Chronic myelomonocytic leukemia

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Chronic myelomonocytic leukemia
Blood film, genetic testing
FrequencyLess than 1 per 100,000 per year

Chronic myelomonocytic leukemia (CMML) is a type of

monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.[1]

CMML shows characteristics of a

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.[3]

Signs and symptoms

One of the most common signs of CMML is

Cause

Although the cause of CMML is unknown, environmental

cytotoxic agents may have a role in causing disease.[8] Approximately one third of cases of MDS with a monocyte count of >10% and <1x109/L will progress to CMML.[10]

Pathogenesis

With a high rate of

Genetic mutations

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.

genetic disease, GATA2 deficiency. This disease 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.[13][14]

Diagnosis

cold agglutinins may be present and 10% of CMML is DCT positive.[7][9]
Bone marrow aspirates will display hypercellularity with increased counts of granulocytic and monocytic cells.[1] Bone marrow core biopsies may show a predominance of myelocytic and monocytic cells, abnormal localisation of immature precursors and dysplastic megakaryocytes.[1] Monocytic nodules are a common feature in biopsies.[16]

The phenotypical characteristics of CMML are;

CD117 found in 5% of cases.[17]

Classification

Haematopoiesis. The two lineages of myeloid and lymphoid cells are formed from haematopoietic stem cells.

Leukemia subtypes are categorised into single clinical entities so that they can be diagnosed and treated appropriately. Leukaemias are subdivided into

myeloid neoplasms, depending on which bone marrow cells are cancerous. The myeloid neoplasms contain acute and chronic leukemias, myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MPNs are characterised by increased production of myeloid blood cells, with a higher than normal number of mature cells. Unlike MPNs, MDSs have a dysfunctional production of myeloid cells with a reduced number of mature cells. Many of the cells produced in MDS are abnormal looking, known as dysplasia. CMML shows characteristics of both groups and thus is a difficult disease to categorise.[7][18]

FAB classification

The

ring sideroblasts, refractory anaemia with excess blasts and refractory anaemia with excess blasts in transformation. The system does have clinical utility; however factors such as cytogenetic status are not within the remit of the classification. For this reason, many disease entities in these groups show a great deal of heterogeneity.[18][19]

WHO classification

In 2001, the WHO Classification of Myeloid Neoplasms was published, classifying CMML into a new group of diseases, the myelodysplastic/myeloproliferative neoplasms (MDS/MPN), reflecting the disease's neoplastic nature. Other diseases in this category are

Diagnostic criteria

FAB criteria

The FAB criteria for diagnosis are as follows:[21]

  • Monocyte count >1x109/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.[12]

WHO criteria

The WHO criteria for diagnosis are as follows:[3]

  • Persistent peripheral blood monocytosis with counts >1x109/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

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, or
  • Myeloblasts, 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. These are diagnosed if the above criteria are met and the blood eosinophil count is >1.5x109/L.[8]

Presence of two or more phenotypic abnormalities can aid a diagnosis of CMML in the absence of identifying cytogenetic or dysplastic features. These can include the expression of CD56 and/or CD2, or under-expression of HLA-DR.[3]

Prognosis

Factors affecting prognosis

CMML-2 has a reduced overall survival as compared with CMML-1, with median survivals of 15 and 20 months, respectively. Myeloproliferative CMML (>13x109 monocytes/L) has a reduced survival compared with myelodysplastic CMML. A platelet count of <100 x109/L reduces overall survival. A haemoglobin level of <10g/dL has a reduced overall survival. Some cytogenetic abnormalities have implications on the prognosis of CMML. 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. Other cytogenetic abnormalities have intermediate prognoses. Somatic mutations in genes such as ASXL1 and EZH2 are associated with a poor prognosis.[12]

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.[12][22][23]

Scoring systems

IPSS

The International Prognostic Scoring System (IPSS) was developed in the mid-1990s to assess the prognosis of MDS patients. This system 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. Due to the scoring system being developed for MDS, the more myeloproliferative cases of CMML (WBC >13x109) are excluded from the scoring system. Although the IPSS scoring system is used clinically, there is a high variability in each group. For this reason, new modalities for assessing prognosis in MDS (and CMML) are being developed.[12][24]

MD Anderson Prognostic Scoring System

A new method developed using data from the

M.D. Anderson Cancer Center found that a haemoglobin 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.[25][26]

The Düsseldorf score

The Düsseldorf score stratifies cases using four categories, giving one point for each; bone marrow blasts ≥5%, LDH >200U/L, haemoglobin ≤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.[10]

Treatment

The treatment of CMML remains challenging due to the lack of clinical trials investigating the disease as its own clinical entity. It is often grouped with MDS in clinical trials, and for this reason 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.[6][10]

Blood transfusions and erythropoietin administration are used to raise haemoglobin levels in cases with anemia.[6]

combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) that was approved for use in the United States in July 2020.[27]

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.[5][28]

Epidemiology

There have been few individual epidemiological studies of CMML, due to the difficulty in the disease classification. CMML has an estimated incidence of less than 1 per 100,000 persons per year.[12] 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.[8]

References

External links