MDS/ MPN

Question 1

What four molecular abnormalities are associated with a diagnosis of CMML?

Answer 1

ASXL1, TET2, SRSF2 and SETBP1

• Co-occurrence of SRSF2 and TET2= strongly suggestive of CMML

Question 2

Discuss how the different expression of CD14 and CD16 by monocytes in the peripheral blood can be predictive of CMML or a reactive process

Answer 2

• When the absolute monocyte count in the peripheral blood is elevated, the expression of CD14 and CD16 can be used (with high sensitivity and specificity) to determine the likelihood of CMML
• Classical MO1: CD14+/ CD16- in >94% of monocytes= >90% sensitivity and >95% specificity for CMML
• Intermediate MO2: CD14+/ CD16+= uncommon in CMML monocytes, more common in other MDS/ MPN and reactive monocytosis
• Non-classical MO3: CD14-/ CD16+= common in reactive monocytosis

Question 3

List the poor prognostic features in CMML

Answer 3

Clinical

• Lymphadenopathy
• Splenomegaly

FBC

• Anaemia
• Thrombocytopenia
• High WCC
• Lymphocytosis
• Blasts ≥2%

Other lab
- Elevated LDH

Molecular/ genetics

• Karyotype (trisomy 8, chromosome 7 abnormalities or complex karyotype)
• ASXL1 mutations

Question 4

What are the diagnostic criteria of atypical CML?

Answer 4

Peripheral Blood

• Peripheral blood leukocytosis ≥13
• Neutrophil precursors ≥10% of leukocytes
• Dysgranulopoiesis
• No basophilia or monocytosis

Bone marrow

• Hypercellular with granulocytic proliferation and dysplasia
• May have erythroid and/ or megakaryocytic dysplasia
• <20% blasts

Question 5

What mutations are seen in atypical CML

Answer 5

• SETBP1

- ENK1

Question 6

What mutations are seen in JMML

Answer 6

Mutations of the RAS family seen in 85%

• Can be somatic or germline
• Most common: PTPN11, NRAS, KRAS, NF1 and CBL

Monosomy 7 seen in ~25%
- Associated with red cell macrocytosis

Question 7

What syndromes are associated with JMML?

Answer 7

• Noonans (associated with PTPN11 mutations)

- NF1 (associated with NF1 mutations; loss of negative regulation of RAS)

Question 8

What are the diagnostic criteria of JMML?

Answer 8

· Clinical and haematological criteria (all 4 must be met)
o Monocytes >1
o Blasts <20%
o Splenomegaly
o BCR-ABL1 negative

· Genetic criteria (1 is sufficient)
o Somatic mutation in PTPN11, KRAS or NRAS
o Clinical diagnosis of NF1 or NF1 mutation
o Germline mutation and loss of heterozygosity of
CBL (acquired UPD).

· Other (if genetic criteria not met)
o Monosomy 7 or any other chromosomal abnormality.

OR ≥2 of the following: increased HbF for age, myeloid or erythroid precursors on PBC, CSF2 hypersensitivity, hyperphosphorylation of STAT5.

Question 9

What are the diagnostic criteria of MDS/MPN RS-T

Answer 9

• Anaemia with erythroid dysplasia, +/- multilineage dysplasia
• ≥15% ring sideroblasts
• Persistent thrombocytosis ≥450
• Blasts not elevated
• SF3B1 mutation
• No MDS defining mutations (t(3;3), inv(3) or del(5q-)) or other MPN, MPN/MDS mutations EXCEPT JAK2, CALR or MPL

(The diagnosis of MDS/MPN RS-T is strongly supported by the presence of an SF3B1 mutation together with JAK2, CALR or MPL)

Question 10

What are good prognostic factors in MDS/MPN RS-T

Answer 10

• Shorter life expectancy than ET but longer than MDS-RS-SLD

- Younger age, presence of SF3B1 +/- JAK2 mutations associated with a better prognosis