Myeloproliferative Disorders Flashcards
What are the WHO criteria for the accelerated phase of CML?
1) Blasts 10- 19% in the peripheral blood or bone marrow
2) Peripheral blood basophils >20%
3) Persistent leukocytosis, >10, despite treatment
4) Persistent thrombocytosis, >1000, unresponsive to therapy
5) Persistent thrombocytopenia, <100, unrelated to therapy
6) Persistent splenomegaly despite therapy
7) Presence of additional chromosomal abnormalities (both at diagnosis and acquired during therapy (clonal evolution)
What are the WHO criteria for blast phase of CML?
1) Blasts ≥20% in blood or bone marrow
2) Presence of extramedullary proliferation of blasts
What parameters are used to calculate the sokal and Eutos scores?
1) Sokal: age, spleen size, platelet count, blasts
2) Eutos: spleen size, basophil count
What is the Philadelphia chromosome?
Defective and abnormally short chromosome 22 caused by a reciprocal translocation between chromosomes 9 and 22.
Results in the generation of a fusion protein/ tyrosine kinase BCR-ABL
What are the most common genetic aberrations seen in CML, other than the Philadelphia chromosome?
Major route cytogenetics:
- Duplication of the Ph chromosome (amplification of BCR-ABL)
- +8, +19, iso17(q)
- Indicate accelerated phase of disease, poor prognosis
What different BCR-ABL breakpoints can be seen?
- P190 breakpoint e1a2: most common in ALL
- P210 breakpoint e13a2 (prev b2a2) and e14a2 (previously b3a2): most common in CML
- P230 and other rare variants also exist
What are the different response criteria to TKIs used for CML disease monitoring?
1) Complete haematological response
- Normal FBC, bone marrow morphology and spleen size
- Aim to achieve by 3 months of treatment
2) CCyR
- Absence of Ph+ metaphases on conventional cytogenetics
- Performed on a BM sample.
3) Using qPCR/ IS standardised baseline
- Log 1= 10% IS
- Log 2= 1% IS (equivalent to a CCyR)
- Log 3= 0.1% IS= MMR
- Log 4= 0.01% IS= MR4
- Log 4.5= 0.0032% IS= MR4.5, sometimes called a complete metabolic response
- Log 5= 0.001% IS= MR5
What are the targets in the treatment of CML with TKIs
1) Complete haematological response/ BCR-ABL <10% IS at 3 months
2) CCyR/ BCR-ABL 1% IS at 6 months
3) MMR at 12 months
What is the definition of treatment failure in CML?
· At 3 months: Ph+ >95% and/or no CHR
· At 6 months: Ph+ >35% and/ or BCR-ABL >10%
· At 12 months: BCR-ABL >1% and or Ph+ >0%
Anytime: loss of CHR, loss of CCyR, loss of MMR, CCA in Ph+ cells
What mutation in CML confers resistance to all TKIs?
T315I (at the TKI binding site)
How is erythropoietin measured?
- ELISA, enzyme immunoassay and radioimmune kits available
- Use a pure form of human erythropoietin from recombinant DNA
What are the differences between essential thrombocytosis and pre-fibrotic myelofibrosis?
Bone marrow cellularity
- Normal in ET, increased in pre-fibrotic MF
M:E
- Normal in ET, increased in pre-fibrotic MF
MK tight clusters
- Rare in ET, common in pre-fibrotic MF
MK size
- Normal- large- giant in ET, variable in pre-fibrotic
MF
MK nuclei
- Hyperlobulated in ET, variable in pre-fibrotic MF:
bulbous, hypolobulated, high N:C ratio, condensed
chromatin, “cloud-like” in pre-fibrotic MF
Reticulin grade
- 0-1 in both ET and pre-fibrotic MF
What is the definition of a small and large cluster in pre-fibrotic MF and PMF
- Small cluster= >3 cells
- Large cluster= >7 cells
At what proportions are JAK2, CALR and MPL mutations seen in ET and PMF?
- JAK2 in 50-60%
- CALR in 25-30%
- MPL in 5%
What are the two different types of CALR mutations? What is the prognostic implications of CALR mutations in ET and PMF
Type 1 CALR= Deletional. Most common.
Type 2 CALR= Insertional.
Type 1 CALR: more indolent course in PMF. Increased risk of transformation to MF in ET.