Myeloproliferative Neoplasms Flashcards
Chronic Myeloproliferative Neoplasms
typically involve an expansion of mature, terminally differentiated cells. Characterized by too many mature cells in the blood.
CMNs are proliferative diseases of…
stem/progenitor cells
All CMNs are characterized by what type of mutation?
tyrosine kinase dysregulation
CMNs are predisposed to transformation into what?
acute leukemia
how are CMNs identified?
asymptomatic patients with abnormal blood counts
consequence of CMNs on bone marrow cavity
cause fibrosis and therefore lead to extra medullary sites of hematopoiesis (splenomegaly & hepatomegaly)
are CMNs curable?
no, indolent growth prevents sensitivity to current therapy
another name for chronic myelogenous leukemia (CML)
BCR-ABL positive MPN
CML
abnormal growth and proliferation of white (myeloid) blood cells. Neutrophils initially accumulate, followed by basophils and eosinophils.
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
epidemiology of CML
rare, increases with age, majority diagnosed at chronic phase, so rarely proceeds to AML
sign/symptoms of CML
most commonly asymptomatic, fatigue, weight loss, splenomegaly
lab findings of CML
high WBC, left shift, basophilia, high LDH & B12
accelerated phase CML
increased blasts and platelets. genetic evolution, increased symptoms, drop in healthy blood cells. 1yr
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
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
treatment for CML
Imatinib (Gleevec)
Imatinib
kinase inhibitor. competitive inhibitor for ATP binding site. leads to death of neoplastic cells.
ways to monitor CML
WBC count, Cytogenic studies (karyotype), FISH, PCR
complete hematologic response (CHR)
normalized CBC and peripheral blood after CML treatment, has limited prognostic significance.
Complete cytogenetic response
0% philadelphia+ cells after CML treatment. MOST PREDICTIVE OF SURVIVAL
major molecular response (MMR)
1000x reduction in bcr-abl transcripts after CML treatment. presence at 1yr predicts 100% progression free survival at 5yrs!
how can we tell if imatinib stops working?
increased WBC (hematologic relapse), increasing Ph+ cells (cytogenetic relapse), increased bcr-abr transcripts (molecular progression)
why would imatinib stop working?
most commonly due to non-adherence. sometimes due to drug resistance
what do we do when imatinib stops working
increase dose, switch to second or third generation tyrosine kinase inhibitors, bone marrow/stem cell transplantation
what mutation is present in most classical philadelphia chromosome negative MPDs?
gain of function point mutation in JAK2
polycythemia vera
elevation in red blood cell mass, somatic/acquired mutation of JAK2. up regulation of Bcl (antiapoptotic machinery)
clinical features of polycythemia vera
high Hb, can be asymptomatic, clot, hyper metabolism, hyperviscositiy, erythromelalgia, bleeding, splenomegagly,
differential diagnosis for erythrocytosis
congenital mutations, polycythemia vera, chronic hypoxia, ectopic EPO production, high oc=xygen affinity hemoglobinopathies
clinical symptom of PV in the eye
congested retinal veins due to hyperviscosity
at what hematocrit does hyper viscosity become a problem?
when it exceeds 55%, thrombotic complications become an issue
treatment for polycythemia vera
therapeutic phlebotomy, aspirin, hydroxyurea (decreases level of all blood cells), interferon, JAK2 inhibitors
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)
essential thrombocytosis
JAK2 and Mpl mutations that causes elevation in platelets via megakaryocytosis in bone marrow
clinical features of essential thrombocytosis
asymptomatic, clots, bleeding
treatments for essential thrombocytosis
observation, aspirin, hydroxyurea, interferon
primary myelofibrosis (PMF)
leukoerythroplastic smear and presence of fibrosis. most likely of the non Ph+ CMNs
clinical features of PMF
anemia, abnormal blood counts, B symptoms (fatigue, weight loss, fever), splenomegaly, leukoerythroblastic peripheral blood smear, marked bone marrow fibrosis
leukoerythroblastic blood smear
teardrop RBC forms, nucleated red blood cells, left shifted granulocytes, blasts
differential diagnosis for leukoerythroblastic blood smear
metastatic disease, AIDS, granulomatous disease, myeloproliferative disorder (myelofibrosis), lipid storage disease
bone marrow biopsy in primary myelofibrosis
abnormal megakaryocytic, intrasinusoidal hematopoiesis, osteosclerosis –> all of which lead to frequent fractures and bony pain
spleen of primary myelofibrosis
extramedullary hematopoiesis
treatment for PMF
observation, EPO transfusions, thalidomide, JAK2 inhibitors (ruxolitinib)
only curative treatment for PMF
donor stem cell transplantation
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
