CML

Question 1

Adults or kids or both?

Answer 1

Adults ONLY

Question 2

Four types of Chronic myeloproliferative disorders?

Answer 2

Chronic myeloid leukemia (neuts)

Polycythemia vera (RBC’s)

Essential thrombocythemia (platelets)

Myelofibrosis (little bit of everything)

Question 3

Characteristics common to all four disorders?

Answer 3

Leukocytosis w/ LEFT SHIFT

Hypercellular marrow —>

Big spleen

long clinical course
only in adults

may evolve into acute leukemia

mutated tyrosine kinase (an activating mutation)

Question 4

Things you must know about CML:

Answer 4

1. Neutrophilic leukocytosis
2. Basophilia
3. PHILADELPHIA chromosome
4. three phases

Question 5

What does the Hgb look like in CML?

Answer 5

LOW

Question 6

What’s LAP and what does it mean?

Answer 6

Leukocyte Alkaline Phosphate
**decreased in CML

**INcreased in benign leukocytosis

Question 7

What are the platelets gonna look like in CML?

Answer 7

Increased at first (lots of malignant megakaryocytes too) then decrease later when neuts take over

Question 8

Three phases of CML:

Answer 8

Chronic phase

Accelerated phase

Bast crisis

Question 9

Criteria for hematologic remission in CML:

Answer 9

no splenomegally

WBC

Question 10

Criteria for cytogenic remission?

Answer 10

no metaphases with t(9:22)

Question 11

Molecular remission criteria of CML?

Answer 11

No BCR/ABL transcripts by PCR

Question 12

4 things you must know about Polycythemia vera?

Answer 12

HIGH RBC (makes blood sludgy)

different from secondary polycythemia

thrombosis and hemorrhage

Jak-2 mutation

Question 13

Difference between primary and secondary polycythemia?

Answer 13

primary– intrinsic myeloid cell prob

secondary– increased erythropoietin (ie. paraneoplastic)

Question 14

Clinical sx of PV?

Answer 14

HA, pruritis, dizziness
-thrombosis, infarction

physical exam findings:
hepatosplenomegally
“Plethora” – old school term for flushing face/cheeks

Question 15

Whats the issue with the JAK-2 mutation in PV?

Answer 15

Increased activity–> cells grow on their own without external stimulus

Question 16

Tx for PV:

Answer 16

Phlebotomy

maybe myelosupressive drugs

Question 17

Prognosis and cause of death from PV?

Answer 17

Median survival 9-14 years

thrombosis or hemorrhage

**leukemic transformation in some patients

Question 18

What must I know about Essential thrombocythemia?

Answer 18

HIGH platelet count

YOUGN WOMEN (early adulthood)

diagnosis of exclusion

thrombosis and hemorrhage

Question 19

Dx criteria for ET?

Answer 19

Plts > 600,000

Hgb

Question 20

Sx and exam findings for ET?

Answer 20

Bleeding (plts don’t work right)

Thrombosis

Purpura, bruising

Pallor, tachycardia

Biggish spleen

Question 21

Tx for ET?

Answer 21

Platelet pheresis

Mayeb myelosupressive drugs

ASA

**median survival 5-8 years

-death from thrombosis or hemorrhage

Question 22

What must I know about chronic myelofibrosis?

Answer 22

• Panmyelosis
• …….then marrow fibrosis

MASSIVE extramedullary hematopoiesis

-TEARDROP RBCs

Question 23

Clinical findings of MF?

Answer 23

HUGE SPLEEN

LUQ “fullness” (from huge spleen, duh)

Pallor tachycardia

weakness, fatigue, palpitations

Question 24

Cause of death in MF:

Answer 24

marrow failure

**median survival 3-5 years

Question 25

Genetic hallmark of CML:

Answer 25

t(9:22)

PHILADELPHIA chromosome

BCR-ABL

Question 26

What cell type incurs the mutation leading to CML?

Answer 26

Hematopoietic stem cell

Question 27

What is BCR-ABL?

Answer 27

a constitutively active tyrosine kinase that activates proliferation and blocks apoptosis in the absence of extracellular signalling

Question 28

Cell lineage affected by CML?

Answer 28

neutrophils

Question 29

What’s the Blast phase of CML?

Answer 29

granulomonocyte progenitors acquire a mutation giving them the ability to self renew–> HUGE expansion of blast cells, 30% extramedullary

Question 30

Wnt-Beta catenin?

Answer 30

gets activated to trigger blast phase of CML

Question 31

CEBPa?

Answer 31

normally promotes differentiation, gets inhibited in blast phase

Question 32

3 big differences between BCR-ABL and normal ABL:

Answer 32

1. BCR-ABL is constitutively active, ABL requires signalling
2. ABL is nuclear, BCR-ABL is cytoplasmic
3. BCR-ABL activates more/different intracellular signalling pathways

Question 33

What does BCR contribute to the oncogenesis?

Answer 33

coil-coil domain promoting dimerization

Y177 is part of this somehow

Question 34

What’s myristate?

Answer 34

lost from ABL

**necessary fro autoinhibition of ABL tyrosine kinase activity

Question 35

Groundbreaking treatment targeting BCR-ABL tyrosine kinase very specifically by preventing ATP binding?

Answer 35

Imatinib

Question 36

3 limitations of Imatinib?

Answer 36

resistance can form via BCR-ABL mutation

not effective against blast phase

must be taken for life

Question 37

Two drugs similar to Imatinib that block ATP binding site of EGFR?

Answer 37

Erlotinib

Gefitinib

Question 38

Three drugs developed to fight cells that have become resistant to Imatinib?

Answer 38

Bosutinib

Dasatinib

Nilotinib

Question 39

Two reasons to worry about drug-drug interactions with Imatinib and the like?

Answer 39

CYP3A4 metabolism

highly plasma protein bound

Question 40

Toxicities for STIs?

Answer 40

relatively minor compared to cytotoxics

CHF–>MI (ABL tyrosine kinase is necessary for normal heart function)

Question 41

Specific toxicity for Imatinib?

Answer 41

edema, BM supression

Question 42

Specific tox for Erlotinib and Gefitinib?

Answer 42

Interstitial pneumonia