Chronic Myeloid Leukemia Flashcards
why type of disease is CML?
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
which cell line is over-proliferating in CML?
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
what are the characteristics of blood in CML?
- shows neutrophilic leukocytosis = high WBC count due to proliferation of neutrophils
- 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
- basophilia
what is the basophil count in CML?
basophil count is always elevated in CML = basophilia
we don’t know why this happens
what do the neutrophils in CML look like morphologically?
they look normal morphologically
BUT lack a normal neutrophil enzyme called leukocyte alkaline phosphatase (LAP)
what does the bone marrow in CML look like?
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
what type of cells are present in the BM of CML?
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)
in what population is CML most common?
CML generally occurs in older adults and does not occur in children
what are the phases of CML?
untreated, the disease has three phases:
- chronic phase
- accelerated phase
- blast crisis
patients normally present in chronic phase, and with treatment, many will remain there indefinitely
what is the chronic phase of CML?
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
what does the BM look like during the chronic phase of CML?
- neutrophilic leukocytosis
- basophilia in the blood
- the marrow is hypercellular with a neutrophilic predominance
- blast count is low
how are the Hb, WBC and platelet count effected during the chronic phase of CML?
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
how can you differentiate acute leukemia vs. chronic phase of CML?
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
what happens during the accelerated phase of CML?
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
what is the blast phase of CML?
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
what mutation causes CML?
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
what does the CML translocation mutation cause?
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
CML is characterized by what chromosomal abnormality?
CML is characterized by the chromosomal translocation t(9;22) –
the new chromosome 22 is called the Philadelphia chromosome
how do you treat CML?
imatinib drug
it’s a tyrosine kinase inhibitor designed to specifically block the BCR-ABL fusion tyrosine kinase seen in CML
In which cell type does the initial genetic defect occur in CML?
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
what laboratory findings would we expect to find in a patient with chronic phase chronic myeloid leukemia?
basophilia
patients with CML always have a basophilia
in fact, it is virtually the only condition in which basophilia is seen
The t(9;22) translocation in CML leads to the production of which aberrant proteins?
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
