutic strategy using demethylating agents and notably azacitidine to target the pathological clone.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Azacitidine; Skin Diseases
PubMed: 37414632
DOI: 10.1016/j.bulcan.2023.02.023 -
Frontiers in Physiology 2023This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to... (Review)
Review
This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115 myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque. We further demonstrated that introducing ACE10 myelomonocytes (microglia and peripheral monocytes) into the double transgenic APP/PS1 murine model of AD (AD mice), diminished neuropathology and enhanced the cognitive functions. These beneficial effects were dependent on ACE catalytic activity and vanished when ACE was pharmacologically blocked. Moreover, we revealed that the therapeutic effects in AD mice can be achieved by enhancing ACE expression in bone marrow (BM)-derived CD115 monocytes alone, without targeting central nervous system (CNS) resident microglia. Following blood enrichment with CD115 ACE10-monocytes versus wild-type (WT) monocytes, AD mice had reduced cerebral vascular and parenchymal Aβ burden, limited microgliosis and astrogliosis, as well as improved synaptic and cognitive preservation. CD115 ACE10-versus WT-monocyte-derived macrophages (Mo/MΦ) were recruited in higher numbers to the brains of AD mice, homing to Aβ plaque lesions and exhibiting a highly Aβ-phagocytic and anti-inflammatory phenotype (reduced TNFα/iNOS and increased MMP-9/IGF-1). Moreover, BM-derived ACE10-Mo/MΦ cultures had enhanced capability to phagocytose Aβ fibrils, prion-rod-like, and soluble oligomeric forms that was associated with elongated cell morphology and expression of surface scavenger receptors (i.e., CD36, Scara-1). This review explores the emerging evidence behind the role of ACE in AD, the neuroprotective properties of monocytes overexpressing ACE and the therapeutic potential for exploiting this natural mechanism for ameliorating AD pathogenesis.
PubMed: 37427403
DOI: 10.3389/fphys.2023.1179315