Chronic Myelomonocytic Leukemia (CMML)

Epidemiology and Etiology:

· Heterogenous clinical, haematological and morphological features

· Note that in some epidemiological surveys CMML is grouped with chronic MPNs and in others it is grouped with MDS

· 65-75y median age

Common sites:

· PB (always)

· BM (always)

· Spleen

· Liver

· Lymph nodes

Gross features:

· Splenomegaly maybe

· Hepatomegaly maybe

· Lymphadenopathy (uncommon) (may signal transformation to more acute phase)

Histologic features:

· PB:

· Monocytes mature with unremarkable morphology generally, but some are abnormal monocytes:

· Abnormal granulation maybe

· Unusual nuclear lobation or chromatin pattern maybe

· Blasts and promonocytes may be present (but < 20%)

· CMML-1: < 5 % blasts plus promonocytes in PB, < 10 % in BM

· CMML-2: >= 5% blasts plus promonocytes in PB, >= 10 % in BM

· Promonocytes (count as blasts in this context):

· Abundant light grey or slightly basophilic cytoplasm

· few granules, lilac-coloured, scattered

· chromatin finely distributed

· stippled nuclear chromatin

· variably prominent nucleoli

· delicate nuclear folding or creasing

· Promyelocytes and myelocytes < 10 % usually

· Dysgranulopoiesis (most cases):

· Neutrophils:

· Hypolobated

· Abnormal cytoplasmic granulation

· May be difficult to distinguish from dysplastic monocytes

· Basophilia, mild (sometimes)

· Eosinophilia maybe

· CMML with eosinophilia if >= 1.5 x 10⁹/L

· Platelets atypical, large (maybe)

· BM:

· Hypercellular (> 75% of cases)

· Normocellular or even hypocellular in some

· Granulocytic proliferation prominent (most)

· Dysgranulopoiesis (most)

· Dyserythropoiesis (> half)

· Megaloblastic, abnormal nuclear contours, ring sideroblasts)

· Megakaryocytic abnormalities (up to 80%):

· Micromegakaryocytes

· Abnormally lobated nuclei

· Reticulin fibrosis (mild to moderate) (nearly 30%)

· Nodules of mature plasmacytoid dendritic cells (plasmacytoid monocytes) (20%)

· Round nuclei

· Finely dispersed chromatin

· Inconspicuous nucleoli

· Eosinophilic cytoplasm rim

· Distinct cytoplasmic membrane / well-defined cytoplasmic borders

· Apoptotic bodies often with starry sky histiocytes (frequently)

· CMML-1: < 5 % blasts plus promonocytes in PB, < 10 % in BM

· CMML-2: 5-19 % blasts plus promonocytes in PB, 10-19 % in BM

·

· Spleen involvement:

· Red pulp infiltration by leukemic cells

· Lymph node involvement (uncommon, may signal transformation):

· Diffuse infiltration by myeloid blasts maybe

· Diffuse infiltration of plasmacytoid dendritic cells (less common)

Immunophenotype:

Marker:	Sensitivity:	Specificity:
CD33	Usually
CD13	Usually
CD14	Variable
CD68	Variable
CD64	Variable
HLA-DR	Variable
CD15	Usually
CD64	Usually
CD36	Usually
CD56	Maybe
CD2	Maybe
CD68R	Most reliable
CD163	Most reliable
Lysozyme (used in conjunction with CAE or cytochemistry)
CD123 (plasmacytoid dendritic cells)
CD14 (plasmacytoid dendritic cells)
CD43 (plasmacytoid dendritic cells)
CD68 (plasmacytoid dendritic cells)
CD68R (plasmacytoid dendritic cells)
CD45RA (plasmacytoid dendritic cells)
CD33 (weak) (plasmacytoid dendritic cells)
CD4 (plasmacytoid dendritic cells)
Granzyme B (plasmacytoid dendritic cells)
TIA1 (neg) (plasmacytoid dendritic cells)
Perforin (neg) (plasmacytoid dendritic cells)
CD56 (variable) (plasmacytoid dendritic cells)	Minority
CD2 (plasmacytoid dendritic cells)	Maybe
CD5 (plasmacytoid dendritic cells)	Maybe

· Cytochemistry:

· Alpha naphthyl acetate esterase

· Alpha naphthyl butyrate esterase

· Naphtol-ASD-chloroacetate esterase (chloroacetate esterase, CAE)

· (aspirate smears) Cytochemical or immunophenotypic studies strongly recommended whenever CMML is considered

· 2 or more aberrant monocyte phenotypes by flow cytometry (often)

· IHC on tissue sections is relatively insensitive compared to flow and cytochemistry

·

Molecular features:

· Karyotypic abnormalities (20-40%)

· None are specific

· +8

· -7 (very poor prognosis)

· Younger age groups

· del(7)(q*)

· 12p structural abnormalities

· i(17)(q10)

· ?association with blastic phase

· note: 11q23 abnormalities are uncommon in CMML, instead suggest AML

· Mutations:

· RAS point mutations (40%)

· JAK2 V617F (8%)

· PDGFRB rearrangements (now considered a distinct entity, not included in CMML)

· t(5;12)(q32;p13) (1%)

· PDGFRB-ETV6

· Multiple (>10) other fusion partners have been identified

· Also seen in other MPN, AML, maybe others (lymphoid?)

· Eosinophilia

· Proliferation of aberrant mast cells maybe

· Responsive to imatinib

· No BCR-ABL1 fusion by definition (must test for p190 isoform)

Other features:

· Diagnostic criteria (WHO 2008):

· Persistent peripheral blood monocytosis > 1 x 10⁹/L

· usually 2 to 5 x 10⁹/L

· > 80 x 10⁹/L in some

· > 10% of leukocytes almost always

· NO BCR/ABL1 fusion OR Philadelphia chromosome

· NO PDGFRA or PDGFRB rearrangement (exclude in cases with eosinophilia)

· Blasts < 20% in PB and BM

· Blasts include myeloblasts, monoblasts, and promonocytes.

· NOT including abnormal monocytes

· Dysplasia in 1 or more myeloid lineages, OR

· Clonal cytogenetic or molecular genetic abnormality is present in the haematopoietic cells AND

· The monocytosis has persisted >= 3 months AND

· All other causes of monocytosis have been excluded, such as:

· Malignancy

· Infection

· Inflammation

· WBC count elevated (most)

· Monocytosis

· Neutrophilia

· Some present with neutropenia resembling MDS

·

· Fever

· Weight-loss

· Fatigue

· Night sweats

· Infections

· Bleeding

· 20-40 month median survival

· Percentage of blasts in PB and BM is most important factor

· Progression to AML in 15-30%

References:

· Swerdlow et al. (eds.) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2008)

· Heim S, Mitelman F. Cancer Cytogenetics. 3rd ed. Wiley-Blackwell; 2009.

· Groupe Francais de Cytogenetique Hematologique. Cytogenetics of Chronic Myelomonocytic Leukemia. Cancer Genet Cytogenet 1986;21:11-20.