CMML is generally diagnosed in the elderly, but the clinical presentation of affected individuals varies largely. Most symptoms are due to hematological alterations, and the latter may be seen in a hemogram. Thus, CMML is usually not suspected until blood sample analyses reveal chronic monocytosis.

In detail, the following signs and symptoms may be associated with bone marrow suppression:

• Lethargy, fatigue and decreased performance due to anemia
• Immunosuppression, susceptibility to infections and fever because of neutropenia
• Eosinophilia may cause eosinophilic inflammation
• Bleeding diathesis due to thrombocytopenia

Furthermore, CMML patients frequently present with lymphadenopathy and hepatosplenomegaly. Infiltration of extramedullary tissues by leukemic cells and development of solid tumors is rare, but not unheard of [12]. They may indicate imminent transformation to acute myeloid leukemia, though.

Comorbidities are present in most cases and may blur the clinical picture.

• Splenomegaly

  Splenomegaly is frequently seen and may be massive. A 56-year-old man with stable CMML and moderate splenomegaly presented to the emergency department with generalized abdominal pain and abrupt drop in hemoglobin. [ncbi.nlm.nih.gov]

  Factors predicting the course of disease are poorly understood and rely on clinical parameters such as anemia, splenomegaly or leukocytosis. Citation Grossmann, V., Kohlmann, A., Eder, C. et al. [fluidigm.com]

• Easy Bruising

  Low numbers of platelets, which can cause bleeding and easy bruising with no apparent cause, a condition called thrombocytopenia. Risk Factors Doctors don't know why some cells become chronic myelomonocytic leukemia (CMML) cells and others don't. [lls.org]

  A shortage of blood platelets (thrombocytopenia) can lead to easy bruising and bleeding. Some people notice frequent or severe nosebleeds or bleeding from their gums. Other symptoms can include weight loss, fever, and loss of appetite. [cancer.org]

  They can also crowd out other blood cells, causing infection, anemia and easy bleeding. [uvahealth.com]

• Anemia

  Abstract Here is reported the case of an elderly woman that, after surgical intervention, showed an important anemia, leucocytosis and thrombocytopenia. The leucocytosis was accompanied with clean increase of the monocytes. [ncbi.nlm.nih.gov]

  […] neutropenia Refractory thrombocytopenia Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with ring sideroblasts (RARS) Refractory anemia with excess blasts (RAEB) MDS associated with isolated del(5q) Childhood myelodysplastic [surgpathcriteria.stanford.edu]

• Fever

  A 67-year-old woman presented with fever, purpura, and confusion. [ncbi.nlm.nih.gov]

  It is the commonest hereditary fever syndrome with recurrent episodes of fever accompanied by abdominal, chest and joint pain. [ojrd.biomedcentral.com]

• Fatigue

  Dose-limiting toxicities (DLTs) consisted of grade 3 fatigue, grade 3 typhilitis, grade 3 syncope and grade 3 QTc prolongation). [ncbi.nlm.nih.gov]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 29, 2019 [patientslikeme.com]

  Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. [icd9data.com]

  Fatigue People with cancer may feel tired during and after treatment. Radiation therapy, chemotherapy, surgery and other treatments may cause you to have less energy. [pennmedicine.org]

• Weight Loss

  Over several months, the patient's symptoms progressed, which resulted in significant weight loss. The patient's course of disease was ultimately complicated by acute disseminated encephalomyelitis and death. [ncbi.nlm.nih.gov]

  Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. [icd9data.com]

  Symptoms can include fatigue, weight loss, fever, and abdominal pain. Treatment may include chemotherapy, radiation, supportive care, surgery, or stem cell transplant. [patientslikeme.com]

• Lymphadenopathy

  Computed tomography (CT) imaging of the chest and abdomen showed lymphadenopathy, including enlarged cervical, axillary, mediastinal, and retroperitoneal lymph nodes. Bone marrow biopsy and histology showed CMML. [ncbi.nlm.nih.gov]

  In this report, we discuss the management of our patient who presented with submandibular lymphadenopathy and gingivitis and was diagnosed with CMML. 1. [hindawi.com]

  Affected individuals present with monocytosis, cytopenias, and extramedullary manifestations like lymphadenopathy and hepatosplenomegaly. [symptoma.com]

  Splenomegaly is present in up to 25 percent of patients with CMML and is often accompanied by hepatomegaly, lymphadenopathy, or nodular cutaneous leukemic infiltrates. [peertechz.com]

  People may be able to feel abnormally enlarged lymph nodes (lymphadenopathy) in the neck (axillary lymph nodes), armpit (cervical lymph nodes), or groin, but lymph nodes that can't be directly palpated can also cause symptoms as well. [verywellhealth.com]

• Pleural Effusion

  Despite three doses of DLI with decitabine, he developed large pleural effusion; analysis showed atypical hematopoietic cell population. Subsequently, he opted for hospice and died a week later. 3. [hindawi.com]

  Other less frequent signs and symptoms consist of anaemia, fever, weight loss, night sweats, infection, bleeding, synovitis, lymphadenopathy, skin rashes, pleural effusion, pericardial effusion and peritoneal effusion.[7][8][9] Cause[edit] Although the [en.wikipedia.org]

  Similarly, clinically meaningful responses, including improvement of life threatening pericardial and pleural effusions, as well as cytopenias were reported for the topoisomerase‐II inhibitor etoposide [ 52 ]. [intechopen.com]

• Abdominal Pain

  This report should alert physicians to consider this diagnosis in patients with CMML and acute abdominal pain. [ncbi.nlm.nih.gov]

  Diarrhea, abdominal pain, and gastrointestinal bleeding can be seen in patients with either disorder, depending on the location and extent of disease. [medscape.com]

  Symptoms can include fatigue, weight loss, fever, and abdominal pain. Treatment may include chemotherapy, radiation, supportive care, surgery, or stem cell transplant. [patientslikeme.com]

• Abdominal Distension

  > Case report A 37-year-old man was admitted to hospital presenting with the symptom of abdominal distension for 3 months in May 2010, and because of aggravating for 2 months in July 2012 successively. [cancerjournal.net]

• Hepatomegaly

  If the liver gets too big (called hepatomegaly), it causes discomfort in the upper right part of the abdomen. [cancer.org]

  Splenomegaly is present in up to 25 percent of patients with CMML and is often accompanied by hepatomegaly, lymphadenopathy, or nodular cutaneous leukemic infiltrates. [peertechz.com]

  Symptoms, when present, are the consequences of cytopenias (notably anemia, which is invalidating in a third of patients), and/or of extramedullary hematopoiesis, notably splenomegaly but also hepatomegaly, skin infiltration, gum infiltration, and serous [atlasgeneticsoncology.org]

• Hepatosplenomegaly

  Affected individuals present with monocytosis, cytopenias, and extramedullary manifestations like lymphadenopathy and hepatosplenomegaly. [symptoma.com]

  Peripheral cytopenias (mainly anemia and thrombocytopenia) and hepatosplenomegaly are common findings. [peertechz.com]

  Hepatosplenomegaly may be present.[ 4, 5 ] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[ 11 ] Care should be taken to identify cases of CMML with eosinophilia, a subtype [cancer.gov]

  These suggestive clinical features make up part of the minimal diagnostic criteria for JMML, as adopted by the International JMML Working Goup (Table 1):17 Hepatosplenomegaly Lymphadenopathy Pallor Fever Skin Rash. [nature.com]

• Night Sweats

  Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. [icd9data.com]

  He had no symptoms of night sweats, fever, or weight loss. Review of his medical records showed a progressively increasing leukocytosis with a peak of 58×109/L. [ncbi.nlm.nih.gov]

  If you have symptoms, they may include: Fatigue Weight loss Night sweats Fever Pain or a feeling of fullness below the ribs on the left side Tests that examine the blood and bone marrow diagnose CML. [icdlist.com]

  Can be variable but many patients tend to present with fatigue, weight loss, fever, and night sweats. It is usually characterized by accumulation of monocytes in the blood and bone marrow, dysplastic hematopoiesis. [radiopaedia.org]

• Petechiae

  Case 1 was a 61-year-old female patient admitted to our hospital because of skin petechiae and purpura for 6 days. [ncbi.nlm.nih.gov]

  Skin manifestations of AML can be nonspecific and may include pallor, petechiae or ecchymoses, neutrophilic dermatitis (Sweet syndrome), and infiltrative lesions such as leukemia cutis or myeloid sarcoma. [hindawi.com]

  However, if you're troubled by any of the following symptoms, see your doctor: Fatigue or no energy anemia Pinhead-sized red spots under the skin petechiae Bruising and bleeding with no clear cause thrombocytopenia. [mali.zhendesao.com]

  They may also develop petechiae, which are small red and purple spots on the body. These indicate that blood is not clotting properly. Petechiae develop when immature white blood cells crowd out platelets, which are crucial for blood clotting. [medicalnewstoday.com]

  […] carry oxygen) Shortness of breath Pale skin Weakness and fatigue Lack of appetite Bleeding in excess (even when you get a minor cut) Sinus infections Skin infections Urinary tract infections ( UTIs ) Headaches Fatigue Bruising easily Night sweats Fevers Petechiae [webmd.com]

• Eruptions

  Generalized eruptive histiocytosis, described in 1963 by Winklemann and Muller, is a reactive, self-healing form of non-Langerhans histiocytosis. [ncbi.nlm.nih.gov]

  […] contact lenses Purulent discharge and/or hypopyon Round corneal infiltrate or ulcer Topical broad-spectrum antibiotics (e.g., ciprofloxacin) Herpes zoster keratitis ↓ Corneal sensation Punctate lesions on the corneal surface (early disease) Vesicular eruption [amboss.com]

• Headache

  Headaches and Other Neurological Symptoms Headaches and other neurologic symptoms such as seizures, dizziness, visual changes, nausea, and vomiting may occur when leukemia cells invade the fluid surrounding the brain and spinal cord (cerebrospinal fluid [verywellhealth.com]

  His headache and fever resolved, and the cell count in the CSF gradually decreased with clinical improvement. [esciencecentral.org]

  Some patients may also experience chronic diarrhea, muscle aches, muscle spasms and headaches as a result of their treatment. [cancercare.org]

  Four months later, she re-presented with aphasia, confusion, headache, and left-sided numbness that gradually resolved without intervention. She lost 18 kg since her last admission. [springerplus.springeropen.com]

• Lethargy

  Patients may suffer from lethargy and fatigue due to anemia, be prone to infections because of an immunosuppression due to reduced immune cell counts, and present with a bleeding diathesis caused by lack of platelets. [symptoma.com]

Laboratory analyses of blood samples may prompt an initial suspicion of CMML. In order to confirm that hypothesis, bone marrow specimens have to be examined, too. Furthermore, routine cytogenetics, fluorescence in situ hybridization (FISH) or molecular biological techniques have to be applied to rule out chromosomal anomalies and gene defects indicative of differential diagnoses.

The following algorithm has been proposed for the diagnosis of CMML [13]:

• Confirmation of persistent monocytosis with cell counts >1 × 10⁹/l
• Confirmation of additional hematological alterations, e.g., anemia, neutropenia, eosinophilia, leukocytosis, thrombocytopenia, while a medical history of a hematopoietic disorder or systemic chemotherapy is as indicative of CMML as the former
• In case all these criteria are fulfilled, a bone marrow biopsy should be carried out
• Otherwise, differential diagnoses like chronic myeloid leukemia (positive for Philadelphia chromosome), chronic eosinophilic leukemia (rearrangement of platelet-derived growth factor receptor-α or β), infection and autoimmune disease should be ruled out by analyzing peripheral blood specimens before a bone marrow biopsy is realized
• Estimation of peripheral blasts and bone marrow blasts in order to distinguish CMML-1, CMML-2, and acute myeloid leukemia

This workup aims at clarifying whether all diagnostic criteria, as proposed by the World Health Organization, are fulfilled. In detail, these criteria are:

• Persistent monocytosis as defined above
• Absence of Philadelphia chromosome or variants of the BCR-ABL fusion gene which encodes for a constitutively active tyrosine kinase
• Absence of rearrangement of genes encoding for platelet-derived growth factor receptor subunits α and β
• Peripheral blasts and bone marrow blasts <20%
• Dysplasia in one or more myeloid lineages, or: detection of cytogenetic or molecular anomalies consistent with CMML in hematopoietic stem cells, or: exclusion of all other causes of monocytosis

• Pericardial Effusion

  However, she was admitted to our hospital due to pericardial effusion. The majority of the cells in the pericardial fluid were monocytes. [ncbi.nlm.nih.gov]

  Ibrahim MI, Maslak PG, Heaney ML, George MS,Downey RJ, Tallman MS (2009) Chronic myelomonocyticleukemia (CMML) associated with symptomatic pericardial effusion. J ClinOncol 29. [esciencecentral.org]

  Pleural and pericardial effusions and ascites can occur in CMML with very high monocyte counts and these signs often resolve with antileukemic therapy. [peertechz.com]

  Two months later, her aphasia returned with accompanying pericardial effusion, biopsy-proven leptomeningeal inflammation, and left elbow arthritis responsive to prednisone. Rheumatoid factor was transiently elevated at 21.8 IU/mL (range 0.0-20.0). [springerplus.springeropen.com]

• Pleural Effusion

  Despite three doses of DLI with decitabine, he developed large pleural effusion; analysis showed atypical hematopoietic cell population. Subsequently, he opted for hospice and died a week later. 3. [hindawi.com]

  Other less frequent signs and symptoms consist of anaemia, fever, weight loss, night sweats, infection, bleeding, synovitis, lymphadenopathy, skin rashes, pleural effusion, pericardial effusion and peritoneal effusion.[7][8][9] Cause[edit] Although the [en.wikipedia.org]

  Similarly, clinically meaningful responses, including improvement of life threatening pericardial and pleural effusions, as well as cytopenias were reported for the topoisomerase‐II inhibitor etoposide [ 52 ]. [intechopen.com]

Drug therapy is chosen for the majority of CMML patients, especially in a case of CMML-1. Hypomethylating agents like azacitidine and decitabine are primarily administered to control MDS-like symptoms; chemotherapeutics such as hydroxyurea and etoposide are used to remedy MPN-like complications. Response rates are 40 and 30% for azacitidine and decitabine, respectively. Hydroxyurea has been shown to be more effective than etiposide [14]. Hypomethylating or cytoreductive therapy may also precede hematopoietic stem cell transplantation.

To date, hematopoietic stem cell transplantation remains the only curative treatment. It is indicated in case of CMML-2 and whenever the general condition of the patient allows for this approach, i.e., its usability is mainly limited by the age of CMML patients and the high prevalence of comorbidities. While stem cell transplantations are associated with a better outcome in younger patients, response rates are still modest. According to a recent multi-center study, little more than half of CMML patients respond to this therapy [15]. Myeloablative regimens are generally chosen to prepare patients younger than 55 years for the procedure, whereas reduced intensity conditioning is recommended for elder individuals.

Supportive care should be provided to all CMML patients and may include the use of erythropoiesis-stimulating agents as well as the transfusion of blood products.

CMML is generally associated with a poor outcome. Recently, median survival times of 13.3 months and an overall three-years survival rate of 19% have been reported [9]. Similar values have been reported elsewhere [3]. Such values do, however, comprise data obtained from patients diagnosed with CMML-1, CMML-2 and those who sustained disease progression to acute myeloid leukemia. A detailed listing of survival times for CMML-1 and CMML-2 is slightly more encouraging since these phases of the disease are associated with median overall survival times of 38 and 24 months, respectively [2]. Moreover, studies regarding the prognosis of CMML patients highlight that there is a considerable heterogeneity with regards to the underlying molecular anomalies and to the provision of adequate treatment. In this context, drug- or radiation-induced CMML may be associated with a better outcome than sporadic cases of the disease [3]. Besides blast counts and bone marrow compromise, monocyte counts >10 × 10⁹/l, leukocyte counts >15 × 10⁹/l, platelet counts <100 × 10⁹/l, hemoglobin concentrations <10 g/dl, ASXL1 mutations as well as age over 65 years have been identified as unfavorable prognostic factors [10] [11].

Both cytogenetic anomalies and gene mutations contribute to disturbances of cell cycle regulation in CMML. Chromosomal aberrations are observed in about 30% of CMML patients, whereas more than 90% of affected individuals show molecular and epigenetic abnormalities [2]. With regards to the former, trisomy 8, trisomy 21, loss of the Y chromosome, monosomy 7 and deletion of the long arms of chromosomes 7 or 20 are among the most common karyotypes. Alterations of sequence segments are as heterogeneous as the aforementioned cytogenetic anomalies and may affect genes encoding for epigenetic regulators (e.g., TET2, ASXL1), transcription factors (e.g., RUNX1), proteins involved in post-translational modification (e.g., SRSF2), and components of intracellular signaling cascades (e.g., RAS). All these gene products are involved in the complex process of hematopoiesis, in the regulation of precursor cell growth, division, differentiation, and death. TET2, for instance, induces the conversion of methylcytosine to 5-hydroxymethylcytosine, a biochemical reaction important in myelopoiesis since the attachment of a methyl and hydroxy group to cytosine is presumed to serve as a signal for increased or reduced gene expression. ASXL1, in contrast, is assumed to enhance the expression of certain genes and suppress the expression of others by modifying chromatin. About half of CMML patients show either TET2 or ASXL1 mutations. Of note, such mutations are not pathognomonic of CMML. Sequence alterations affecting TET2 and ASXL1, for instance, have also been related to myelodysplasia.

In most cases, the precise trigger of malignant transformation of precursor cells is not known. Few cases are ascribed to the administration of alkylating agents or irradiation, though. The former are generally referred to as de novo CMML, the latter as therapy-related CMML [3]. Nine out of ten cases are deemed de novo CMML. It has been speculated that exposure to common carcinogens such as cigarette smoke and ionizing radiation may predispose for CMML. This hypothesis is based on the fact that those environmental factors are known to increase the individual risk of MDS.

The overall incidence of CMML has been estimated to be 0.3 per 100,000 inhabitants in the United States and 0.39 per 100,000 people in Spain [4] [5]. According to the respective studies, CMML is the most common disease classified as myelodysplastic/myeloproliferative neoplasm, with atypical chronic myeloid leukemia and juvenile chronic myeloid leukemia being observed much less frequently. However, CMML only accounts for about 10% of MDS cases. Misdiagnosis of CMML as MDS may have caused an underestimation of incidence rates.

Men are affected more often than women (male-to-female ratio = 1.3), and a trend towards shorter survival in males has been observed. The median age at the time of diagnosis is 65 to 75 years. Few case reports exist on CMML in pediatric patients and young adults. In these patients, CMML is generally induced by chemotherapeutics or radiation therapy.

The pathogenesis of CMML is incompletely understood, but current knowledge regarding the diversity of cytogenetic and molecular anomalies as well as the clinical presentation of affected individuals implies heterogeneous mechanisms to account for symptom onset. As has been indicated above, TET2 mutations are frequently detected in affected cells obtained from CMML patients. Although a detailed list of genes whose expression is enhanced or suppressed upon failure of TET2 cannot be provided, it has been shown that early dominance of TET2-deficient stem cell clones favors the proliferation of granulomonocytic precursors [6]. The pathophysiological importance of TET2 may also be illustrated by the fact that the presence of TET2 mutations predicts an MSD patient's response to hypomethylating agents [7]. ASXL1 mutations have also been related to an excess proliferation of myeloid precursor cells: While the precise function of its gene product remains unknown, it could be shown that ASXL1 gene defects are associated with reduced histone H3 lysine 27 (H3K27) trimethylation [8].

Most cases of CMML cannot be ascribed to any trigger. However, exposure to cigarette smoke, ionizing radiation, and cytotoxic chemotherapy is known to be related to the onset of MDS. It may be assumed that these factors also play a role in CMML pathogenesis and thus, it is recommended to minimize such exposure as much as possible.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder. According to the current classification of tumors of the hematopoietic and lymphoid tissues, as published by the World Health Organization, CMML is a myelodysplastic/myeloproliferative neoplasm [1]. This classification responds to the fact that CMML comprises both features of myelodysplasia and myeloproliferative diseases, namely pathological alterations of hematopoiesis and a proliferation of a particular cell type. The clinical hallmark of CMML is monocyte count that exceeds 1 × 10⁹/l and persists for more than three months. Additionally, patients often suffer from anemia, neutropenia, and thrombocytopenia. CMML may transform to acute myeloid leukemia at any time, a condition that is not always treated as an own entity but rather referred to as the blast phase of CMML. Disease progression is associated with a worse prognosis, and the following degrees of severity have been defined accordingly:

• CMML-1: 5% peripheral blasts including monoblasts and promonocytes, <10% bone marrow blasts
• CMML-2: 5-19% peripheral blasts including monoblasts and promonocytes and/or 10-19% bone marrow blasts
• Acute myeloid leukemia: >20% peripheral blasts or bone marrow blasts

Therapeutic regimens are derived from those established for treatment of myelodysplastic syndromes and myeloproliferative neoplasms. To date, the only curative treatment option is hematopoietic stem cell transplantation. CMML is generally associated with a poor outcome.

Chronic myelomonocytic leukemia (CMML) is a hematopoietic disorder, i.e., affected individuals suffer from an impairment of bone marrow function. On the one hand, hematopoietic stem cells and later precursors of blood cells are no longer able to differentiate into functional cells. This condition is referred to as myelodysplasia. On the other hand, stem cells undergo malignant transformation and start to proliferate in an uncontrolled manner. This process is characteristic of blood cancer and further interferes with blood cell maturation.

Symptoms related to CMML thus result from bone marrow suppression. Patients may suffer from lethargy and fatigue due to anemia, be prone to infections because of an immunosuppression due to reduced immune cell counts, and present with a bleeding diathesis caused by lack of platelets. Since these symptoms are very unspecific, detailed analyses of blood and bone marrow specimens are required to diagnose CMML. Findings obtained in those analyses also allow for an estimation of disease severity, which is important at the moment of deciding for a determined treatment regimen. To this end, the general condition of the patient also plays a crucial role.

CMML patients may either receive medication to control symptoms associated with myelodysplasia and myeloproliferation, or they may be recommended for hematopoietic stem cell transplantation. While the latter is the only curative therapy known to date, there are inherent risks to this procedure. Thus, debilitated patients and individuals diagnosed with less severe CMML generally receive drug therapy.

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