Myeloproliferative Neoplasms

Question 1

Chronic Myeloproliferative Neoplasms

Answer 1

typically involve an expansion of mature, terminally differentiated cells. Characterized by too many mature cells in the blood.

Question 2

CMNs are proliferative diseases of…

Answer 2

stem/progenitor cells

Question 3

All CMNs are characterized by what type of mutation?

Answer 3

tyrosine kinase dysregulation

Question 4

CMNs are predisposed to transformation into what?

Answer 4

acute leukemia

Question 5

how are CMNs identified?

Answer 5

asymptomatic patients with abnormal blood counts

Question 6

consequence of CMNs on bone marrow cavity

Answer 6

cause fibrosis and therefore lead to extra medullary sites of hematopoiesis (splenomegaly & hepatomegaly)

Question 7

are CMNs curable?

Answer 7

no, indolent growth prevents sensitivity to current therapy

Question 8

another name for chronic myelogenous leukemia (CML)

Answer 8

BCR-ABL positive MPN

Question 9

CML

Answer 9

abnormal growth and proliferation of white (myeloid) blood cells. Neutrophils initially accumulate, followed by basophils and eosinophils.

Question 10

Chronic phase of CML

Answer 10

least severe phase. characterized by presence of differentiation in peripheral blood smear and hyper cellular marrow biopsy. often no symptoms, 4-6yrs

Question 11

epidemiology of CML

Answer 11

rare, increases with age, majority diagnosed at chronic phase, so rarely proceeds to AML

Question 12

sign/symptoms of CML

Answer 12

most commonly asymptomatic, fatigue, weight loss, splenomegaly

Question 13

lab findings of CML

Answer 13

high WBC, left shift, basophilia, high LDH & B12

Question 14

accelerated phase CML

Answer 14

increased blasts and platelets. genetic evolution, increased symptoms, drop in healthy blood cells. 1yr

Question 15

blast crisis of CML

Answer 15

3-6mos survival, blasts>20%, resistant to chemo, speed of growth resembles acute leukemia. More likely to be AML, but 1/3 are ALL

Question 16

molecular basis of CML

Answer 16

t(9;22) Philadelphia chromosome. creates fusion gene BCR/ABL. ABL is tyrosine kinase that is over activated, leading to abnormal proliferation and genetic instability

Question 17

treatment for CML

Answer 17

Imatinib (Gleevec)

Question 18

Imatinib

Answer 18

kinase inhibitor. competitive inhibitor for ATP binding site. leads to death of neoplastic cells.

Question 19

ways to monitor CML

Answer 19

WBC count, Cytogenic studies (karyotype), FISH, PCR

Question 20

complete hematologic response (CHR)

Answer 20

normalized CBC and peripheral blood after CML treatment, has limited prognostic significance.

Question 21

Complete cytogenetic response

Answer 21

0% philadelphia+ cells after CML treatment. MOST PREDICTIVE OF SURVIVAL

Question 22

major molecular response (MMR)

Answer 22

1000x reduction in bcr-abl transcripts after CML treatment. presence at 1yr predicts 100% progression free survival at 5yrs!

Question 23

how can we tell if imatinib stops working?

Answer 23

increased WBC (hematologic relapse), increasing Ph+ cells (cytogenetic relapse), increased bcr-abr transcripts (molecular progression)

Question 24

why would imatinib stop working?

Answer 24

most commonly due to non-adherence. sometimes due to drug resistance

Question 25

what do we do when imatinib stops working

Answer 25

increase dose, switch to second or third generation tyrosine kinase inhibitors, bone marrow/stem cell transplantation

Question 26

what mutation is present in most classical philadelphia chromosome negative MPDs?

Answer 26

gain of function point mutation in JAK2

Question 27

polycythemia vera

Answer 27

elevation in red blood cell mass, somatic/acquired mutation of JAK2. up regulation of Bcl (antiapoptotic machinery)

Question 28

clinical features of polycythemia vera

Answer 28

high Hb, can be asymptomatic, clot, hyper metabolism, hyperviscositiy, erythromelalgia, bleeding, splenomegagly,

Question 29

differential diagnosis for erythrocytosis

Answer 29

congenital mutations, polycythemia vera, chronic hypoxia, ectopic EPO production, high oc=xygen affinity hemoglobinopathies

Question 30

clinical symptom of PV in the eye

Answer 30

congested retinal veins due to hyperviscosity

Question 31

at what hematocrit does hyper viscosity become a problem?

Answer 31

when it exceeds 55%, thrombotic complications become an issue

Question 32

treatment for polycythemia vera

Answer 32

therapeutic phlebotomy, aspirin, hydroxyurea (decreases level of all blood cells), interferon, JAK2 inhibitors

Question 33

diagnostic criteria for polycythemia vera

Answer 33

elevated red blood cell mass, presence of JAK 2 mutation. (bone marrow trilineage myeloproliferation, low serum EPO as minor criteria)

Question 34

essential thrombocytosis

Answer 34

JAK2 and Mpl mutations that causes elevation in platelets via megakaryocytosis in bone marrow

Question 35

clinical features of essential thrombocytosis

Answer 35

asymptomatic, clots, bleeding

Question 36

treatments for essential thrombocytosis

Answer 36

observation, aspirin, hydroxyurea, interferon

Question 37

primary myelofibrosis (PMF)

Answer 37

leukoerythroplastic smear and presence of fibrosis. most likely of the non Ph+ CMNs

Question 38

clinical features of PMF

Answer 38

anemia, abnormal blood counts, B symptoms (fatigue, weight loss, fever), splenomegaly, leukoerythroblastic peripheral blood smear, marked bone marrow fibrosis

Question 39

leukoerythroblastic blood smear

Answer 39

teardrop RBC forms, nucleated red blood cells, left shifted granulocytes, blasts

Question 40

differential diagnosis for leukoerythroblastic blood smear

Answer 40

metastatic disease, AIDS, granulomatous disease, myeloproliferative disorder (myelofibrosis), lipid storage disease

Question 41

bone marrow biopsy in primary myelofibrosis

Answer 41

abnormal megakaryocytic, intrasinusoidal hematopoiesis, osteosclerosis --> all of which lead to frequent fractures and bony pain

Question 42

spleen of primary myelofibrosis

Answer 42

extramedullary hematopoiesis

Question 43

treatment for PMF

Answer 43

observation, EPO transfusions, thalidomide, JAK2 inhibitors (ruxolitinib)

Question 44

only curative treatment for PMF

Answer 44

donor stem cell transplantation

Question 45

why is there bone marrow fibrosis in PMF?

Answer 45

reactive, polyclonal expansion of marrow fibroblasts in response to cytokines derived from both marrow monocytes and ineffective megakaryocyteopoiesis