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Blood Research Apr 2021Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoietic cells and is a complex of heterogeneous conditions with both myeloproliferative and... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoietic cells and is a complex of heterogeneous conditions with both myeloproliferative and myelodysplastic features. The diagnosis of CMML is made using morphologic criteria including monocyte-dominant leukocytosis, dysplastic changes, and increased blasts in the bone marrow. Recently, the identification of monocyte subtypes in peripheral blood using multiparameter flow cytometry has been actively studied. Chromosomal abnormalities are the basis of CMML risk stratification, and mutations in several genes including ASXL1 are known to be important not only for the diagnosis and treatment of this disease but also for predicting its prognosis. The standard treatment principles for CMML have not yet been clearly defined; however, hypomethylating agents are mainly considered the frontline therapy in most cases. Although allogeneic hematopoietic stem cell transplantation has limited applications owing to its toxicity, it still plays an important role as the only curative treatment option. Researchers are continuing to develop new drugs for CMML treatment and to prove their clinical usefulness. This review summarizes what is known to date on the diagnosis, treatment, and prognostic factors of CMML and presents future directions by analyzing recent research trends.
PubMed: 33935030
DOI: 10.5045/br.2021.2020321 -
International Journal of Laboratory... Apr 2020The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic... (Review)
Review
The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 10 /L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of "overlapping" myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing "dysplastic" features and others a predominant "proliferative" phenotype. Accounting for this diversity, two variants of CMML are recognized: "dysplastic" CMML defined by WBC < 13 × 10 /L and "proliferative" CMML with WBC ≥ 13 × 10 /L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the "oligomonocytic" variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5-0.9 × 10 /L. It can be considered a "pre-phase," as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new "CMML-0" category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Prognosis
PubMed: 31841277
DOI: 10.1111/ijlh.13145 -
Leukemia & Lymphoma May 2021In recent years CMML has received increased attention as the most commonly observed MDS/MPN overlap syndrome. Renewed interest has occurred in part due to widespread... (Review)
Review
In recent years CMML has received increased attention as the most commonly observed MDS/MPN overlap syndrome. Renewed interest has occurred in part due to widespread adoption of next-generation sequencing panels that help render the diagnosis in the absence of morphologic dysplasia. Although most CMML patients exhibit somatic mutations in epigenetic modifiers, spliceosome components, transcription factors and signal transduction genes, it is increasingly clear that a small subset harbors an inherited predisposition to CMML and other myeloid neoplasms. More intriguing is the fact that the mutational spectrum observed in CMML is found in other types of myeloid leukemias, begging the question of how similar genetic backgrounds can lead to such divergent clinical phenotypes. In this review we present a contemporary snapshot of the genetic complexity inherent to CMML, explore the relationship between genotype-phenotype and present a stepwise model of CMML pathogenesis and progression.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Mutation; Myelodysplastic-Myeloproliferative Diseases; Myeloproliferative Disorders
PubMed: 33337259
DOI: 10.1080/10428194.2020.1856837 -
Current Opinion in Hematology Jan 2022Monocytes serve as the phagocytic defense surveillance system of the human body. Although there is comprehensive evidence regarding monocyte development,... (Review)
Review
PURPOSE OF REVIEW
Monocytes serve as the phagocytic defense surveillance system of the human body. Although there is comprehensive evidence regarding monocyte development, characterization and function under steady state hematopoietic continuum, the deviations and complexities in the monocyte secretome during myeloid malignancies have not been comprehensively examined and delineated.
RECENT FINDINGS
This review summarizes the aspects of development, functions, transcriptional and cytokine-mediated regulation of monocytes during steady state hematopoiesis and also contrasts the aberrations observed in myelomonocytic leukemias like chronic myelomonocytic leukemia (CMML). It presents the findings from the major studies highlighting the novel markers for identifying CMML monocytes, altered signaling cascades, roles in disease progression and potential therapeutic interventions to reduce the monocyte mediated inflammatory milieu for disease amelioration.
SUMMARY
Recent findings provide rationale for the development of therapeutic strategies aimed at disrupting the leukemic initiating cells and malignant monocyte axis.
Topics: Cell Differentiation; Hematopoiesis; Humans; Leukemia, Myelomonocytic, Chronic; Monocytes; Secretome
PubMed: 34854831
DOI: 10.1097/MOH.0000000000000689 -
Cytometry. Part a : the Journal of the... Feb 2023Here we consider how high-content flow cytometric methodology at appropriate scale and throughput rapidly provided meaningful biological data in our recent studies of... (Review)
Review
Here we consider how high-content flow cytometric methodology at appropriate scale and throughput rapidly provided meaningful biological data in our recent studies of COVID-19, which we discuss in the context of other similar investigations. In our work, high-throughput flow cytometry was instrumental to identify a consensus immune signature in COVID-19 patients, and to investigate the impact of SARS-CoV-2 exposure on patients with either solid or hematological cancers. We provide here some examples of our 'holistic' approach, in which flow cytometry data generated by lymphocyte and myelomonocyte panels were integrated with other analytical metrics, including SARS-CoV-2-specific serum antibody titers, plasma cytokine/chemokine levels, and in-depth clinical annotation. We report how selective differences between T cell subsets were revealed by a newly described flow cytometric T assay to distinguish actively cycling T cells in the peripheral blood. By such approaches, our and others' high-content flow cytometry studies collectively identified overt abnormalities and subtle but critical changes that discriminate the immuno-signature of COVID-19 patients from those of healthy donors and patients with non-COVID respiratory infections. Thereby, these studies offered several meaningful biomarkers of COVID-19 severity that have the potential to improve the management of patients and of hospital resources. In sum, flow cytometry provides an important means for rapidly obtaining data that can guide clinical decision-making without requiring highly expensive, sophisticated equipment, and/or "-omics" capabilities. We consider how this approach might be further developed.
Topics: Humans; COVID-19; SARS-CoV-2; Flow Cytometry; Cytokines; T-Lymphocyte Subsets
PubMed: 34811890
DOI: 10.1002/cyto.a.24516 -
Pediatric Blood & Cancer Nov 2022Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive clonal neoplasm of early childhood, classified as an overlap myeloproliferative/myelodysplastic neoplasm... (Review)
Review
Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive clonal neoplasm of early childhood, classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization. In 90% of the patients with JMML, typical initiating mutations in the canonical Ras pathway genes NF1, PTPN11, NRAS, KRAS, and CBL can be identified. Hematopoietic stem cell transplantation (HSCT) currently is the established standard of care in most patients, although long-term survival is still only 50-60%. Given the limited therapeutic options and the important morbidity and mortality associated with HSCT, new therapeutic approaches are urgently needed. Hyperactivation of the Ras pathway as disease mechanism in JMML lends itself to the use of targeted therapy. Targeted therapy could play an important role in the future treatment of patients with JMML. This review presents a comprehensive overview of targeted therapies already developed and evaluated in vitro and in vivo in patients with JMML.
Topics: Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelomonocytic, Juvenile; Mutation; Myelodysplastic Syndromes; Proto-Oncogene Proteins p21(ras)
PubMed: 36094370
DOI: 10.1002/pbc.29930 -
Haematologica Nov 2023Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based...
Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.
Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide (Lena) to act synergistically with Aza/DLI to improve outcome. We, therefore, prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia. Patients were scheduled for eight cycles Aza (75 mg/m2 day 1-7), Lena (2.5 or 5 mg, days 1-21) and up to three DLI with increasing T-cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of myelodysplastic syndromes (n=24), acute myeloid leukemia (n=23) or chronic myelomonocytic leukemia (n=3) received a median of seven (range, 1-8) cycles including 14 patients with 2.5 mg and 36 with 5 mg Lena daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lena dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade 2-4 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lena can be safely added to Aza/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse (clinicaltrials gov. Identifier: NCT02472691).
Topics: Adult; Humans; Azacitidine; Lenalidomide; Leukemia, Myelomonocytic, Chronic; Lymphocyte Transfusion; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Transplantation, Homologous; Chronic Disease; Graft vs Host Disease; T-Lymphocytes; Recurrence; Hematopoietic Stem Cell Transplantation
PubMed: 37259567
DOI: 10.3324/haematol.2022.282570 -
Journal of Diabetes and Its... Apr 2022Diabetes mellitus is a state of chronic low-grade inflammation. Scavenger receptor CD163, expressed on monocyte/macrophage cells with anti-inflammatory functions, has... (Review)
Review
AIMS
Diabetes mellitus is a state of chronic low-grade inflammation. Scavenger receptor CD163, expressed on monocyte/macrophage cells with anti-inflammatory functions, has been observed in diabetes complications. This review aimed to systematically survey human studies published until 31st January 2022 for CD163 expression, in particular diabetes complications and additionally to investigate whether CD163 may be implicated as a biomarker of, and mediator in, the progression of diabetes complications.
METHODS
A systematic literature search undertaken in Scopus, Embase and Medline established 79 papers of relevance. Data extraction and assessment followed the PRISMA workflow.
RESULTS
Based on specific criteria, 11 studies totalling 821 participants were included in this review. CD163 was quantified in various forms including soluble, cell surface, and mRNA measures. This review found that soluble CD163 was upregulated in diabetes complications in various local body fluids and systemically in plasma or serum and therefore implicated in the progression of those complications. CD163+ cells and mRNA were variably expressed across diabetes complications.
CONCLUSIONS
CD163 was altered in series of diabetes complications and the circulating sCD163 has potential utility as an inflammation biomarker. The variable expression of CD163 on cell surfaces and its mRNA across different diabetes complications warrants further systematic investigation.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Diabetes Complications; Diabetes Mellitus; Humans; Inflammation; Monocytes; RNA, Messenger; Receptors, Cell Surface
PubMed: 35190247
DOI: 10.1016/j.jdiacomp.2022.108150 -
British Journal of Haematology Mar 2020Mastocytosis is a rare disease with varied presentation, myriad symptomatology and variable prognosis. Most patients present with cutaneous disease and mediator-related... (Review)
Review
Mastocytosis is a rare disease with varied presentation, myriad symptomatology and variable prognosis. Most patients present with cutaneous disease and mediator-related symptomatology with a small subset having systemic disease (systemic mastocytosis, SM). A subset of the latter develops synchronous or metachronous haematologic neoplasms (SM-AHN), most commonly chronic myelomonocytic leukaemia (CMML). Advanced systemic mastocytosis (ASM) is seen in a relatively small number of patients and is usually associated with organ dysfunction, and may present with hepatosplenomegaly, lymphadenopathy and ascites with progression to leukaemic transformation (mast cell leukaemia/acute myeloid leukaemia) occurring in a few patients. This paper discusses the clinical and pathologic features of the entire spectrum of SM in adults.
Topics: Adult; Humans; Leukemia, Myelomonocytic, Chronic; Mastocytosis, Systemic
PubMed: 31985050
DOI: 10.1111/bjh.16288