CMML

Question 1

What is the definition of

CMML ?

Answer 1

• features of both an MPN and MDS
• categorized into different groups based on percentage of blasts in PB and BM
  
  • 0, 1, and 2
• heterogeneous group on which predominates, MDS vs. MPN component but both are there to some degree
• IMP:
  
  • JAK2 V617F mutation is uncommon

Question 2

When should you NOT call

CMML ?

Answer 2

• cases with previously diagnosed MPN or MDS
• evolution to a CMML phenotype generally constitutes disease progression and should NOT be classified as CMML

Question 3

What is another instance where

the diagnosis of CMML should be cautiously made ?

Answer 3

• MPNs can be associated with monocytosis or the monocytosis can develop over the course of disease and mimic CMML
• if there is a documented history of an MPN
  
  • CMML is excluded
• presence of MPN features in BM and or MPN mutations (JAK2, CALR, or MPL)
  
  • supports MPN with monocytosis rather than CMML

Question 4

What genes, if present, are supportive

of the morphology of CMML ?

Answer 4

• TET2
• SRSF2
• ASXL1
• SETBP1

Question 5

What is the epidemiology of

CMML ?

Answer 5

• incidence is highest in older patients >70
• more common in women 1.5: 3.1 ratio M:F

Question 6

What is the etiology and localization

of CMML ?

Answer 6

• etiology is unknown but ionizing radiation is a probably cause
• therapy-related CMML is also an entity
• blood and bone marrow are always involved
• extramedullary leukemic infiltrate
  
  • spleen
  • liver
  • skin
  • lymph nodes

Question 7

What are the clinical features of

CMML ?

Answer 7

• half or more present with increased WBC
  
  • but it can be normal or slightly decreased
  • variable neutropenia
• IMP: separating CMML into the dysplastic vs. proliferative groups has some clinical significance
  
  • constitutional symptoms are more common in the proliferative type
• splenomegaly and hepatomegaly are seen in both
• in rare cases life threatening leukocytosis can be seen

Question 8

What are the diagnostic criteria

for CMML ?

Answer 8

• persistent peripheral blood monocytosis (>1 x 10^9/L) with monocytes accounting for >10% of WBC
• criteria for other MPNs are not met
• No rearrangement of PDGFRA, PDGFRB, FGFR1 and PCM1-JAK2
• blasts are <20% of the PB and BM
• Dysplasia involving > 1 myeloid lineage OR
  
  • if MDS is absent or minimal the first 4 criteria are met plus
  • acquired clonal cytogenetic abnormality
  • monocytosis has persisted for >3 months with exclusion of other causes

Question 9

What are the microscopic findings

in CMML ?

Answer 9

• in general the monocytes are mature with unremarkable morphology
  
  • can have unusual segmentation and chromatin pattern
  • better called “abnormal’ monocytes
  • monoblasts and promonocytes should be < 20%
• other changes can be variable
• neutrophil precursors usually <10%
• eosinophils are usually normal but can be strikingly increased
• platelets vary but thrombocytopenia usually present
• hypercellular bone marrow usually

Question 10

What are common findings in the

bone marrow in CMML ?

Answer 10

• granulocytic proliferation is most striking but can have increased erythroids
• monocytic proliferation can be difficult to recognize
• micromegas are seen in 80% of biopsies
• no pseudo-Gaucher cells are seen
• mild to moderate reticulin fibrosis is present

Question 11

What other cell proliferation has been

associated with CMML ?

Answer 11

• nodules composed of mature plasmacytoid dentritic cells in the bone marrow biopsy seen in 20% of cases
  
  • closely related to the CMML
• morphology of PDCs
  
  • round nuclei, fine chromatin
  • inconspicuous nucleoli
  • rim of eosinophilic cytoplasm with distinct cytoplasmic borders
• when the disease progresses they can sometimes infiltrate the LNs
  
  • can be the presenting manifestation

Question 12

What is the percentage of

blasts usually in CMML ?

Answer 12

• PM: <5%
• BM: <10%
• a higher proportion at diagnosis may indicate a poor prognosis and faster transformation

CMML is subcategorized by the percentage of blasts and promonocytes

Question 13

What is the definition of

CMML-0 ?

Answer 13

• <2% blasts in blood
• <5% blasts in BM
• No Auer rods

Question 14

What is the definition of

CMML-1 ?

Answer 14

• 2-4% blasts in the PB or 5-9% in BM
• <5% blasts in PB
• <10% in BM
• No Auer rods

Question 15

What is the definition of

CMML 2 ?

Answer 15

• 5-19% blasts in the blood
• 10-19% blasts in the BM
• or Auer rods are seen
• <20% blasts in either compartment

Question 16

Review IHC

p. 85

Question 17

What is the immunophenotype of

the PDCs associated with CMML ?

Answer 17

• Positive:
  
  • CD123, CD2, CD4, CD43, CD45RA, CD68, CD303 and Granzyme B
• Other possible markers
  
  • CD2, CD5, CD7, CD10, CD13, CD14, CD15, CD33 and rarely CD56
• Negative
  
  • TIA-1
  • Perforin

Question 18

What is the genetic profile

of CMML ?

Answer 18

• 20-40% of cases have a clonal cytogenetic abnormality but none are specific
• Most common recurrent abnormalities
  
  • gain of chromosome 8
  • loss of chromosome 7 or del 7q
• Note:
  
  • some myeloid neoplasms with a loss of 17q have featues of CMML
• abnormalities of 11q23.3 and NPM1 are uncommon in CMML
  
  • should exclude leukemia in these cases

Question 19

Which disease entity can closely mimic

CMML ?

Answer 19

• CML with p190 BCR-ABL isoform
• even if t(9;22) is not seen by conventional karyotype should do PCR analysis for p210 or p190 and FISH for BCR-ABL

Question 20

What are the prognostic and predictive

factors in CMML ?

Answer 20

• reported survival 1 month to >100 months
  
  • median 20-40 months
• progression to AML
  
  • 15-30% of cases
• % of blood and BM blasts are most important factor for survival
  
  • along with karyotype
  • WBC count
• AML transformation from CMML is aggressive