Module 1: Heme: CML and PM

Question 1

One of the last Leukemias to be discussed is Chronic Myeloid Leukemia. What is the pathogenesis for this?

Answer 1

malignant tumor of relatively mature granulocytes, resulting in proliferation
–basophils, neutrophils, metamyelocytes, myelocytes and eosinophils
–t(9;22): BCR-ABL — overactivity of TK receptor
White cell cancer of granulocytes so neutrophils, basophils, band cells, eosinophils and metamyelocytes take over the bone marrow.

Question 2

what do you see on Bone Marrow biopsy for these patients?

Answer 2

Bone Marrow:

• -not pancytopenia (normochromic normocytic anemia) due to lack of neutropenia (the neutrophils are just malignant so thats why you get anemia with lots of neutrophils). Low Lap score = recurrent infections because neutrophils are malignant
• –Increased Total WBC count (lots of granulocytes and band cells)
• -increased band cells = bandemia = left shift = increased risk of developing blast crisis
• -Mimic Leukomoid reaction (but normal leukomoid reaction has increased LAP score)

Question 3

What do you see on PB smear in CML?

Answer 3

PB smear:

-PMNs, basophils, eosinophils and blast cells and band cells

Question 4

What is seen on BM aspirate in CML?

Answer 4

less than 10% lymphoblasts

–if converts to AML — blast crisis — greater than 20% blasts

Question 5

What is the most accurate test for CML?

Answer 5

FISH

• -looking for t(9;22) Philadelphia chromosome
• -overactivation of the tyrosine kinase receptor due to BCR-ABL

Question 6

What symptoms does the patient present with?

Answer 6

1. Anemia
2. Recurrent infections (low LAP score)
3. No neutropenia = no pancytopenia
4. Thrombocytopenia
5. Heptaosplenomegaly + Lymphadenopathy (Extramedullary hematopoiesis)
6. Pruritis following hot showers (basophils secreting histamine, would also been seen in polycythemia vera)
7. Gout: high cell turnover (uric acid)
8. WBC extremely high = left shift

Question 7

What are complications associated with CML?

Answer 7

1. Recurrent infections= most common cause of death (neutrophila with low LAP score)
2. Heart failure (Anemia)
3. Renal Failure (high uric acid destroying renal tubules)
4. Gout
5. CML —AML (blast crisis)

Question 8

What are treatments for patients with CML?

Answer 8

1. Tyrosine Kinase Inhibitor (Imatinib/Gleevec): can also be used to treat GIST in the GIT
2. Bone Marrow transplant is definitive treatment

Question 9

CML can under go a spent phase, what does this mean?

Answer 9

Lots of collagen — secondary myelofibrosis

• -teardrop cells seen in blood
• –dry tap
• only time CML will produce a dry tap and only time we will see tear drop RBCs

Question 10

Finally the last neoplasm that will be discussed is Primary Myelofibrosis. What is the associated mutation and pathogenesis in this neoplasm?

Answer 10

Mutation in JAK2
—atypical megakaryocytes secrete TGFbeta and PDGF leads to abnormal deposition of collagen — BM fibrosis — pancytopenia

Question 11

Side note: what other conditions have JAK2 mutations?

Answer 11

1. Polycythemia vera
2. Essential Thrombocytosis
3. SCID

Question 12

What is the main symptom you see in patients with primary myelofibrosis?

Answer 12

Massive hepatosplenomegaly: due to extramedullary hematopoiesis

Question 13

What do you see on BM aspirate of patients with primary myelofibrosis?

Answer 13

BM aspirate:

Dry tap due to fibrosis of the BM

Question 14

What do you see on bone marrow biopsy on patients with primary myelofibrosis?

Answer 14

BM biospy:
Hypocellular marrow
lots of collagen
reticulin stain: stain the collagen black

Question 15

What do you see on PB smear in patients with primary myelofibrosis?

Answer 15

PB:
Dacrocytes: teardrop shaped RBCs due to fibrosis
Immature WBCs and RBCs (leukoerythroblastosis)

Question 16

What are complications of Primary Myelofibrosis?

Answer 16

1. Recurrent infections - most common cause of death
2. Heart Failure
3. AML (blasts with greater than 20-25%)

Question 17

What is the treatment for Primary Myelofibrosis?

Answer 17

Bone marrow transplant

Question 18

What age do you see CML in?

Answer 18

40-50 year olds

Question 19

What is leukomoid reaction?

Answer 19

no translocation 
no basophilia 
High LAP score (Because neutrophils are normal and not malignant like in CML)
Left shift 
Neutrophilia 
Elevated WBC count

Question 20

What population do you see polycythemia vera in?

Answer 20

more common in older ppl 40-60s

Question 21

Is polycythemia vera a secondary or primary polycythemia?

Answer 21

Primary Polycythemia: because oxygen tension is normal (no hypoxia), EPO levels are very low because of negative feed back you are making to many red blood cells

Question 22

What is the mutation in polycythemia vera?

Answer 22

JAK2 (also seen in primary myelofibrosis and ET)

Question 23

Why do patients with polycythemia vera have red cheeks?

Answer 23

Too many red cells so very red complexion

Question 24

Polycythemia vera can cause hyper viscosity syndrome, what is this?

Answer 24

Symptoms: recurrent symptoms and blurred vision (due to ischemia to retina and cerebral hemispheres)
–syndrome leads to thrombosis (Cells are moving slow because blood is super thick) – infarcts in the spleen and this causes bleeding

Question 25

On PCR for polycythemia vera, what do you look for?

Answer 25

JAK2 and low EPO levels

Question 26

Why is iron low in polycythemia vera?

Answer 26

Because your body is using iron to make red cells (serum iron is therefore super low).
–not anemia because you have lots of red cells but a deficiency in iron

Question 27

What is the treatment for polycythemia vera?

Answer 27

Phlebotomy: bleeding patients out

Question 28

What is secondary polycythemia?

Answer 28

Low oxygen tension

EPO levels very high because of chronic hypoxia aka COPD and right to left shunts and high altitudes