At a Glance

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) as it shares features of both dysplasia and proliferative neoplasia. It is characterized by a sustained increase of monocytes that have no known reactive cause. Although many cases do show dysplasia in the granulocytic component of the bone marrow, other cases of CMML may only show proliferative features.

Most patients present with fatigue, weight loss, night sweats, and fevers. Patients typically have an increased white count (MPN feature), although a subset does present with normal or only modestly elevated leukocytes. Anemia and thrombocytopenia (MDS features) are common, as are hepatomegaly and splenomegaly (MPN features).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A complete blood count (CBC) to confirm monocytosis should be ordered. Bone marrow biopsy and aspirate, karyotype, and fluorescent in site hybridization (FISH) for BCRABL fusion should all be used to confirm the diagnosis. The bone marrow biopsy is typically hypercellular with a myeloid hyperplasia, erythroid hypoplasia and dysplasia of granulocytes, erythrocytes, and megakaryocytes. Although dysplasia is not mandatory for a diagnosis of CMML, it is evident in most patients at presentation.

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Dysgranulopoiesis can be marked, making distinction of myeloid precursors from monocytic precursors difficult without the use of cytochemical stains or immunohistochemistry. Dyserythropoiesis, including increased ringed sideroblasts, can be common. Megakaryocytes are small and hypolobated or atypically lobated. Nearly one-third of patients also present with increased reticulin fibrosis in the bone marrow.

Blasts and promonocytes together must comprise less than 20% of total cells. There are 2 subcategories of CMML based on the percentage of blasts and promonocytes, which are considered blast-equivalents in CMML. In CMML-2, blasts and promonocytes are 5-19% of total cells in blood or 10-19% in marrow. In CMML-1, blasts and promonocytes comprise less than 5% of cells in the blood and less than 10% of cells in the bone marrow.

Abnormal cytogenetics are detected in approximately 30% of CMML patients at presentation. There is no single pathognomonic cytogenetic finding in CMML. Common cytogenetic findings in CMML include del20q, -Y, +8, -7, and complex karyotypic changes.

FISH for PDGFRß and BCRABL should be performed as well to rule out myeloid neoplasia with eosinophilia and CML.

Test Results Indicative of the Disorder

WHO 2008 diagnostic criteria for CMML include:

Persistent peripheral blood monocytosis greater than 1,000 per microliter

No evidence of other MPN associated translocations, such as BCRABL, PDGFRα, PDGFRß

Fewer than 20% blasts (or blast equivalents, such as promonocytes) in the blood and bone marrow

Dysplasia in 1 or more myeloid lineages OR evidence of an acquired clonal or molecular genetic abnormality AND monocytosis for at least 3 months with no reactive cause identified

What Other Diseases Should Be Considered and How Do I Distinguish Between Them?

There are many causes of reactive monocytosis that must be excluded before a diagnosis of CMML is made. Monocytosis may occur in chronic infections (e.g., tuberculosis (TB), Listeria, syphilis, subacute bacterial endocarditis), in autoimmune/rheumatologic conditions (e.g., connective tissue disorders, sarcoidosis, celiac disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP)), and as a response to hematologic or nonhematologic malignancies. These reactive conditions must be excluded before making a diagnosis of CMML.

ETV6-PDGFRß fusion associated with t(5;12)(q31-33;p12) can cause a myeloid neoplasm with eosinophilia and marked monocytosis. In the past, many of these cases were diagnosed as CMML with eosinophilia; however, by the new WHO 2008 criteria, these are best diagnosed as “myeloid neoplasia with PDGFRß abnormalities.”

Chronic myeloid leukemia (CML) with monocytosis can also be difficult to distinguish from CMML. Because the megakaryocytes in CMML can often appear small and monolobated, similar to megakaryocytes in CML, and because CML with monocytosis is often associated with the p190 variant of the BCRABL fusion gene that can be difficult to detect by standard polymerase-based chain reaction (PCR), FISH for BCRABL is recommended to rule out CML.

Of course, most BCRABL translocations can be seen by traditional karyotype as t(9;22), but, if there is a concern for a cryptic translocation, BCRABL FISH is often more sensitive for the p190 variant than PCR. If the BCRABL is detected, whether p190 or p210, the most appropriate diagnosis is CML and a diagnosis of CMML is precluded, regardless of the degree of monocytosis.

What Lab Results Are Absolutely Confirmatory?

No lab test is absolutely confirmatory for CMML. In cases with eosinophilia, rearrangements of PDGFR subunits or FGFR1 should be tested for by FISH. In cases with minimal dysplasia and features of myeloproliferation, FISH for BCRABL fusion should be evaluated.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Multicolor flow cytometry (MFC) can be useful to detect atypical marker expression in chronic myelomonocytic leukemia. Many studies have shown atypical monocytic maturation as detected by MFC in CMML, as well as atypical marker expression. In particular, CMML monocytes often show aberrant expression of CD2, CD56, or underexpression for typical monocytic markers. Of note, MFC often fails to distinguish between monoblasts, promonocytes, and dysplastic monocytes. Morphology remains the gold standard for this distinction.

Cytogenetic abnormalities are relatively rare in CMML occurring in 25-35% of cases. Molecular analysis shows some common mutations with none being pathognomonic:

Mutations in NRAS or KRAS occur in approximately 35% of cases leading to activation of proliferation, anti-apoptotic pathways, and differentiation.

A mutation of the gene for Runx1 (AML1), a transcription factor involved in the regulation of gene expression of multiple genes important in hematopoiesis, is shown in 20-40% of cases.

Mutations in TET2 are found in approximately 40% of CMML cases. Tet2 is believed to be a tumor suppressor with precise functioning being unknown.

JAK2 mutations occur in approximately 10% of patients and CBL mutations in 20%.

Although these mutations altogether are thought to occur in up to 80% of CMML patients, they are not specific and are rarely tested in clinical labs for that reason.

Frequent follow-up to evaluate for blast percentage in the bone marrow is advised, as CMML shows a propensity to transform to acute myeloid leukemia (AML) in approximately 20% of cases.

What is the Prognosis for the Disorder?

Overall, CMML patients have a median overall survival of 20-40 months with highly heterogeneous subgroups contained within the overarching diagnosis. Multiple scoring systems have been developed to better predict which patients will do better or worse. In most systems, even the best prognosis group has a mean overall survival between 2 and 3 years.

In the M.D. Anderson prognostic scoring system for CMML, the best prognosis subgroup showed a median overall survival of 24 months, whereas the worst was at 5 months, with intermediate groups falling at 15 and 8 months. Poor prognostic factors in this analysis were hemoglobin less than 12 g/dL, lymphocytosis greater than 2,500/ microliter, circulating immature myeloid cells, and blasts greater than or equal to 10% of bone marrow.

The Dusseldorf scoring system is based on hemoglobin less than 9g/dL, platelets less than 100,000/ microliter, increased lactate dehydrogenase (LDH), and bone marrow blasts greater than 5%.

Of note, although the best prognostic group had a median survival of more than 90 months, only 6% of patients were classified into this group. The other subgroups, representing 94% of patients, showed 26- and 11-month median overall survival times. In the other major scoring systems, increased blasts, decreased hematopoietic function, and increased LDH are all poor prognostic factors and yield similar groupings of patients.

Death in CMML is due to AML transformation in 20% of cases. Infection (30%), bleeding (20%), heart failure (10%), other CMML-related causes (10%), and non-CMML-related causes (10%) represent the remainder.

The only curative therapy for CMML is allogeneic bone marrow transplantation, although newer pharmaceutical approaches with RAS inhibitors and histone deacetylation inhibitors are being pursued.