Chronic Myeloid Leukemia

Question 1

CML (chronic myelogenous leukemia) - overview

Answer 1

*cancer of the white blood cells of the myeloid cell line (neutrophils, eosinophils, basophils)
*malignant cell is a relatively immature cell, but the cells are able to differentiate
*result is excess production of MATURE CELLS of MULTIPLE LINEAGES

-defined by the Philadelphia Chromosome: t(9;22) BCR-ABL p210

Question 2

CML (chronic myelogenous leukemia) - 3 different phases

Answer 2

1. chronic: slow growing
2. accelerated: faster growing
3. blast crisis: aggressive; acts like acute leukemia

Question 3

what cell is excessively active in CML (chronic myelogenous leukemia)?

Answer 3

myeloid stem cell is excessively active; results in lots of mature cells that come from the myeloid stem cells (increase in number of neutrophils AND their precursors)

recall: CML is defined by the Philadelphia Chromosome t(9;22) → BCR-ABL fusion protein

Question 4

CBC findings in CML (chronic myelogenous leukemia) - chronic phase

Answer 4

*elevated WBC count
*elevated neutrophils
*elevated levels of all different stages of neutrophils precursors (meaning these immature cells are present in the peripheral blood)

*elevated platelets
*normal to decreased RBCs/Hb
*normal to decreased lymphocytes
*eosinophils/basophils may or may not be increased

Question 5

CML (chronic myelogenous leukemia) - epidemiology

Answer 5

*median age of presentation: 50s (although not uncommon to dx patients in 20s-30s)
*85% of patients present in the chronic phase

Question 6

symptoms of CML (chronic myelogenous leukemia) - chronic phase

Answer 6

*oftentimes, no symptoms
*if symptomatic: fevers, splenomegaly

note - because patients with accelerated phase or blast crisis are developing cytopenias, their presenting symptoms are typically associated with those cytopenias

Question 7

diagnosis for CML (chronic myelogenous leukemia)

Answer 7

*FIND THE PHILADELPHIA CHROMOSOME - t(9;22) translocation → BCR-ABL fusion protein
*can be found by:
1. karyotype
2. FISH (fluorescent in situ hybridization)
3. PCR testing

Question 8

philadelphia chromosome and CML (chronic myelogenous leukemia)

Answer 8

*chromosome 9: abl gene; chromosome 22: bcr gene
*the abl protein is a tyrosine kinase, which is an enzyme involved in signal transduction
*when t(9;22) is present, the tyrosine kinase is always on/active, and therefore always ready to bind ATP
*this provides a constant signal to certain pathways that result in cell growth that exceeds apoptosis

Question 9

2 different BCR-ABL protein products

Answer 9

1. p190 (190 kDa protein): seen in ALL
2. p210 (210 kDa protein): seen in CML

Question 10

which BCR-ABL protein is transcribed in CML

Answer 10

210 kDa BCR-ABL protein

Question 11

diagnostic criteria for chronic phase CML

Answer 11

*t(9;22) translocation (philadelphia chromosome)
*no more than 5% blasts in the marrow

Question 12

diagnostic criteria for blast crisis CML

Answer 12

*t(9;22) translocation (philadelphia chromosome)
*20%+ blasts in the marrow
*just like any other acute leukemia
*can be myeloid or lymphoid

Question 13

diagnostic criteria for accelerated phase CML

Answer 13

*t(9;22) translocation (philadelphia chromosome)
*6-19% blasts in the marrow

Question 14

treatment for CML (chronic myelogenous leukemia)

Answer 14

*TYROSINE KINASE INHIBITORS (ex. IMATINIB)
*aka signal transduction inhibitors or small molecule inhibitors
*pill taken once a day

Question 15

side effects of CML (chronic myelogenous leukemia) treatment

Answer 15

*generally well tolerated:
-mild nausea and vomiting
-periorbital edema
-pleural effusions

Question 16

imatinib as a treatment for CML (chronic myelogenous leukemia)

Answer 16

*MOA: prevents BCR-ABL from binding to ATP

other ways that imatinib works:
*binds to c-kit on GISTs
*binds to PDGFR-alpha seen in chronic leukemia

Question 17

worrisome mutation to imatinib in CML treatment

Answer 17

T31FI mutation is concerning