Myeloproliferative Neoplasms Flashcards Preview

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Flashcards in Myeloproliferative Neoplasms Deck (45):
1

Chronic Myeloproliferative Neoplasms

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

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CMNs are proliferative diseases of...

stem/progenitor cells

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All CMNs are characterized by what type of mutation?

tyrosine kinase dysregulation

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CMNs are predisposed to transformation into what?

acute leukemia

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how are CMNs identified?

asymptomatic patients with abnormal blood counts

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consequence of CMNs on bone marrow cavity

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

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are CMNs curable?

no, indolent growth prevents sensitivity to current therapy

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another name for chronic myelogenous leukemia (CML)

BCR-ABL positive MPN

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CML

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

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Chronic phase of CML

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

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epidemiology of CML

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

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sign/symptoms of CML

most commonly asymptomatic, fatigue, weight loss, splenomegaly

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lab findings of CML

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

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accelerated phase CML

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

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blast crisis of CML

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

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molecular basis of CML

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

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treatment for CML

Imatinib (Gleevec)

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Imatinib

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

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ways to monitor CML

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

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complete hematologic response (CHR)

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

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Complete cytogenetic response

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

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major molecular response (MMR)

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

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how can we tell if imatinib stops working?

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

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why would imatinib stop working?

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

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what do we do when imatinib stops working

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

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

gain of function point mutation in JAK2

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polycythemia vera

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

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clinical features of polycythemia vera

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

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differential diagnosis for erythrocytosis

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

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clinical symptom of PV in the eye

congested retinal veins due to hyperviscosity

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at what hematocrit does hyper viscosity become a problem?

when it exceeds 55%, thrombotic complications become an issue

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treatment for polycythemia vera

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

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diagnostic criteria for polycythemia vera

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

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essential thrombocytosis

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

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clinical features of essential thrombocytosis

asymptomatic, clots, bleeding

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treatments for essential thrombocytosis

observation, aspirin, hydroxyurea, interferon

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primary myelofibrosis (PMF)

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

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clinical features of PMF

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

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leukoerythroblastic blood smear

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

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differential diagnosis for leukoerythroblastic blood smear

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

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bone marrow biopsy in primary myelofibrosis

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

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spleen of primary myelofibrosis

extramedullary hematopoiesis

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treatment for PMF

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

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only curative treatment for PMF

donor stem cell transplantation

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why is there bone marrow fibrosis in PMF?

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