Chronic Myeloid Leukemia And Other Mpns

Front 1

Define myeloproliferative neoplasms.

Back 1

A clonal myeloid (bone marrow) neoplasm in which a genetic alteration in a hematopoietic progenitor cell results in an increase in peripher WBCs, RBCs, platelets, or a combination of these

Front 2

What are the 4 main MPNs?

Back 2

Chronic Myelogenous Leukemia (CML)
Polycythemia Vera (PV)
Essential Thrombocytosis (ET)
Primary Myelofibrosis (PMF)

Front 3

What is a one or two sentence overview of CML?

Back 3

The predominant feature is a leukocytosis with a left shift. A mild anemia, normal to elevated platelet count, and a peripheral blood basophilia are often seen.

Front 4

What is a one or two sentence overview of PV?

Back 4

Predominant feature is elevated RBC indices (count, hemoglobin, and hematocrit). Patients often also have a mild leukocytosis and thrombocytosis. The main problem is the increase in blood viscosity due to these RBCs leading to thromboses

Front 5

What is a one or two sentence overview of ET?

Back 5

Predominant feature is an elevated platelet count. Patients also often have a mild leukocytosis and polycythemia

Front 6

What is a one or two sentence overview of PMF?

Back 6

Predominant feature is evidence of extramedullary hematopoiesis in the form of hepatomegaly, splenomegaly, and lymphadenopathy. Patients often have a mild anemia, but their WBC and platelet counts can be quite variable. Leukoerythroblastosis (tear drops, nucleated RBCs, and early myeloid progenitors) are often seen in the peripheral blood

Front 7

What are the genetic mutations associated with the 4 main MPNs?

Back 7

CML - BCR-ABL (Philadelphia chromosome)

PV, ET, PMF - JAK2V617F (95%, 50%, 50%)

Front 8

What is the dominant abnormal cell line in each of the 4 main MPNs? (but remember, this is not the only cell line involved often)

Back 8

CML - neutrophils
PV - RBCs
ET - platelets
PMF - monocytes

Front 9

What are some risk factors for CML?

Back 9

MOAR!!
Male
Organic solvent exposure (lab solvents, not weed killer)
Age (OMS)
high dose RADIATION exposure

Front 10

What are the three phases of CML? How are they determined?

Back 10

Determined by the percent of blasts of the WBCs

Chronic phase (<10% blasts)
Accelerated phase (10-19% blasts)
Blast phase (>20% blasts)

Front 11

What is the Philadelphia chromosome?

Back 11

Translocation between 9 and 22; results in formation of the Bcr-Abl tyrosine kinase

Front 12

How does a patient with CML present?

Back 12

15% asymptomatic
Fatigue, weight loss, fever

Splenomegaly (abdominal fullness, pain and/or early satiety)

Easy bruising and purpura

Leukostasis (pulmonary and neurologic symptoms)

Front 13

What do you see in a CML peripheral blood smear? (5)

Back 13

Leukocytosis with a left shift
Normocytic anemia
Thrombocytosis (50% of patients)
Absolute eosinophilia
Absolute increase in basophils

Front 14

How do you diagnose CML?

Back 14

DEMONSTRATE PHILADELPHIA CHROMOSOME

Karyotype (not as great)
FISH (fluorescent in-situ hybridization)
Quantitative RT-PCR for Bcr-Abl

Front 15

What is the drug class that treats CML?

Back 15

Tyrosine Kinase Inhibitors (TKI) because that's what Bcr-Abl is

Front 16

What are some of the TKIs?

Back 16

Imatinib
Dasatinib
Nilotinib

Front 17

What is the main mechanism of TKI resistance?

Back 17

Mutation in Bcr-Abl kinase that prevents drug binding

Front 18

How do you treat a TKI-resistant CML?

Back 18

Escalate dose of imatinib
Use a different TKI - dasatinib, nilotinib, bosutinib that might 'fit' better
Bone marrow transplant
Clinical trial participation

Front 19

When don't you want to use imatinib for CML?

Back 19

Well, when there is some resistance, but mainly when the patient has advanced CML. The longer it takes to start on imatinib, the less effective the treatment is

Front 20

What does JAK2 code for?

Back 20

Non-receptor tyrosine kinase

Front 21

What happens in the mutant JAK2?

Back 21

You get constitutive expression of JAK2 (which is a proximal step in the Ras/Raf pathway and so you get proliferation and survival of the cell)

Front 22

What is on your differential diagnosis when you see an increase in RBC or hemoglobin?

Back 22

Absolute polycythemia (increase in RBC mass):
-Primary PV
-hypoxia
-Carboxyhemoglobinemia
-Cushing's syndrome or corticosteroids
-EPO-secreting tumors

Relative polycythemia (decrease in plasma volume):
-Dehydration
-Stress erythrocytosis leads to contraction in plasma volume. Most often seen in hypertensive, obese men

Front 23

What is the clinical presentation of PV?

Back 23

Symptoms:
Non-specific - headache, weakness, dizziness, and excessive sweating
Pruritus, especially following a warm bath or shower (KNOW)
Erythromelalgia (burning pain in feet/hands with erythema, pallor, or cyanosis)
Symptoms related to arterial/venous thrombosis

Signs:
Facial plethora (red face)
Splenomegaly
Hepatomegaly
Gouty arthritis and tophi

Front 24

What is the diagnostic algorithm for PV?

Back 24

Screen for JAK2 V617F and get serum EPO

+JAK2 and low EPO: PV highly likely, don't need BM biopsy

+JAK2 but normal/high EPO: PV likely, get BM biopsy to confirm

-JAK2 but low EPO: PV possible, get BM biopsy and more in depth JAK2 screening

-JAK2 and normal EPO: probably not PV

Front 25

How do you treat PV?

Back 25

Low Risk: phlebotomy + low dose ASA

High Risk: phlebotomy + ASA + hydroxyurea

Front 26

What makes someone high risk in PV?

Back 26

One of:
Age over 70
Prior thrombosis
Platelet count > 1,500,000/uL
Presence of CV risk factors

Front 27

What is the differential diagnosis for thrombocytosis?

Back 27

Malignancies
Infections/inflammatory disorders
Medications (recovery from chemo/corticosteroids)
Post surgical status
Connective tissue disorders
Iron deficiency anemia
Splenectomy
Essential thrombocythemia

Front 28

What is the clinical presentation of ET?

Back 28

Many asymptomatic

Vasomotor symptoms: headache, syncope, atypical chest pain, acral paresthesia, livedo reticularis, and erythromelalgia

Thrombosis and hemorrhage (5-25%)

Splenomegaly (early satiety and abdominal bloating)

Front 29

What is the prognosis in ET?

Back 29

Most have a normal life expectancy

Like PV, major risks are thrombosis and disease transformation into myelofibrosis or AML

Front 30

How do you treat ET?

Back 30

Low risk: ASA if vasomotor symptoms

High risk (age > 60; previous thrombosis): hydroxyurea + ASA (but screen for an acquired vWD if platelets > 1.5 million because they could be using up all of the vWF and may put the patient at increased bleeding risk, so you don't want to give them aspirin if they are)

Front 31

What is the clinical presentation of PMF?

Back 31

Severe fatigue
SPLENOMEGALY
hepatomegaly
FEVER and NIGHT SWEATS
Anemia or thrombocytopenia symptoms
Bone or joint involvement

Front 32

What do you see in the CBC in PMF?

Back 32

Anemia, leukoerythroblastosis

Front 33

What's one big thing you're looking for in PMF?

Back 33

Bone marrow fibrosis (the name, silly)

Front 34

What is the prognosis of PMF?

Back 34

Not good

Low 3-year survival and some evolution to acute leukemia

Front 35

How do you treat PMF?

Back 35

Low risk with symptoms: hydroxyurea, corticosteroids, splenectomy (if adequate BM hematopoiesis), splenic irradiation, ruxolitinib, thalidomide)

High risk and age < 55: consider a reduced intensity allogeneic BMT