Chronic Myelomonocytic Leukemia

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.

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

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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