Chronic

Myelomonocytic
Leukemia
• Lakshmi Manogna Chintalacheruvu
 Introduction
• CMML is a clonal hematological malignancy that shares features with
MPNs and MDS syndromes

• It is characterized by peripheral monocytosis in combination with

hyper cellular bone marrow with varying degrees of dysplasia

• It was first formally classified as 1 of 5 sub categories of FAB group in

1978

• Later grouped in MDS/MPN category by WHO in 2001  

• In 2008, the WHO separated CMML via blast proportion into CMML-0
CMML-1 and CMML-2

• In 2016, the WHO again revised its classification, recommending that

CMML be classified into two subtypes- proliferative (MPN-CMML) and
dysplastic (MDS-CMML) depending on the patient’s white blood cell
count(13,000)
 Introduction
• Chronic myelomonocytic leukemia (CMML) is rare,
only occurring in 4 of every million people in the
United States each year

• Median age of diagnosis is 70. Nine out of ten

cases are diagnosed in 60 or older

• Male predilection
Molecular pathogenesis of
CMML

https://www.youtube.com/watch?v=S9SuDp5UJLk
 Clinical features
• Blood and Bone marrow are invariably involved

• Liver, spleen, skin and lymph nodes are the most

common extra medullary sites involved

• Anemia, bleeding, recurrent infections

• Weight loss, night sweats, abdominal discomfort

from splenomegaly can be present

• Leukemia cutis
 Diagnosis

• The diagnosis of CMML depends upon combination of

morphologic, histopathologic and chromosomal
abnormalities

• It is important to exclude other MPN and other causes

of monocytosis

• Infectious causes of monocytosis include brucellosis,

chronic fungal infections, viral infections

• Autoimmune causes of monocytosis- SLE, Sarcoidosis

Diagnostic work up to
CMML

Solary E et al. How I treat chronic myelomonocytic leukemia.Blood. 2017 Jul 13;130(2):126-136.

Solary E et al. How I treat chronic myelomonocytic leukemia.Blood. 2017 Jul 13;130(2):126-136.

Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia

• Retrospective done by Buet et al demonstrated CMML is characterized by increase

in the fraction of classical monocytes

• They divided monocytes into three groups. CD 14+/CD16- (Classical) ,

CD14+/CD16+(intermediate) and CD14 low/CD16+(nonclassical) 

• CMML patients demonstrate characteristic increase in classical monocytes with cut

off of 94% with specificity (95.1%) and sensitivity(90.6%)

• Accumulation of classical monocytes is independent of mutational back ground

• Increased Intermediate and decreased non classical monocytes are suggestive of

CMML associated with autoimmune disease. Repeat flow cytometry after treatment
with immunosuppressive agents will reveal typical increase in classical monocytes

Selimoglu-Buet D et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia.

Blood. 2015 Jun 4;125(23):3618-26.

 Diagnosis

Selimoglu-Buet D et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia.

 Histopathology

• Bone marrow is often hyper cellular and shows a

myelomonocytic proliferation resulting in increased
M:E ratio

• Monocytic differentiation is always present

• Dysgranulopoiesis is almost always present

• Mild to moderate reticulin fibrosis is present

 Histopathology

Bone marrow aspirate showing increased monocytes and

Bone marrow involved by CMML Granulocytes which are dysplastic and hypo granular
H&E: 200x
 2016 WHO Classification of Myeloid neoplasms and acute leukemia

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
Daniel A. Arber , Attilio Orazi , Robert Hasserjian , Jürgen Thiele , Michael J. Borowitz , Michelle M. Le Beau , Clara D. Bloomfield , Mario Cazzola , James W. Vardiman
 Mutational landscape in
CMML
• CMML mutational landscape predominantly includes epigenetic modifiers, Splicing mutations and
cytokine signaling

• Epigenetic modifiers

• TET2 , DNMT3A , IDH1 , IDH2 , ASXL1

• ASXL1 (frame shift and non sense mutations) and DNMT3A mutations associated with reduced OS and
greater risk of transformation to AML

• Splicing factors

• More common in MDS than MPN

• SRSF2 ( more frequently found with no prognostic significance)

• SF3B1 , U2AF1 , ZRSR2 

• Transcription factors and Cytokine signaling

• More common in MPN

• RUNX1, JAK2 , RAS , CBL , FLT3

Geevarghese A et al. Evolving Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treatment Paradigms. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):519-527. 

 Mutational landscape in
CMML
• Both mutated TET2 alone and concomitant
mutations with SRSF2 associated significantly with
CMML (93% cases)

• SRSF2, TET2 and ASXL1 were early events in the

pathogenesis of CMML

• Mutations in KRAS , NRAS , RUNX1 , and CBL were

found at later time points, indicating that these
lesions are second hits that may be important in
defining the CMML phenotype
 Mutational landscape in
CMML

Geevarghese A et al. Evolving Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treatment Paradigms. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):519-527. 

 Mutational land scape in
CMML

Geevarghese A et al. Evolving Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treatment Paradigms. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):519-527. 

 Cytogenetic risk stratification in CMML
• Most common cytogenetic abnormalities are
Trisomy 8, Complex karyotype and abnormalities of
chromosome 7

• Low risk- Normal karyotype, Loss of chromosome Y

as a single anomaly ( Median OS- 31 months)

• High risk- Trisomy 8, abnormalities of chromosome

7, complex karyotype ( Median OS- 4months)

• Intermediate risk- Other abnormalities (Median OS-

24 months)

Such E et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011 Mar;96(3):375-83. 
Cytogenetic risk stratification in CMML

Such E et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011 Mar;96(3):375-83. 
 Proliferative vs Dysplastic
CMML
• In a retrospective study conducted at Mayo Clinic; 139(53%) patients had
proliferative and 122(47%) dysplastic subtypes

• No differences in CMML subtypes in terms of age, gender districution, Hb

level, PLT count

• Patients with proliferative CMML had higher circulating immature myeloid

cells, blasts and higher absolute monocyte counts

• ASXL1 (54% VS 37%), JAK2 (11% vs 3%) and CBL (11% vs 8%) gene
mutations were commonly found in proliferative vs dysplastic

• Trend towards higher prevalence of NRAS, CSF3R mutations

• No difference in the incidence of TET2, DNMT3A and SRSF2 mutation

M Patnaik, MBBS et al. Proliferative" Versus "Dysplastic" Chronic Myelomonocytic Leukemia: Molecular and Prognostic Correlates. Blood (2016) 128 (22): 1987.
 Prognosis
• Prognosis is poor, with a median overall survival of
2 - 3 years 

• Rates of CMML transformation to AML range from

15-30%

• Older age, High WBC count and Thrombocytopenia

associated with worse prognosis
CMML classification and prognosis

Schuler E et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias.
  
Leuk Res. 2014 Dec;38(12):1413-9.
 Risk stratification models in CMML

of the prognostic scores have been established in elderly patient so these should be interpreted with caution in younger

Itzykson R et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet.

Hemasphere. 2018 Nov 29;2(6):e150. 

 Treatment
considerations

Solary E et al. How I treat chronic myelomonocytic leukemia.Blood. 2017 Jul 13;130(2):126-136.

 HMA
• Hypomethylating agents have been approved in CMML based on MDS phase 3 trials which include
less than 20 CMML patients each

• Small dedicated clinical trials showed overall response rates ranging between 30% and 60%, with
a complete response in fewer than 15% of patients

• HMA agents induce dramatic changes in DNA methylation and gene expression there by restoring
a more balanced hematopoiesis

• They might not prevent the occurrence of new genetic events leading to acute transformation

• They do not reduce the mutated allele burden, nor permit the re-expansion of wild-type
hematopoietic cells.

• Median overall survival ranged between 12 and 37 months

• MP CMML has shorter survival when treated with HMA compared to MD CMML patients

• Myelosuppression is the most common toxicity

• Role of HMA in transplant eligible MP CMML is disputed

 HMA
• Median overall survival ranged between 12 and 37
months

• MP CMML has shorter survival when treated with

HMA compared to MD CMML patients

• Myelosuppression is the most common toxicity

• Role of HMA in transplant eligible MP CMML is

disputed
 Recommendations of
HMA agents
• In patients ineligible for transplant, AZA should be
considered in MD-CMML with more than 10% of
blasts

• Use of HMA in patients with a blast excess >5%

and significant cytopenias or myeloproliferation
should be considered, preferably within clinical
trials

• In patients eligible for transplant, it is unclear when

HMA should be used before transplant, especially
compared with Induction chemotherapy.
 Hydroxyurea
• Hydroxyurea is recommended in proliferative
CMML in the absence of cytopenia

• Hydroxyurea showed its superiority over oral

etoposide in elderly patients with MP-CMML and
high-risk features

• No single level of WBC count or spleen size can be

recommended as being the optimal level to
introduce treatment. Decision should be based on
patient symptoms.
Leukocytosis Is Associated with End Organ Damage in
Chronic Myelomonocytic Leukemia (CMML) and Can be
Mitigated with Cytoreductive Therapy

• MP CMML is associated with greater end organ

damage including AKI ( 40% vs 27.8%), Pleural
effusion (21.7% vs 11.5%) compared with MD
CMML

• They recommended that cases with a WBC

>33.95cells/dL are at particularly high risk for end
organ damage and cytoreductive therapy should
be routinely considered to mitigate this risk.
Phase1 Trial of Ruxolitinib
in patients with CMML
• Patients (N=20) with CMML-1 were included in the
study

• Exclusion criteria included an absolute neutrophil

count (ANC) <0.25 × 10(3) cells/dL and a platelet
count <35 × 10(3) cells/dL

• Four cohorts were enrolled with doses ranging from

5 to 20 mg twice daily of ruxolitinib in 5-mg dose
escalations.

• Total response rate of 35% was observed, phase II

trial is undergoing with recommended dose of 20
mg twice daily
Padron E et al. A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML).

Clin Cancer Res. 2016 Aug 1;22(15):3746-54.

 Allogenic Stem Cell Transplant

• In CMML most of the patients have either intermediate/high risk cytogenetics

• Allogeneic HCT remains the only potentially curative treatment for patients with CMML

• No randomized clinical trials comparing transplant to non-transplant

approaches

• CPSS-mol score at diagnosis has been shown to be predictive of survival and risk of
progression to AML

• Upfront HSCT is recommended in cases of CPSS Intermediate-2 or high risk CMML

• IPSS-R score may also be used for patients with dysplastic type CMML

• Achievement of better remission state before HSCT is the most important prognostic risk
factor

• Intensive chemotherapy is not recommended in patients with CMML, except in CMML-2

patients as a bridge to HSCT, or when the disease appears to be very close to AML
(presence of Auer rods, NPM1 mutation) 
 Lower risk CMML

Poor-risk cytogenetics

- Persistent blast increase (>50% or with >15% BM blasts)

- Life-threatening cytopenias [neutrophil counts, <0.3 × 109/L; platelet counts, <30 × 109/L]

- high red blood cell transfusion intensity ≥2 units per months for 6 months

- Poor-risk molecular features (NRAS,ASXL1,RUNX1,SETBP1)

Itzykson R et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet.

 Higher risk CMML

Itzykson R et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet.

 CMML treatment
contd

For anemia, as for MDS, Hb levels <10 g/dL are generally poorly tolerated by elderly patients and tend to trigger treatment onset.

For thrombocytopenia, treatment is generally triggered when the platelet count falls below 30 × 10 9/L or in case of bleeding sympto

Itzykson R et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet.

 Future lines of
treatment

Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treat

 Future lines of
treatment

Geevarghese A et al. Evolving Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treatment Paradigms. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):519-527. 

 Future lines of
treatment

Similar response rate

Geevarghese A et al. Evolving Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treatment Paradigms. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):519-527. 

 Summary
• CMML is a heterogenous hematological malignancy classified under
MDS/MPN

• CMML Classifications

• The diagnosis of CMML depends upon combination of morphologic,

histopathologic and chromosomal abnormalities

• TET2, SRSF2 most common somatic mutations

• ASXL1, SETBP1, NRAS,RUNX1 associated with adverse prognosis

• Non transplant strategies include ESA,HMA,Cytoreductive strategies

• Upfront HSCT should be considered in CPSS-Mol Intermediate-2 and

high risk population
Thank You