Atypical CML BCR-ABL1-Negative

Question 1

What is the definition of

atypical CML ?

Answer 1

• an MDS/MPN syndrome
• principal involvement of the neutrophil lineage
  
  • leukocytosis results from increase in morphologically dysplastic neutrophils and their precursors
• multilineage dypslasia is common
• no BCR-ABL1 fusion
  
  • or eosinophilia related myeloid/lymphoid neoplasm fusions

Question 2

What are the diagnostic

criteria for atypical CML ?

Answer 2

• peripheral blood leukocytosis >13 x 10^9/L
  
  • due to increased neutrophils and their precursors
  • precursors >10% of leukocytes
• dysgranulopoiesis
• no or minimal basophilia (<2% of leukocytes)
• no or minimal absolute monocytosis (<10%)
• hypercellular bone marrow with granulocytic dysplasia, with or without dysplasia of the erythroids and megas
• <20% of blasts
• No evidence of critier for other WHO entities

Question 3

Which mutations when present

and in the appropriate context support the

diagnosis of atypical CML ?

Answer 3

• SETBP1
• ETNK1

Question 4

What mutation is rare in atypical CML

and should prompt evaluation for

differenti diagnosis ?

Answer 4

• CSF3R
  
  • evaluate from chronic neutrophilic leukemia

Question 5

What is the epidemiology and

localization of aCML ?

Answer 5

• usually 1-2 aCML for every 100 CML cases
• generally elderly patients (70s)
  
  • but has been reported in teenagers
• usually 1:1 M:F ratio
• peripheral blood and BM always involved
  
  • note: spleen and liver commonly involved as well

Question 6

What are the clinical features

of aCML ?

Answer 6

• symptoms are usually related to anemia and thrombocytopenia
• or splenomegaly
• nothing disease specific

Question 7

What is one of the main morphologic

features that characterizes aCML ?

Answer 7

• dysgranulopoiesis
• may see dyspoiesis of the other lineages

Question 8

What other disease must aCML

be distinguished from morphologically?

Answer 8

• Chronic neutrophilic leukemia
  
  • no dysgranulopoiesis
  • neutrophil precursors <10% of WBC count in PB
  • also will have different genetic associations

Question 9

What are the findings in the bone marrow

for aCML ?

Answer 9

• M:E ratio >10:1
  
  • reflects the increased granulopoiesis and decreased erythropoiesis but in some cases erythroids account for >30% of the cellularity
  • dyserythropoisis is seen in 40% of cases
• dysgranulopoiesis is present
• megakaryopoiesis can be normal but sometimes decreased
  
  • will be dysplastic and can see micromegs
• blasts can be increased but are usually <20%

Question 10

What is a described variant of

aCML ?

Answer 10

• syndrome of abnormal chromatin clumping
  
  • high percentage of neutrophils and precursors with exaggerated chromatin clumping

Question 11

What when identified by IHC

or morphology should call in to question

the diagnosis of aCML ?

Answer 11

• the presence of monocytosis

Question 12

What is the genetic profile of aCML ?

Answer 12

• most common: gain of chromosome 8 and del 20q
• NO BCR-ABL fusion or eosinophilia associated gene translocations (PDGFRA etc)
• isochromsome 17q isolated
  
  • have features of aCML but otherwise fulfill criteria for CMML
• JAK2 has been rarely reported so it actually excludes aCML
• IMP:
  
  • SETBP1 and ETNK1 mutations are common

Question 13

What are the prognostic and predictive

factors for aCML ?

Answer 13

• they do poorly
• Adverse prognostic factors:
  
  • age >65 years
  • female sex
  • WBC >50 x 10^9/L
  • thrombocytopenia
  • hemoglobin level <10 g/dL
• survival may improve with stem cell transplant
• 30-40% evolve into AML and the rest die of marrow failure