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HemeOnc
Chronic Myeloid Leukemia and Myeloproliferative Disorders
23
Accounting
Pre-School
01/12/2011

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Cards

Term
CML presentation:
Definition
• Presentation – can be asymptomatic, or have constitutional Sx, weight loss, HSM, bruising, leukostasis
o Weight loss – due to increased cells & thus increased metabolism
o Leukostasis – rare; overproduction of cells leads to pulmonary/neurologic Sx, priapism due to thrombi
Term
Diagnosis: Labs, palpation, cytogenetic...
Definition
• Dx – based on leukocytosis with left shift, hypercellular marrow, increased M:E ratio, mild anemia and eosino/basophilia
o Splenomegaly – also diagnostic feature, as spleen fills up with cells
o QUIZ: Philadelphia chromosome – common feature of many CML patients 9-22 translocation (necessary and sufficient)
 BCR/ABL gene – codes for hybrid protein causing CML, due to 9-22 translocation
 BCR/ABL amplication – can be done through RNA PCR  detect hybrid gene
 Fluoresence – can fluorescent tag BCR/ABL gene, and fluorescence ~ protein load
 High load – high amounts of BCR/ABL gene = more severe CML
Term
Pathophys of CML
Definition
• Pathophysiology – protein kinase coded by bcr-abl fusion alters all cell functions  proliferation/transformation, anti-apoptosis, proliferation and adhesion
Term
Best methods of testing for it?
Definition
• Testing (PCR = most sensitive, cytogenetics = least sensitive)
o Cytogenetics – looks for Ph chromosome, confirms dx, evaluates for other abnormalities (clonal evolution)
o FISH – looks for juxtaposition of bcr and abl; confirms dx, monitor therapeutic response Red9+Green22 => Yellow
o RT-PCR – amplify bcl-abl mRNA; can detect breakpoints of fusion gene, most sensitive and allows quantitative!
Term
CML vs. MDS?
CMS vs. reactive leukocytosis?
Definition
• Vs. MDS – CML has hyperproliferation of normal cell lines, whereas MDS has dysplastic
• Vs. Leukemoid Reaction (Reactive leukocytosis) – elevated leukocytes in blood due to stimulus
o Leukocyte alkaline phosphatase – has a high level in reactive leukocytosis, low in CML
o Non-basophilic – leukemoid doesn’t show basophilia; CML has basophilia
Term
CML Stages? Chronic, accelerated, blast crisis
Definition
• Chronic Phase – usually minimal symptoms
• Accelerated Phase – 10-19% blasts, progressive anemia/thrombocytopenia/thrombocytosis, clonal evolution (additional genetic abnormalities not present at time of chronic phase dx)
• Blast Crisis – >20% of blasts in blood/marrow, often refractory to treatment, large foci of blasts in bone marrow
• Treatment goals – prevent progression to blast crisis
Term
Polycythemia - def, relative vs. true
Definition
• Polycythemia (erythrocytosis) – an elevated RBC concentration in the blood, categorized as: hi hct or hgb production…
o Relative polycythemia – elevated concentration due to decreased plasma volume (dehydration)
o True polycytehmia – elevated concentration due to excess RBCs
 Polycythemia vera – a specific type of true polycythemia which is EPO-independent
Term
• True Polycythemia Etiology
Definition
– due to primary or reactive EPO excess, or Epo independent:
o Hypoxia, carboxyhemoglobinemia, Cushing’s, EPO secreting tumors (renal cell ca.)
o Epo-independent true polycythemia – polycythemia vera
Term
• Polycythemia Vera Dx –
Definition
anemia, JAK2V617F mutation (95%), marrow trillineage expansion, subnormal EPO, endogenous erythroid colony growth
Term
role of JAK2 & Polycythemia Vera
Definition
• JAK2 – a tyrosine kinase mutated in polycythemia vera & other myeloproliferative disorders
o Function – relays signal of Epo-binding receptor outside HSC into cell, signaling proliferation
o JAK2 Mutation – a gain-of-function mutation will activate JAK2 regardless of Epo binding; V617F substitution
o Chromosome 9p – site of gene mutation, these are ACQUIRED…genetic mutation ONLY in bone marrow!
• JAK2 Dx – not perfect diagnostic marker, not found in all PCV patients, although common mutation
• Therapeutic Target – currently developing therapies targeting JAK2 kinase
Term
presentation of PV patient
Definition
• Presentation – high RBC count manifests as ruddy complexion, conjunctival plethora, thick blood:
o Blood hyperviscosity – neurologic (& resp?) symptoms  headache, vertigo, confusion
o Thrombotic Risk – characteristic of PCV  CVA, MI, DVT, ischemia
o Occult GI bleeding – presents with Fe deficiency
Term
treatment of PV
Definition
goal is to lower RBC in order to reduce thrombosis risk:
o Phlebotomy – remove a chunk of RBCs from blood through a bleed
o Hydroxyurea – chemotherapeutic agent causing RBC destruction for high risk pts (>70, prior thrombosis, platelets > 1.5mm, CV risk factors)
Term
DDx of Thrombocytosis
Definition
• DDx – most commonly 2o to other causes, otherwise related to myeloproliferative disorders, or essential:
o Compensatory to Cause – acute hemorrhage response, bone marrow recovery
o Other Causes – malignancy, asplenia, Fe deficiency anemia, drug-induced
o Myeloproliferative disorder – makes for viscous blood, coagulability risk
o Essential thrombocytosis – diagnosis of exclusion
Term
• Essential Thrombocytosis Presentation
Definition
o Vasomotor symptoms – HA, syncope, atypical chest pain, acral paresthesia, livedo reticularis, erythromelalgia
o Thrombosis and hemorrhage
o Early satiety – abdominal bloating due splenomegaly
o JAK2V617F – present in 50% of pateients
Term
Dx of ET
Definition
o Platelet count > 450k
o Megakaryocytic proliferation – large, mature morphology
o Rule out – CML, PV, PMF, MDS or other neoplasm
o Clonal marker – JAK2V617F or other marker or lack of evidence of a secondary marker
Term
Prognosis of ET
Definition
o Normal life expectancy – most patients
o Thrombosis – major risk if over 60, prior thrombosis, long term plt count > 1mm
o Transformation – to myelofibrosis or AML
Term
treatment of ET
Definition
low risk, give ASA; attempt to lower platelet count if high risk:
o Hydroxyurea, INFα – chemotherapeutics lowering platelet count
o Anagrelide – interferes with megakaryocyte development  lowers platelet count but assoc w/ increased risk of vascular events
Term
Sx and presentation of px: • S/Sx – can be asymptomatic, but most have symptoms: fatigue, hepato/splenomegaly, fever/night sweats, anemia, thrombocytopenia, foci of extramedullary hematopoiesis outside of BM that’s not effective, bone or joint involvement.
• CBC – anemia, ansiopoikilocytosis, teardrop RBCs, nuc RBCs, leukoerythroblastosis, variable WBC and plt counts
What's the diagnosis?
Definition
Primary myelofibrosis
Term
BM biopsy in primary myelofibrosis shows:
Definition
increased fibrosis
Term
Primary Myelofibrosis Prognosis –
Definition
cytopenias worsen as fibrosis progresses; rare transformation to acute leukemia
Term
JAK2 V617F is there 100% of the time in Primary myelofibrosis?
Definition
False: 50%
Term
Tx for primary myelofibrosis:
Definition
asymptomatic can just manage
o Symptomatic – hydroxyurea, androgens, corticosteroids, splenectomy, splenic irradiation, thalidomide/lenalidomide
o High risk and < 55 – reduced intensity allogeneic BMT
o Only curative => TRANSPLANT…the worse the blood counts/Sx, worse the outcome
Term
PCR is sufficient to diagnose the BCR-ABL gene/translocation
Definition
False: PCR can be negative b/c of minor differences in break points leading to unusual gene product so in those cases you have to use FISH as the diagnostic tool!
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