Chronic monomyelocytic leukemia

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Chronic myelomonocytic leukemia (CMML)

See myelodysplastic  syndrome and myeloproliferative neoplasms and has inherent tendency to transform to acute myeloid leukemia.

Often results in persistent peripheral blood monocytosis.

CMML median age at diagnosis is approximately 71-74 years.

Has a male predominance 1.5-3.0:1.

Incidence approximately four cases for hundred thousand persons per year.

Therapy related CMML is associated with poor clinical outcomes.

Presentation is myelodysplastic-CMMl and myeloproliferative-CMML.

Almost 80% of patients will demonstrate micromegakaryocytes with abnormal nuclear contours and lobations, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Twenty percent of patients can demonstrate nodules composed of mature plasmacytoid dendritic cells.

Myelodysplastic phenotype tend to present with blood cytopenias, easy bruisability, recurrent infections, and transfusion dependence.

Myeloproliferative-CMML phenotype patients tend to present with Leukocytosis, monocytosis, hepatomegaly, splenomegaly, and features of a myeloproliferative syndrome such as fatigue, night sweats, symptoms from enlarged organs, bone pain, weight loss, and cachexia.

Patients may present with leukemia cutis.

Patients may present with blast phase disease.

Median survival has increased from 3 years to 7 years.

Chronic myelomonocytic leukemia

Monocytosis and the presence of myelocytes, metamyelocytes and promyelocytes is typical of CMML.

Causes Environmental carcinogens, ionizing radiation, cytotoxic agents.

Frequency Less than 1 per 100,000 per year.

The median age of diagnosis is 65–75.

CMML has a propensity for males rather than females, at a ratio of 1.5–3:1.

CMML is a rare type of leukemia, which are cancers of the blood-forming cells of the bone marrow.

In CMML, there are increased numbers of monocytes and immature blood cells i.e., blasts in the peripheral blood and bone marrow, as well dysplasia in at least one type of blood cell.

For a diagnosis of CMML, the World Health Organization (WHO) states that the blood monocyte count must be >1×109/L, no Philadelphia chromosome or mutations in the PDGFRA or PDGFRB gene should be present, the blast count must be <20% and dysplasia of at least one lineage of myeloid blood cell should be present. Azacitidine is a drug used to treat CMML most commonly. Stem cell transplant is also used to treat CMML, and involves the transplantation of donor haematopoietic stem cells into the recipient. Blood transfusion and erythropoietin are used to treat disease associated anaemia. Splenomegaly, is found in approximately half of cases. 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. Approximately one third of cases of MDS with a monocyte count of >10% and <1x109/L will progress to CMML. There is a high rate of Ras mutation in CMML. Deregulation of this signalling pathway has been linked to the pathogenesis of the disease. Tumor necrosis factor, GM-CSF, interleukin-3, interleukin-4, interleukin-6, and interleukin-10 may have a role in hyperproliferative CMML cells. Hypermethylation of cytosine residues, usually in the promoter regions of genes, occurs in many malignancies to regulate gene expression. One commonly hypermethylated gene in CMML is p15INK4b, a gene involved in cell cycle regulation. Clonal genetic abnormalities are common in CMML but they are not specific for diagnosis of the disease. The most common found are the 8+, −7/del (7q) and structural 12p abnormalities. KRAS and NRAS are mutated in 25–40% of the cases of CMML. The Jak2 V617F mutation is found in 10% of cases. Mutations in transcription factors such as RUNX1, CEBPA, NPM1 and WT1 have been found in up to 30% of cases. Mutations of CBL are found in approximately 5–18% of cases. Mutations in the TET2 gene are found in approximately 40–50% of CMML. A rare autosomal dominant genetic disease, GATA2 deficiency is associated with a highly variable set of disorders including the myelodysplastic syndrome, acute myeloid leukemia, and CMML. GATA2-deficiency-induced CMML, like other types of CMML, is commonly preceded by monocytosis. Diagnosis A monocyte count of >1×109/L is essential for a diagnosis of CMML.

Other features may include; leukocytosis in 50% of cases, left shift and dysplasia of monocytes and granulocytes; presence of metamyelocytes, myelocytes and promonocytes; monocytes with hypersegmented/abnormal shaped nuclei, increased cytoplasmic basophilia and/or the presence of cytoplasmic granules; eosinophilia and spherocytosis may occur.

Platelet counts may be reduced, increased or normal.

Hemoglobin levels are usually reduced with normocytic and normochromic red blood cells.

Autoantibodies and cold agglutinins may be present and 10% of CMML.

Bone marrow aspirates will display hypercellularity with increased counts of granulocytic and monocytic cells.

Bone marrow core biopsies may show a predominance of myelocytic and monocytic cells, abnormal localisation of immature precursors and dysplastic megakaryocytes.

Monocytic nodules are a common feature in biopsies.

The phenotypical characteristics of CMML are; CD11b, CD11c, CD14, CD33, CD45 and CD64 seen in 100% of cases.

CD13 found in 95% of cases; CD4 found in 76% of cases; HLA-DR found in 71% of cases; CD56 found in 53% of cases; CD2 found in 34% of cases; CD16 found in 29% of cases; CD10 found in 28% of cases; CD23 and CD7 found in 9% of cases; and CD117 found in 5% of cases.

The FAB criteria for diagnosis:

Monocyte count >1×109/L

0–19% blasts in bone marrow

<5% blasts in peripheral blood The FAB also arbitrarily categorises CMML into myelodysplastic-like and myeloproliferative-like groups. A white blood count of 13x109 is used as a cut-off to differentiate the two. The WHO criteria for diagnosis: Persistent peripheral blood monocytosis with counts >1×109/L

No Philadelphia chromosome or BCR-ABL1 fusion gene

No rearrangement of PDGFRA or PDGFRB gene

<20% myeloblasts, monoblasts and promonocytes in peripheral blood or bone marrow Dysplasia in one or more of the myeloid lineages; if myelodysplasia is absent or minimal then a diagnosis of CMML can be made if other requirements are met and: A molecular genetic abnormality is present in haematopoietic cells, or Monocytosis present for ≥3 months and other causes of monocytosis have been ruled out WHO defined CMML has two main subsets, CMML-1 and CMML-2. CMML-1 is diagnosed if myeloblasts, monoblasts and promonocytes are <5% of peripheral blood and <10% of bone marrow. CMML-2 is diagnosed if: Myeloblasts, monoblasts or promonocytes are 5-19% in blood, orMyeloblasts, monoblasts or promonocytes are 10-19% in bone marrow, or Auer rods are present. CMML-1 and CMML-2 can be additionally grouped as CMML-1 or CMML-2 with eosinophilia. Presence of two or more phenotypic abnormalities can aid a diagnosis of CMML in the absence of identifying cytogenetic or dysplastic features. The expression of CD56 and/or CD2, or under-expression of HLA-DR are seen in CML. CMML-2 has a reduced overall survival as compared with CMML-1, with median survivals of 15 and 20 months, respectively. Myeloproliferative CMML (>13×109 monocytes/L) has a reduced survival compared with myelodysplastic CMML.

A platelet count of <100 x109/L reduces overall survival. A hemoglobin level of <10g/dL has a reduced overall survival. Normal karyotypes or the single loss of the Y chromosome have low risk prognoses. Trisomy 8, chromosome 7 abnormalities and complex karyotypes comprise a high risk group. Somatic mutations in genes such as ASXL1 and EZH2 are associated with a poor prognosis. CMML has a 20–30% chance of transformation to AML, a lower rate than other similar diseases. The CMML-2 subtype is associated with increased risk of transformation and ASXL1 and RUNX1 mutations also increase the risk of transition to AML. The International Prognostic Scoring System (IPSS) was developed to assess the prognosis of MDS patients. IPSS stratifies cases into 2 groups; a lower-risk group (sub divided into low and intermediate-1) and a higher risk (subdivided into intermediate-2 and high). It uses the blast percentage, number of cytopenias and bone marrow cytogenetics data to place cases of CMML into these groups. More myeloproliferative cases of CMML (WBC >13×109) are excluded from the scoring system.

MD Anderson Prognostic Scoring System found that a hemoglobin level of <12g/dL, total circulating lymphocyte count of >2.5 x 109/L, >0% immature myeloid cells, >10% bone marrow blasts causes a reduced overall survival.

This data allows cases of CMML to be stratified into low, intermediate-1, intermediate-2 and high risk groups.

These groups have median survival times of 24, 15, 8 and 5 months respectively.

The Düsseldorf score stratifies cases using four categories, giving one point for each; bone marrow blasts ≥5%, LDH >200U/L, hemoglobin ≤9g/dL and a platelet count ≤100,000/uL.

A score of 0 indicates a low risk group’ 1-2 indicates an intermediate risk group and 3-4 indicates a high risk group.

The cumulative 2 year survival of scores 0, 1-2 and 3-4 is 91%, 52% and 9%; and risk of AML transformation is 0%, 19% and 54% respectively.

The treatment of CMML is very similar to that of MDS.

Most cases are dealt with as supportive rather than curative because most therapies do not effectively increase survival.

Indications for treatment include the presence of B symptoms, symptomatic organ involvement, increasing blood counts, hyperleukocytosis, leukostasis and/or worsening cytopenias.

Blood transfusions and erythropoietin administration are used to raise haemoglobin levels in cases with anemia.

Azacitidine is a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of CMML, for high risk non-proliferative CMML with 10–19% marrow blasts.

It is a cytidine analogue that causes hypomethylation of DNA by inhibition of DNA methyltransferase.

Decitabine is a similar drug to azacitidine and is approved by the FDA for treatments of all subtypes of MDS, including CMML.

Hydroxyurea is a chemotherapy that is used in the myeloproliferative form of CMML to reduce cell numbers.

Hematopoietic stem cell transplantation remains the only curative treatment for CMML.

However, due to the late age of onset and presence of other illnesses, this form of treatment is often not possible.

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