Click here to go to the home page.
The Leukemia/Bone Marrow Transplant Program of BC

Healthcare Professionals
Cancer Management Guidelines

Chronic Myelomonocytic Leukemia (CMML)

Updated: May 2017

Diagnosis

Chronic myelomonocytic leukemia (CMML) is a hematologic cancer with overlapping features of both a myelodysplastic syndrome (MDS) and a myeloproliferative neoplasm (MPN).  The disease is characterized by a persistent monocytosis (defined as an absolute monocyte count >1x109/L).  Clinical presentation of CMML is variable and some patients have signs and symptoms of a MPN with an elevated WBC count and enlargement of the liver and spleen as the predominant features.  In contrast, others present with a MDS picture with a normal or decreased WBC count and symptoms related primarily to low blood counts – fatigue, shortness of breath, easy bleeding/brusing, fever/night sweats and/or frequent infections. 

Diagnosis of CMML is made according to 2008 World Health Organization (WHO) criteria (table 1), which requires examination of peripheral blood (PB) and bone marrow (BM) samples [1]. Bone marrow monocytosis is frequently observed, but not required for diagnosis. Cases with ≥20% blasts (myeloblasts + monoblasts + promonocytes) should be classified as acute myeloid leukemia (AML). Cases with PB blasts <5% and BM <10% are classified as CMML-1 and cases with PB blasts 5-19% and/or BM blasts 10-19% are classified as CMML-2.

Bone marrow examination is important to do in all suspected cases of CMML as it allows for exclusion of other hematologic neoplasms, which can have overlapping clinical and hematologic characteristics. It is recommended that chronic myeloid leukemia (CML) be excluded during diagnostic work-up and testing for BCR-ABL1 rearrangements using FISH or PCR should be performed for this purpose.  In addition, testing for rearrangements of PDGFRA and PDGFRB genes is necessary in cases with associated eosinophilia.  In contrast to CMML, patients with lymphoid and myeloid neoplasms associated with PDGFRA/B rearrangement often achieve durable responses with Imatinib treatment.

Conventional karyotyping and, if indicated, molecular mutation testing, should be performed to aid in diagnosis and for estimating prognosis.  In cases where overt dysplasia is absent in morphologic evaluation, a diagnosis of CMML can be made if an acquired clonal cytogenetic or molecular genetic abnormality (e.g. a TET2 mutation) is present.  If overt dysplasia is not present and no clonal genetic abnormality is identified, monocytosis should be persistent for at least 3 months and other causes of monocytosis (i.e. infection, solid tumours and autoimmune disease) should be systematically excluded before assigning a diagnosis of CMML. 

Etiology and Pathogenesis

CMML is most prevalent in older adults (age > 50 years), and the median age at diagnosis is approximately 70 years [2]. In general, the etiology of CMML is unknown in the majority of patients, although it appears to be related to prior chemotherapy or radiotherapy in some individuals[3]. Similarly to MDS, there is some evidence that risk may be increased with exposure to ionizing radiation, organic solvents such as benzene, agricultural chemicals and smoking[4].

Genome sequencing studies indicate that genetic abnormalities are present in the majority of CMML cases, although no genetic anomaly is pathognomonic. Stepwise acquisition of specific genetic mutations within myeloid and monocytic precursors likely contributes to the development of CMML. Although these genetic lesions also occur in other myeloid malignancies, the relatively frequency in CMML appears to be different and the most commonly mutated genes (≥10% of cases) have been reported as: SRSF2, TET2, ASXL1, SETBP1, KRAS, NRAS, CBL and EZH2[6].

Prognosis

CMML patients were included in the cohorts used for the development of risk-stratification systems for MDS (IPSS -15%, IPSS-R – 9%)[7, 8]. These cohorts excluded patients with higher WBC counts (>12 x 109/L), possibly limiting their applicability in patients with “myeloproliferative” CMML. Several other CMML-specific scoring systems have been developed including: the MD Anderson Scoring System, MD Anderson Prognostic Score, Düsseldorf Score (DUSS), Mayo prognostic model and CMML-specific prognostic scoring system (CPSS). These have recently been compared in a prospective cohort, and the results generally confirm the validity of each and reported comparable performance in estimating prognosis[9]. At our centre, we most often use the CPSS as this is a CMML-specific score that was developed and validated in two separate, relatively large cohorts and is simple to calculate(Table 2)[10]. The reported median overall survival in the validation cohort for the four risk categories (Low, Int-1, Int-2, High) was 61, 31 15 and 9 months; the corresponding 2-year risk of transformation to AML was 8%, 25%, 49% and 100%, respectively. Mutations in ASXL1, which occur in approximately 40% of CMML cases, also appear to be independently associated with worse prognosis [6, 11].

Treatment

Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the only possibility for cure in CMML. Reported long-term survival following this treatment has been less favourable than that seen in other myeloid malignancies but has generally been reported to be in the 30-40% range [12]. We consider HSCT for eligible patients with a well matched donor in non-low-risk disease (CPSS Int-1/Int-2/high risk). There are no prospective studies in CMML that have evaluated this approach, although a previously published retrospective analysis of MDS patients suggests delaying HSCT in lower risk MDS is associated with a survival benefit[13]. Similarly to MDS, CMML patients with low-risk disease have a superior survival and lower risk of transformation to AML, suggesting that the majority of these patients are unlikely to benefit from HSCT given the increased early mortality associated with this treatment.

Hypomethylating agents: Azacitidine

We recommend considering treatment with Azacitidine in non-low-risk CMML patients. A landmark, phase III trial demonstrating a survival advantage of Azacitidine over conventional care regimens in MDS included some patients with CMML (3%), suggesting a benefit might extend to some of these patients [14]. Several smaller retrospective and prospective studies of Azacitidine in CMML have reported overall response rates of approximately 40%, comparable response rates to that observed in MDS [15, 16]. There are no prospective studies exclusively in CMML patients comparing azacitidine to other treatments, although a retrospective matched-pairs analysis reported a longer median OS for Azacitidine over Hydroxyurea in first-line treatment (p = 0.072, median OS 27.7 vs. 6.2 months)[17]. Treatment with Azacitidine prior to HSCT appears to be safe and may decrease disease burden as well as preventing progression to AML before transplant if significant delay is anticipated [18]. The most frequent toxicities related to Azacitidine include: cytopenias, GI side-effects (nausea, constipation and diarrhea) and reactions at injection sites. Cytopenias often worsen initially (initial 1-3 months) with subsequent improvement in responding patients.

Hydroxyurea

Hydroxyurea is frequently used in CMML and an older clinical trial has demonstrated its superiority over etoposide (VP16) in proliferative CMML[19]. It does not produce significant bone marrow responses or improve cytopenias but can be helpful in alleviating splenomegaly, decreasing leukocytosis and improving symptoms related to myeloproliferation.

Transfusion support

Red cell transfusions can provide relief of fatigue and shortness of breath in anemic CMML patients. Transfusion thresholds vary from patient to patient depending upon age, activity level and other medical problems (especially heart and lung disease). In general, red cells should be considered for a hemoglobin <80 g/L, but a higher threshold can be considered based on the presence of symptoms related to anemia. Patients that have had ≥25 units of red cells and a serum ferritin >1000-1500 can be considered for iron chelation therapy provided they have lower risk CMML and an estimated life-expectancy of greater than 2 years (i.e. Int-1). Platelet transfusions are often given when the platelet count is <10 x 109/L and may be required more than once weekly. However, patients with clinical bleeding issues may have to have a higher transfusion threshold (i.e., <20-30 x 109/L) while those without bleeding may not need (or wish) to have preemptive platelet transfusions.

 

Table 1 - Diagnostic criteria for CMML

1. Persistent peripheral blood monocytosis >10 x 109/L

2. No Philadelphia chromosome or BCR-ABL1 fusion gene

3. No rearrangement of PDGFRA or PDGFRB genes (should be excluded in cases with eosinophilia)

4. Less than 20% blasts in peripheral blood and bone marrow -blasts included myeloblasts, monoblasts and promonoblasts

5. Dysplasia in 1 or more myeloid lineages. If dysplasia is minimal or absent then a diagnosis of CMML can be made if other requirements are met and:

-an acquired, clonal cytogenetic or molecular genetic abnormality is present in hematopoietic cells or

-monocytosis has persisted for at least 3 months and

-all other causes of monocytosis have been excluded

Adapted from 2008 WHO classification of tumours of hematopoietic and lymphoid tissues

 

Table 2 – CPSS Score

Variable Score

Variable

0

1

2

WHO subtype

CMML-1 (Blasts + PM < 5% in PB and < 10% BM)

CMML-2 (Blasts + PM 5 - 19% in PM and 10 - 19% in BM or Auer rods)

--

FAB subtype

CMML-MD (WBC < 13 x 109/L)

CMML-MP (WBC < 13 x 109/L)

--

Cytogenetics*

Low

Intermediate

High

RBC transfusion dependent**

No

Yes

--

*Cytogenetic classification: Low: Normal, isolated –Y, Intermediate: other abnormalities, High: trisomy 8, complex karyotype (≥3 abnormalities), chromosome 7 abnormalities

**RBC transfusion dependency is defined as having at least 1 RBC transfusion every 8 weeks over a period of 4 months.

Risk groups: low - 0, intermediate-1 - 1, intermediate-2 – 2-3, high 4-5

Table adapted from (Such et al, Blood, 2013)

Algorithms

CMML Treatment Algorith Chronic

Protocols

BCCA Chemotherapy Protocols and PPOs

Publications

  1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, ed. S. Swerdlow, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW.2008, Lyon: International Agency of Research on Cancer (IARC).
  2. Germing, U., et al., Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res, 2000. 24(12): p. 983-92.
  3. Takahashi, K., et al., Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. Blood, 2013. 122(16): p. 2807-11; quiz 2920.
  4. Strom, S.S., et al., Risk factors of myelodysplastic syndromes: a case-control study. Leukemia, 2005. 19(11): p. 1912-8.
  5. Itzykson, R., et al., Clonal architecture of chronic myelomonocytic leukemias. Blood, 2013. 121(12): p. 2186-98.
  6. Mason, C.C., et al., Age-related mutations and chronic myelomonocytic leukemia. Leukemia, 2015.
  7. Greenberg, P., et al., International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood, 1997. 89(6): p. 2079-88.
  8. Greenberg, P.L., et al., Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 2012. 120(12): p. 2454-65.
  9. Padron, E., et al., An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J, 2015. 5: p. e333.
  10. Such, E., et al., Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood, 2013. 121(15): p. 3005-15.
  11. Itzykson, R., et al., Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol, 2013. 31(19): p. 2428-36.
  12. Kekre, N. and V.T. Ho, Allogeneic hematopoietic stem cell transplantation for myelofibrosis and chronic myelomonocytic leukemia. Am J Hematol, 2016. 91(1): p. 123-30.
  13. Cutler, C.S., et al., A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood, 2004. 104(2): p. 579-85.
  14. Fenaux, P., et al., Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol, 2009. 10(3): p. 223-32.
  15. Ades, L., et al., Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res, 2013. 37(6): p. 609-13.
  16. Drummond, M.W., et al., A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia. Leukemia, 2014. 28(7): p. 1570-2.
  17. Pleyer, L., et al., Azacitidine in CMML: matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival. Leuk Res, 2014. 38(4): p. 475-83.
  18. Kongtim, P., et al., Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression-Free Survival for Patients with Chronic Myelomonocytic Leukemia. Biol Blood Marrow Transplant, 2016. 22(1): p. 47-53.
  19. Wattel, E., et al., A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group. Blood, 1996. 88(7): p. 2480-7.

 

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patientís care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BCís terms of use available at Terms of Use.

^ Top

Go to "About Our Services" Go to "For Patients and Families" Go to "For Healthcare Professionals"