AssessmentsLeukemia: Clinical practice
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 45-year-old woman presents at a the doctor’s office visit with fatigue and weakness. These symptoms have persisted for the past three weeks. She complains of excessive sweating at night. Physical examination reveals splenomegaly. Fluorescence in situ hybridization cytogenetic testing detects a 9;22 translocation and the BCR-ABL fusion gene within somatic cells, and she receives Imatinib as treatment. Which of the following describes the mechanism by which this drug works?
Contributors:Tanner Marshall, MS
Leukemia is a cancer of bone marrow progenitor cells that spreads into the bloodstream, and it typically causes the white blood cell count to exceed 11 x 10^9 cells/liter.
This is in contrast to lymphoma, which is a malignancy of white blood cells that arises from the lymph nodes.
Leukemia can be classified based on cellular lineage - so it’s myeloid for granulocytes, which include basophils, eosinophils, neutrophils and mast cells, and lymphoid for lymphocytes, which include T-cells, B-cells, and natural killer cells.
If the maturational process is blocked at an early stage of cell differentiation, so that the cancerous cells are immature blast cells with tiny nuclei and lots of cytoplasm, it’s called acute leukemia.
If the block happens at a later stage, the cancerous cells are slightly more mature with large nuclei and little cytoplasm, and it’s called chronic leukemia.
Immature cells tend to be less capable of doing their intended job, so they often cause more problems then slightly more mature cells.
Acute leukemia patients tend to have more symptoms like fatigue and bone pain, while, chronic leukemia patients are often asymptomatic and go unnoticed until a routine complete blood count or CBC is done, which often shows a white blood cell count that may be as high as 100 x 10^9 cells/liter.
If leukemia is suspected based on symptoms like frequent infections, easy bleeding, fatigue, and weight loss, then a workup typically includes a CBC, looking for high white blood cell count.
If the majority of the white blood cells are neutrophils, the likely diagnosis is AML or CML.
If the majority of cells are lymphocytes, then the likely diagnosis is CLL if chronic, and ALL if acute.
Additionally, a peripheral blood smear is done to look for the malignant cells and their level of maturity, based on their microscopic features.
Once leukemia is suspected based on the appearance of lots of immature white blood cells, a bone marrow biopsy and cytogenetic testing can be done to confirm the diagnosis and guide treatment.
Let’s start with CML, which is more common in the elderly and presents in one of three phases.
Patients often move from one phase to another, and with each phase, the malignant hematopoietic cells become more immature and therefore more difficult to treat.
In other words the symptoms result from the presence of lots of abnormal cells incapable of serving their function, rather than the lack of cells.
Next is the accelerated phase, in which cellular proliferation accelerates, and third is the blast phase or crisis, in which cellular proliferation gets to a point where it becomes acute leukemia, which can be AML.
In some cases, it can even become ALL, which may be triggered by a gene mutation that affects how an early progenitor cell differentiates into a lymphoid cell.
It’s important to distinguish CML from a leukemoid reaction.
A leukemoid reaction is a normal overreaction of the bone marrow to infections or stressors, and it can cause a white blood cell count of more than 40,000 and a left shift.
We all know people who overreact, from now on just call them leukemoid.
The main way to differentiate CML from leukemoid; is that normal leukemoid cells take up the enzyme leukocyte alkaline phosphatase, or LAP, whereas CML cells don’t.
If CML seems likely, it’s important to do a bone marrow biopsy, which will show an increase in the ratio of myeloid to erythroid cells, which is normally somewhere around 3:1. But taken alone, this is a non-specific finding, since the ratio can increase in an infection as well.
In addition, in a bone marrow biopsy, in the chronic phase, there will be <10% blast cells, in the accelerated phase they’ll be 10-20% blast cells, and in the blast phase, they’ll be more than 20% blast cells.
Finally, we can do karyotype analysis to look for chromosomal translocations.
CML is associated with the 9:22 translocation, which is where there’s fusion of the BCR gene on chromosome 22 and the ABL tyrosine kinase gene on chromosome 9. This is called the Philadelphia chromosome.
We can look for this fusion gene by doing fluorescence in situ hybridization, or FISH analysis.
The presence of the Philadelphia chromosome is absolutely necessary for the diagnosis of CML.
The Philadelphia chromosome is also a target of tyrosine kinase inhibitors, or TKIs, such as imatinib and nilotinib.
But CML can develop resistance to these medications and a person can go into blast crisis, which can require allogeneic hematopoietic stem cell transplantation.
All right, on to CLL, which is the most common leukemia in adults and is also a disease of the elderly.
CLL is considered synonymous to it’s lymphoma variant, small lymphocytic lymphoma, or SLL; the difference is that SLL starts in a lymph node instead of the bone marrow.
Like CML, CLL is usually asymptomatic and often discovered incidentally, but can sometimes cause lymphadenopathy and hepatosplenomegaly.
The CBC may reveal anemia or thrombocytopenia, which may be due to two possible causes.
One possibility is that the CLL cells are infiltrating the bone marrow.
Another possibility is that the CLL cells are making auto-antibodies against red blood cells called autoimmune hemolytic anemia, or AIHA, or against platelets called idiopathic thrombocytopenic purpura, or ITP.
AIHA can be diagnosed by a positive direct Coombs test, while ITP is a diagnosis of exclusion.
CLL is also associated with hypogammaglobulinemia, because although there are a lot of lymphocytes, they’re abnormal and don’t make useful antibodies, which increases the risk of infection.
In other words, CLL cells make antibodies that can attack our own cells, but not antibodies that attack actual pathogens.
Finally, a minority of CLL patients can develop Richter syndrome, which is a transformation of CLL into an aggressive form of lymphoma called diffuse large B-cell lymphoma.
In CLL, the peripheral blood smear will show an absolute lymphocyte count higher than 5000.
Sometimes smudge cells are seen on peripheral blood smear, which are fragile CLL cells that get smooshed when spread on a glass slide. Good riddance.
Next is flow cytometry, which identifies the CLL cells by their cellular surface markers - CD5, CD19, and CD23.
So a diagnosis of CLL requires an absolute lymphocytosis and confirmation with flow cytometry.
You don’t need a bone marrow biopsy, but if you were to do one, you’d see a hypercellular bone marrow with >30% lymphocytes.
Treatment of CLL depends on the Rai system, which has stages 0 through 4.
Stage 0 is absolute lymphocytosis only.
Stage 1 adds lymphadenopathy, stage 2 adds hepatosplenomegaly, stage 3 adds anemia that isn’t due to AIHA, and stage 4 adds thrombocytopenia that isn’t due to ITP, rather both are due to bone marrow infiltration.
Asymptomatic patients that are in stage 0, or those with stage 1 or stage 2 disease are simply observed because in those early stages, CLL is fairly indolent and progresses slowly. As a result, it often isn’t the cause of death in elderly patients.
On the other hand, young patients or stage 3 and 4 patients are often given chemotherapy.