Chronic Myeloid Leukemia

Question 1

CML

Answer 1

myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation
neutrophils, but also basophils and eosinophils

CML is associated with the fusion of two genes: BCR (on chromosome 22) and ABL1 (on chromosome 9)4

Question 2

phases CML

Answer 2

CML usually progresses from a relatively indolent disease (termed chronic stable phase), easily controlled with oral agents, to a more aggressive disorder (accelerated phase), during which time disease control is more difficult to achieve.

chronic
accelerated
blast

Question 3

chronic stable CML

Answer 3

Untreated progresses from chronic phase
(3-5 years) to blast crisis

Peripheral blood blasts fewer than 10% in the blood and bone marrow

easily controlled

Tyrosine kinase inhibitors — First- and second-generation oral tyrosine kinase inhibitor (TKIs) (eg, imatinib, dasatinib, nilotinib)

Question 4

Accelerated phase CML

Answer 4

Blasts 10-19% of white blood cells in peripheral and/or nucleated bone marrow cells

unresponsive/less responsive to therapy
failure of initial therapy

Question 5

Blast phase CML

Answer 5

Peripheral blood blasts ≥ 20% of peripheral blood white blood cells or nucleated bone marrow cells

behaves like an acute leukemia

Question 6

Treatment of CML

Answer 6

RTK inhibitors form the basis of treatment
largely replaced chemo / hydroxyurea based therapy

goal is molecular response
aim less than 0.1% blast cells within 3 months of starting therapy

can get complete molecular response
less than 0.01% blast cells

imatinib
dasatinib 2nd gen
nilotinib 2nd gen

in accelerated phase or blast crisis the only durable treatment remains allogenic stem cell transplant

Question 7

Imatinib

Answer 7

tyrosine kinase inhibitor
It occupies the TK active site, leading to a decrease in activity.

used in treatment of CML

side effects:
nausea
fluid retention
congestive heart failure***

Question 8

Dasatinib

Answer 8

tyrosine kinase inhibitor

side effect to watch out for is pleural effusions / pneumonitis
not the drug of choice in individuals with lung disease

Question 9

Nilotinib

Answer 9

tyrosine kinase inhibitor

side effect is increased risk of cardiovascular diseae
thought to be due to increased lipids
prescribe with statin

can be used in cml that is refractory to imatinib

Question 10

hydroxyurea

Answer 10

Hydroxyurea suppresses the production of granulocytes in the bone marrow

selectively inhibits ribonucleoside diphosphate reductase, preventing the conversion of ribonucleotides to deoxyribonucleotides, halting the cell cycle at the G1/S phase and therefore has radiation sensitizing activity by maintaining cells in the G1 phase and interfering with DNA repair