Chronic Myeloid Leukemia

Question 1

why type of disease is CML?

Answer 1

CML is one of a group of disorders called chronic myeloproliferative disorders

these disorders all have malignant, maturing myeloid cells filling up the marrow and spilling out into the blood

Question 2

which cell line is over-proliferating in CML?

Answer 2

the neutrophil line is proliferating even more than the other myeloid lines, so the marrow is hypercellular with a huge number of neutrophils and precursors

these cells spill into the blood, causing a neutrophilic leukocytosis and a left shift

Question 3

what are the characteristics of blood in CML?

Answer 3

1. shows neutrophilic leukocytosis = high WBC count due to proliferation of neutrophils
2. there’s also a left shift, which means that in addition to mature, segmented neutrophils, there are also immature neutrophil precursors, like myelocytes, that typically are not present in the blood
3. basophilia

Question 4

what is the basophil count in CML?

Answer 4

basophil count is always elevated in CML = basophilia

we don’t know why this happens

Question 5

what do the neutrophils in CML look like morphologically?

Answer 5

they look normal morphologically

BUT lack a normal neutrophil enzyme called leukocyte alkaline phosphatase (LAP)

Question 6

what does the bone marrow in CML look like?

Answer 6

moderately to markedly hypercellular depending on how far the disease has progressed

there’s not a lot of fat cells so that BM is nearly 100% cellular which is hyper cellular for any adult

most cells present are neutrophils and their precursors with not many myeloblasts

lots of megakaryocytic present and RBC precursors too

Question 7

what type of cells are present in the BM of CML?

Answer 7

virtually all of the cells present in this image are malignant

there are probably a few normal hematopoietic cells present, but they are definitely getting squeezed out by the malignant cells, and their numbers are declining rapidly

the patient is likely having symptoms like fatigue (from anemia), infections (from not having enough normal leukocytes around), and bleeding (from thrombocytopenia)

Question 8

in what population is CML most common?

Answer 8

CML generally occurs in older adults and does not occur in children

Question 9

what are the phases of CML?

Answer 9

untreated, the disease has three phases:

1. chronic phase
2. accelerated phase
3. blast crisis

patients normally present in chronic phase, and with treatment, many will remain there indefinitely

Question 10

what is the chronic phase of CML?

Answer 10

may be completely asymptomatic, and the disease may be discovered on a routine CBC for some other reason

but many patients have vague symptoms such as fatigue or a dragging feeling in the left upper quadrant due to splenomegaly

Question 11

what does the BM look like during the chronic phase of CML?

Answer 11

1. neutrophilic leukocytosis
2. basophilia in the blood
3. the marrow is hypercellular with a neutrophilic predominance
4. blast count is low

Question 12

how are the Hb, WBC and platelet count effected during the chronic phase of CML?

Answer 12

they’re stable, they don’t increase or decrease

over time though as the disease progresses, the hemoglobin, the normal leukocyte number, and the platelet count will drop because the marrow is being filled with malignant cells

Question 13

how can you differentiate acute leukemia vs. chronic phase of CML?

Answer 13

in acute leukemia, the counts can vary wildly: the WBC may double in a few days, and the platelet count may drop precipitously in the same amount of time

in chronic phase CML, the counts change slowly over time

Question 14

what happens during the accelerated phase of CML?

Answer 14

characterized by a general destabilization of the “counts”

WBC count starts to rise, despite treatment

blast counts also start to go up - when it rises over 10%, then it’s officially in accelerated phase

platelet count can increase or decrease and they’re unresponsive to treatment

worsening symptoms

this phase is very difficult to treat and typically transitions into blast crisis within 6-12 months

Question 15

what is the blast phase of CML?

Answer 15

this phase is basically the same thing as an acute leukemia

blast count is over 20%

most of the time, the blast crisis is myeloid, but about 30% of the time, the blasts are lymphoblasts - seems strange until we remember that in some cases of myeloproliferative disorders, the initial genetic mutation occurs in a stem cell that is so early and undifferentiated that it hasn’t even decided whether it wants to be lymphoid or myeloid

this phase of CML is extremely difficult to treat, and survival is generally on the order of weeks to a few months

Question 16

what mutation causes CML?

Answer 16

a translocation between chromosomes 9 and 22 (called the t(9;22) translocation)

this moves an oncogene called ABL from the long arm of chromosome 9 next to the breakpoint cluster region (BCR) on the long arm of chromosome 22 (now known as the Philadelphia chromosome)

when parts of each chromosome are moved, genes that are not normally related to each other can be connected = gene fusion

in CML the t(9;22) causes the fusion of the BCR gene on chromosome 22 with the ABL gene from chromosome 9

Question 17

what does the CML translocation mutation cause?

Answer 17

the fusion of the BCR and ABL genes creates a hybrid BCR-ABL gene, which encodes an overactive tyrosine kinase protein, which in turns leads to uncontrolled cell growth

Question 18

CML is characterized by what chromosomal abnormality?

Answer 18

CML is characterized by the chromosomal translocation t(9;22) –
the new chromosome 22 is called the Philadelphia chromosome

Question 19

how do you treat CML?

Answer 19

imatinib drug

it’s a tyrosine kinase inhibitor designed to specifically block the BCR-ABL fusion tyrosine kinase seen in CML

Question 20

In which cell type does the initial genetic defect occur in CML?

Answer 20

stem cell

all chronic myeloproliferative disorders are stem cell disorders

the initial genetic defect occurs in a stem cell and since there is no block in differentiation or maturation, the defect is passed down to all cell progeny

Question 21

what laboratory findings would we expect to find in a patient with chronic phase chronic myeloid leukemia?

Answer 21

basophilia

patients with CML always have a basophilia

in fact, it is virtually the only condition in which basophilia is seen

Question 22

The t(9;22) translocation in CML leads to the production of which aberrant proteins?

Answer 22

tyrosine kinase protein

in CML the translocation between chromosome 9 and 22 causes a new, fusion gene called bcr-abl that encodes a constitutively active (“always on”) tyrosine kinase, which leads to uncontrolled cell proliferation