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American Journal of Hematology Mar 2022Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative... (Review)
Review
DISEASE OVERVIEW
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3-5 years).
DIAGNOSIS
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10 /L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact overall survival.
RISK-STRATIFICATION
Molecularly integrated prognostic models include the Groupe Français des Myélodysplasies, Mayo Molecular Model (MMM), and the CMML specific prognostic model. Risk factors incorporated into the MMM include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 10 /L, hemoglobin <10 g/dL, platelet count <100 × 10 /L, and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups: high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.
RISK-ADAPTED THERAPY
Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ~40%-50% and complete remission rates of ~7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option but is associated with significant morbidity and mortality.
Topics: Chromosome Aberrations; Disease-Free Survival; Humans; Leukemia, Myelomonocytic, Chronic; Neoplasm Proteins; Risk Assessment; Risk Factors; Survivors
PubMed: 34985762
DOI: 10.1002/ajh.26455 -
Hematology. American Society of... Dec 2020Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are unique myeloid neoplasms, with overlapping features of MDS and MPN. They consist... (Review)
Review
Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are unique myeloid neoplasms, with overlapping features of MDS and MPN. They consist of four adult onset entities including chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), BCR-ABL1 negative atypical chronic myeloid leukemia (aCML) and MDS/MPN-unclassifiable (MDS/MPN-U); with juvenile myelomonocytic leukemia (JMML) being the only pediatric onset entity. Among these overlap neoplasms, CMML is the most frequent and is hallmarked by the presence of sustained peripheral blood monocytosis with recurrent mutations involving TET2 (60%), SRSF2 (50%) and ASXL1 (40%); with RAS pathway mutations and JAK2V617F being relatively enriched in proliferative CMML subtypes (WBC ≥13 × 109/L). CMML usually presents in the 7th decade of life, with a male preponderance and is associated with a median overall survival of <36 months. Adverse prognosticators in CMML include increasing age, high WBC, presence of circulating immature myeloid cells, anemia, thrombocytopenia and truncating ASXL1 mutations. While allogeneic stem cell transplantation remains the only curative option, given the late onset of this neoplasm and high frequency of comorbidities, most patients remain ineligible. Hypomethylating agents such as azacitidine, decitabine and oral decitabine/cedazuridine have been US FDA approved for the management of CMML, with overall response rates of 40-50% and complete remission rates of <20%. While these agents epigenetically restore hematopoiesis in a subset of responding patients, they do not impact mutational allele burdens and eventual disease progression to AML remains inevitable. Newer treatment modalities exploiting epigenetic, signaling and splicing abnormalities commonly seen in CMML are much needed.
Topics: Administration, Oral; Antineoplastic Agents; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Juvenile; Mutation; Myelodysplastic Syndromes; Neoplasm Proteins
PubMed: 33275673
DOI: 10.1182/hematology.2020000163 -
Haematologica Jul 2022Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by sustained peripheral blood monocytosis and an...
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by sustained peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia (15-30% over 3-5 years). While CMML is morphologically classified into CMML-0, 1 and 2 based on peripheral blood and bone marrow promonocyte/blast counts, a more clinically relevant classification into dysplastic and proliferative subtypes, based on the presenting white blood cell count, is helpful in prognostication and therapeutics. CMML is a neoplasm associated with aging, occurring on the background of clonal hematopoiesis, with TET2 and SRSF2 mutations being early initiating events. The subsequent acquisitions of ASXL1, RUNX1, SF3B1 and DNMT3A mutations usually give rise to dysplastic CMML, while ASXL1, JAK2V617F and RAS pathway mutations give rise to proliferative CMML. Patients with proliferative CMML have a more aggressive course with higher rates of transformation to acute myeloid leukemia. Allogeneic stem cell transplant remains the only potential cure for CMML; however, given the advanced median age at presentation (73 years) and comorbidities, it is an option for only a few affected patients (10%). While DNA methyltransferase inhibitors are approved for the management of CMML, the overall response rates are 40-50%, with true complete remission rates of <20%. These agents seem to be particularly ineffective in proliferative CMML subtypes with RAS mutations, while the TET2mutant/ASXL1wildtype genotype seems to be the best predictor for responses. These agents epigenetically restore hematopoiesis in responding patients without altering mutational allele burdens and progression remains inevitable. Rationally derived personalized/targeted therapies with disease-modifying capabilities are much needed.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Mutation; Myelodysplastic-Myeloproliferative Diseases; Prognosis
PubMed: 35236051
DOI: 10.3324/haematol.2021.279500 -
International Journal of Molecular... Oct 2021Chronic myelomonocytic leukemia (CMML) is a rare and challenging type of myeloproliferative neoplasm. Poor prognosis and high mortality, associated predominantly with... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a rare and challenging type of myeloproliferative neoplasm. Poor prognosis and high mortality, associated predominantly with progression to secondary acute myeloid leukemia (sAML), is still an unsolved problem. Despite a growing body of knowledge about the molecular repertoire of this disease, at present, the prognostic significance of CMML-associated mutations is controversial. The absence of available CMML cell lines and the small number of patients with CMML make pre-clinical testing and clinical trials complicated. Currently, specific therapy for CMML has not been approved; most of the currently available therapeutic approaches are based on myelodysplastic syndrome (MDS) and other myeloproliferative neoplasm (MNP) studies. In this regard, the development of the robust CMML animal models is currently the focus of interest. This review describes important studies concerning animal models of CMML, examples of methodological approaches, and the obtained hematologic phenotypes.
Topics: Animals; Epigenesis, Genetic; Heterografts; Humans; Leukemia, Experimental; Leukemia, Myelomonocytic, Chronic; Mice; Mutation; Oncogenes; Phenotype
PubMed: 34768940
DOI: 10.3390/ijms222111510 -
Hematology. American Society of... Nov 2018Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction... (Review)
Review
Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (), which define genetically and clinically distinct JMML subtypes. Three subtypes, , and -mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in non syndromic children, while two subtypes, JMML in neurofibromatosis type 1 and in JMML in children with CBL syndrome, are characterized by germ line RAS disease and acquired biallelic inactivation of the respective tumor suppressor genes in hematopoietic cells. In addition to the initiating RAS pathway lesion, secondary genetic alterations within and outside of the RAS pathway are detected in about half the patients. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive of outcome. JMML is a stem cell disorder, and most JMML patients require allogeneic stem cell transplantation for long-term survival. However, spontaneous disease regression is noted in the majority of children with -mutated JMML and in some -mutated cases. In the absence of 1 of the 5 canonical RAS pathway alteration, rare mutations in other RAS genes and non-JMML myeloproliferative disorders need to be excluded. Understanding the genetic basis of myeloproliferative disorders in early childhood will greatly improve clinical decision making.
Topics: Allografts; Child; DNA Methylation; DNA, Neoplasm; Decision Making; Genome-Wide Association Study; Humans; Leukemia, Myelomonocytic, Juvenile; Mutation; Neoplasm Proteins; Signal Transduction; Stem Cell Transplantation
PubMed: 30504325
DOI: 10.1182/asheducation-2018.1.307 -
International Journal of Molecular... Feb 2021The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the... (Review)
Review
The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly controlled by substrate-induced activation and TNFα-induced locally upregulated protein secretion. However, the present-day descendants are produced and converted to mature enzymes in precursor cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The potential site and duration of action of these cell-associated serine proteases are tightly controlled by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have been achieved by exploiting the high structural plasticity of the trypsin fold.
Topics: Animals; Cathepsin G; Cell Lineage; Humans; Leukocyte Elastase; Monocytes; Myeloblastin; Myeloid Cells; Serine Proteases
PubMed: 33562184
DOI: 10.3390/ijms22041658 -
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 -
Blood Cancer Journal Feb 2016Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform to acute myeloid... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform to acute myeloid leukemia. CMML has overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Clonal cytogenetic changes are seen in ~30%, whereas gene mutations are seen in >90% of patients. Common cytogenetic abnormalities include; trisomy 8, -Y, -7/del(7q), trisomy 21 and del(20q), with the Mayo-French risk stratification effectively risk stratifying patients based on cytogenetic abnormalities. Gene mutations frequently involve epigenetic regulators (TET2 ~60%), modulators of chromatin (ASXL1 ~40%), spliceosome components (SRSF2 ~50%), transcription factors (RUNX1 ~15%) and signal pathways (RAS ~30%, CBL ~15%). Of these, thus far, only nonsense and frameshift ASXL1 mutations have been shown to negatively impact overall survival. This has resulted in the development of contemporary, molecularly integrated (inclusive of ASXL1 mutations) CMML prognostic models, including Molecular Mayo Model and the Groupe Français des Myélodysplasies model. Better understanding of the prevalent genetic and epigenetic dysregulation has resulted in emerging targeted treatment options for some patients. The development of an integrated (cytogenetic and molecular) prognostic model along with CMML-specific response assessment criteria are much needed future goals.
Topics: Animals; Cell Cycle Proteins; Chromatin; Chromosomal Proteins, Non-Histone; Chromosome Aberrations; DNA Damage; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Histones; Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Prognosis; Protein Multimerization; Signal Transduction; Spliceosomes; Transcription Factors; Cohesins
PubMed: 26849014
DOI: 10.1038/bcj.2016.5 -
Blood Jul 2017Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 10/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 10/L) and proliferative (white blood cell count ≥13 × 10/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient's quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.
Topics: Adult; Aged; Aged, 80 and over; Aging; Antineoplastic Agents; Cell Proliferation; Clinical Decision-Making; Cytotoxins; Disease Management; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Monocytes; Quality of Life; Transplantation, Homologous
PubMed: 28572287
DOI: 10.1182/blood-2017-04-736421 -
The Oncologist May 2021Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk-adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm. IMPLICATIONS FOR PRACTICE: Chronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high-risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Leukemia, Myelomonocytic, Chronic; Mutation; Risk Assessment
PubMed: 33792103
DOI: 10.1002/onco.13769