Chronic myelomonocytic leukemia

What every physician needs to know:

Chronic myelomonocytic leukemia (CMML) is a clonal stem-cell disorder that has features of both a myelodysplastic syndrome (MDS) and a myeloproliferative neoplasm (MPN) and is thus classified by World Health Organization (WHO) as a mixed MDS/MPN disorder. The typical manifestation of CMML is peripheral blood monocytosis. Patients typically present with cytopenias and splenomegaly. It is a rare disorder, with poor long-term prognosis and few effective treatment options.

Are you sure your patient has chronic myelomonocytic leukemia? What should you expect to find?

According to the WHO 2008 classification, a diagnosis of CMML requires the following:

  • Persistent monocytosis in peripheral blood (greater than 1×109/L)

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  • Fewer than 20% blasts in the blood or bone marrow (including myeloblasts, monoblasts, and promonocytes)

  • Absence of Philadelphia chromosome and BCR/ABL fusion gene

  • Myelodysplastic features: Dysplasia involving one or more myeloid lineages

If myelodysplastic features are absent, the diagnosis of CMML can still be made if the other three criteria above are met and an acquired clonal abnormality is present, or there is persistent peripheral blood monocytosis and all other causes of monocytosis have been ruled out.

CMML can be further subdivided into two categories depending on the number of blasts found in the peripheral blood and bone marrow, CMML-1 with less than 5% blasts in peripheral blood and less than 10% in bone marrow, and CMML-2 with 5 to 19% blasts in peripheral blood and/or 10 and 19% in the bone marrow.

The clinical, hematologic, and morphologic features of CMML are heterogeneous, and disease presentation can range from a mostly myelodysplastic variant to a mostly myeloproliferative appearance. Common signs and symptoms include fatigue, splenomegaly and hepatomegaly, weight loss, fevers, and night sweats. About 50% of patients have normal or slightly decreased white blood cell count (WBC) with monocytosis. Patients may be neutropenic, and have other features of MDS. In the rest of the patients, WBC count is increased at the time of diagnosis and disease has features that are myeloproliferative in nature.

Cytogenetic abnormalities are found in 20 to 40% of patients with CMML, but there are no consistently recurring features.

Beware of other conditions that can mimic chronic myelomonocytic leukemia:

In order to confirm the diagnosis of CMML, other myeloid malignancies must be ruled out.

Chronic myeloid leukemia (CML) should be ruled out by screening for BCR-ABL gene fusion. In addition, atypical Philadelphia chromosome negative (Ph-) CML needs to be excluded. Cases of MDS/MPN with eosinophilia associated with t(5;12) (q31-33;p12)/ETV6-PDGFRBwhich were previously included in CMML category are now assigned to a separate group of myeloid neoplasms associated with eosinophilia, and abnormalities of PDGFRA, PDGFRB, or FGFR1 (fibroblast growth factor receptor 1).This group of myeloid neoplasms is usually sensitive to imatinib treatment.

Other malignant and non-malignant disorders that can cause peripheral blood monocytosis need to be considered in the differential diagnosis. These include acute and chronic infections (tuberculosis, herpes viruses), chronic inflammatory conditions (sarcoid), and other malignant conditions such as Hodgkin’s lymphoma.

Which individuals are most at risk for developing chronic myelomonocytic leukemia:

There are no reliable incidence data available for CMML, as it was often grouped into different diagnostic categories such as CML or MDS.

CMML is a male-predominant disorder, with approximately twice as many males as females having the disease. The median age at presentation is in the range of 65 to 75 years.

The etiology of this hematologic malignancy is unknown. Environmental carcinogens, ionizing radiation, and previous exposure to cytotoxic agents may be responsible for some of the cases.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The following laboratory testing is necessary for diagnosis and management of suspected CMML

Routine blood tests

Complete blood count with careful examination of peripheral smear, kidney and liver function tests, electrolytes, uric acid and lactate dehydrogenase. Cytogenetics and FISH analysis should be performed. Peripheral blood monocytosis is the key finding on peripheral smear. Blasts and promonocytes may be seen, but should be less than 20%. Other changes in peripheral blood are variable. Neutrophil precursors usually account for less than 10% of WBCs. Eosinophils are usually normal in number, but in specific cases can be increased dramatically; the latter is usually associated with specific cytogenetic abnormalities. Mild anemia is a common finding. Platelet counts vary, but thrombocytopenia is often present. Large platelets can be observed.

Invasive procedures

Bone marrow biopsy and aspiration. The bone marrow of CMML is usually hypercellular and may demonstrate monocytic or granulocytic hyperplasia. Monocytic proliferation is always present, but can be difficult to appreciate. Dysgranulopoiesis is present in the marrow of most patients and dyserythropoiesis is observed in over one-half of patients. Micromegakaryocytes or megakaryocytes with abnormally lobated nuclei are found in majority of patients. Some degree of fibrosis is seen in up to 30% of patients with CMML.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of chronic myelomonocytic leukemia?

There are no specific imaging studies that are necessary for the diagnosis of CMML.

If you decide the patient has chronic myelomonocytic leukemia, what therapies should you initiate immediately?

No emergent therapy is usually required. In case of transformation to acute myeloid leukemia (AML), appropriate treatment may need to be instituted rapidly.

More definitive therapies?

Treatment for CMML is highly heterogenous, ranging from best supportive care, cytoreductive treatments and hypomethylating agents, to allogenic stem-cell transplantation.

Since CMML was, until recently, included within the MDS category, most of the data on treatment of CMML comes from the MDS trials, and at this point the two hypomethylating agents, azacitidine and decitabine are the only two Food and Drug Administration (FDA) approved agents for the treatment of CMML. However, only a small number of patients with CMML were included in the trials testing these agents in MDS.

A few small studies investigating hypomethylating agents specifically in patients with CMML also show activity. One single center azacitidine study looked at 38 patients with CMML. The overall response rate was 39%, with 11% complete remission (CR), 3% partial remission (PR), and 28% showing hematologic improvements as per International Working Group (IWG) criteria. The median overall survival was 12 months. There was a survival advantage in responders compared to non responders; 15.5 months versus 9 months, respectively.

In another study looking at decitabine, 19 patients with CMML who were treated with decitabine were analyzed. The overall response rate was 69%, with 58% of patients achieving complete response and 11% having hematologic improvement. These and other studies show that hypomethylating agents are able to induce complete or partial responses in a subset of patients with CMML with acceptable toxicities, however additional studies are needed.

Allogenic stem cell transplantation remains the only possible curative option for CMML. Because the median age at diagnosis is 65 to 75 years, this option is only available to a minority of patients. Both fully myeloablative regimens and reduced intensity conditioning have been used in this group of patients, with reduced intensity conditioning allowing for a larger cohort of patients to be considered for transplantation. Due to the rare occurrence of this disorder and advanced age of most patients, limited data exist on outcomes of allogenic stem-cell transplants for patients with CMML.

Treatment related mortality is reported to be 30 to 40%, with 2 to 3 year overall survival of 25 to 40%. Patients receiving transplants in a relatively early stage of disease appear to have the best outcomes.

What other therapies are helpful for reducing complications?

Cytoreductive therapy is commonly used in CMML and includes low-dose cytarabine, etoposide, and topotecan, though response rates are very low.

The combination of hydroxyurea with supportive care (transfusion support, growth factors) is often used for patients with poor performance status and older patients.

What should you tell the patient and the family about prognosis?

Median survival of patients with CMML is reported to be approximately 12 to 40 months. Progression to acute leukemia occurs in approximately 15 to 30% of cases.

Since the International Prognostic Scoring System (IPSS) should not be used for CMML, other prognostic models have been proposed. A number of clinical and hematological parameters, including severity of anemia, degree of leukocytosis, cytogenetics, and percentage of blood and bone marrow blasts have been reported to be important factors in prognostication.

The MD Anderson Prognostic Score is based on a study of a cohort of 213 patients with CMML, where disease characteristics were correlated with survival times. Median survival was 12 months in this group of patients. Hemoglobin level below 12g/dL, presence of circulating immature myeloid cells, absolute lymphocyte count above 2.5 x109/L, and bone marrow blasts 10% or more were independently associated with shorter survival by multivariate analysis, and were used to generate a prognostic score. This model identified four subgroups of patients with median overall survival of 24, 15, 8, and 5 months, and was later validated in a prospective study.

In another model looking specifically at cytogenetics of 414 patients from Spanish Registry for Myelodysplastic Syndromes, who were diagnosed with CMML according to WHO criteria, an abnormal karyotype was associated with poorer overall survival and higher risk of leukemic transformation.

"What if" scenarios.

What if patients have eosinophilia?

CMML with eosinophilia is diagnosed when the criteria for CMML are present, and the eosinophil count in the peripheral blood is more than 1.5 x 109/L. These patients are at risk for complications related to the degranulation of eosinophils.

Patients with t(5:12) (q31;p12) which results in the formation of fusion gene TEL/PDGFβR are now included in a unique entity of myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. These translocations result in constitutive activation of the tyrosine kinase function of PDGFRB and these patients should be treated with imatinib.

Focal increase of eosinophils may also be due to accompanying mastocytosis. CMML is the most frequent accompanying myeloid neoplasm in systemic mastocytosis with associated clonal haematological non-mast cell lineage disease.

Pathophysiology

Clonal cytogenetic abnormalities are found in 20 to 40% of patients with CMML, but none are disease specific. The most frequent recurring abnormalities include trisomy 8, deletion 7/7q-, and structural abnormalities of 12p. Activating point mutations in the RAS oncogene appear to be more frequent in CMML than in other MPN or MDS disorders and are seen in up to 40% of patients at diagnosis or during the course of the disease. Patients with myeloproliferative CMML appear to have a higher mutation rate when compared to myelodysplastic variant. Patients with myeloproliferative CMML have been shown to have worse survival rates, and it is possible that RAS mutations are relevant for progression of CMML.

Runt-related transcription factor 1 (RUNX1) plays an important role in normal hematopoiesis. Sequencing studies showed RUNX1 mutations in 37% of patients with CMML at the time of diagnosis. Mutations in the TET2 gene have been identified in several myeloid malignancies, and a high frequency of TET2 mutations has been described in CMML (15 to 50% in different studies). In fact, it appears to be mutated in much higher frequency in CMML as compared to other subtypes of MDS. Mutations in the CBL gene, IDH1 and IDH2, and ASXL1have also been described to exist in higher frequencies in CMML. Studies looking at prognostic significance of these mutations in CMML are conflicting, and further investigation is ongoing.

Approximately 5% of patients with CMML harbor the JAK2 V617F mutation. These patients have the myeloproliferative variant of the disease, and present with splenomegaly, bone marrow fibrosis, and increased megakaryopoiesis. Analysis of mutations in CMML shows molecular heterogeneity of this disease and that it can be associated with multiple mutations that likely accumulate during the course of the disease. In the future, further sub-classification of the patients based on mutations present will likely aid in prognosis and therapy decisions.

What other clinical manifestations may help me to diagnose chronic myelomonocytic leukemia?

The spleen, liver, skin, and lymph nodes are the most common sites of extramedullary leukemic infiltration, and generalized lymphodenopathy may be the presenting manifestation of CMML.

Splenomegaly is usually the result of infiltration of the red pulp by the leukemia cells. Lymphodenopathy is an uncommon presentation, but it may be a sign of disease acceleration and transformation to a more acute phase.

What other additional laboratory studies may be ordered?

Cytochemical studies that aid in identification of monocytes, such as alpha naphthyl acetate esterase or alpha naphthyl butyrate esterase are strongly recommended when the diagnosis of CMML is suspected.

What’s the evidence?

Bacher, U, Haferlach, T, Schnittger, S. “Recent advances in diagnosis, molecular pathology and therapy of chronic myelomonocytic leukemia”. Br J Haemat.. vol. 153. 2011. pp. 149-67. [Excellent review on recent advances in molecular genetics and treatment options for CMML.]

Costa, R, Abdulhaq, H, Haq, B. “Activity of azacitidine in chronic myelomonocytic leukemia”. Cancer.. vol. 117. 2011. pp. 2690-6. [This small study showed activity for azacitidine specifically in patients with CMML.]

Onida, F, Kantarjian, H, Smith, T. “Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients”. Blood.. vol. 99. 2002. pp. 840-9. [This study was the basis for M.D. Anderson Prognostic Scoring System, one of the main prognostic models for patients with CMML.]

Beran, M, Wen, S, Shen, Y. “Prognostic factors and risk assessment in chronic meylomonocytic leukemia: Validation study of the M.D. Anderson Prognostic Scoring System”. Leukemia and Lymphoma.. vol. 48. 2007. pp. 1150-60. [Study validating M.D. Anderson Prognostic Scoring System in a prospective fashion.]

Emanuel, P. “Mixed myeloproliferative and myelodysplastic disorders”. Current Hematologic Maligancy Reports.. vol. 2. 2007. pp. 9-12. [Review on mixed MPD/MDS (myelodysplastic syndromes/myeloproliferative diseases) disorders.]

Krishnamurthy, P, Lim, ZY, Nagi, W. “Allogeneic haematopoietic stem cell transplant (SCT) for chronic myelomonocytic leukemia: a single-centre experience”. Bone Marrow Transplant.. vol. 45. 2010. pp. 1502-7. [Report of single center experience with stem cell transplantation in 18 patients with CMML, demonstrating approximately 30% relapse-free survival.]

Golub, TR, Barker, GF, Lovett, M, Gilliland, DG. “Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t (5;12) chromosomal translocation”. Cell.. vol. 77. 1994. pp. 307[Original report demonstrating the tel-PDGFRβ fusion in CMML associated with t(5;12).]

Braun, T, Itzykson, R, Renneville, A. “Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase II trial”. Blood.. vol. 118. 2011. pp. 3824-31. [Phase 2 trial of decitabine in 39 patients with advanced CMML. Demonstrates 40% response rate, and molecular correlates are analyzed.]

Ricci, C, Fermo, E, Corti, S. ” mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant”. Clinical Cancer Research. vol. 16. 2010. pp. 2246-56. [Analysis of RASmutation in progression of disease to a more advanced stage.]

Smith, AE, Mohamedali, AM, Kulasekararaj, A. “Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low abundance mutant clones with early origins, but indicates no definite prognostic value”. Blood.. vol. 116. 2010. pp. 3923-32. [Molecular analysis of TET2 mutations in MDS and CMML.]

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