Myeloproliferative Diseases Flashcards
What are the four myeloproliferative syndromes?
Chronic Granulocytic Leukemia
Idiopathic Myelofibrosis
Primary Thrombocytopenia
Polycythemia Ruba Vera
Explain the epidemiology of CML
Median age = 45-55
Incidence increases with age 12-30% above 60
Slightly more men than women
At presentation: 85% ddx in chronic phase
What are the three etiologic factors associated with Chronic Granulocytic Leukemia?
Idiopathic
Radiation
Chemical
What are symtoms of Chronic Granulocytic Leukemia?
Fatigue Weight Loss Abdominal Fullness Easy bruising or bleeding Abdominal Pain
What are physical findings of CGL?
Splenomegaly Hepatomegaly Sternal Tenderness Purpura Retinal Hemmorhage Fever Palpable Lymph Nodes
What are some common lab findings in CML?
Elevated Uric ACid Low Leukocyte Alkaline Phosphatase Score Elevated b12 b12 binding protein elevation transcobalamine 12
What are the three phases of CML?
Chronic Phase (median 5-6 yrs)
Accelearated Phases 6-9 mnts
Blast crisis median survival 3-6 months
What is the classic molecular abnormality in chronic myelogenous leukemia?
Philadelphia Chromosome
What is the philadelphia chromosome?
9/22 translocation
found in 95% of patients with CML
Present in 100% of RBC WBC MONOCYTES AND PLTS
What does the philadelphia chromosome do?
It makes high levels of tyrosine kinase activity at bcr-abl
What did preclinical studies about the philadelphia chromosome determine?
By putting bcr-abl in mice, they were able to produce the disease
What are drugs that control cml?
hydroxyurea, interferon and targetted agents, imatinib
What is the significance of allogeneic sct in cml?
good match produces 60% survival, only tx available, transplants have become less common
How does imatinib work?
It blocks the atp receptor at the bcr-abl tyrosine kinase, preventing abnormal proliferation
What are the characteristics of imatinib?
rapidly absorbed after oral admin
absolute bioavailability at 98%
terminal half-life = 18-22 hrs
What were the results of imatinib phase one trials/
They worked in ifn-a resistant and blast phase patients. in a month peripheral blood returned to normal
Whatdoes taking imatinib do if you take it longer?
The longer you use it, the longer you stay in remission.
what do you treat with in a px with resistnace in imatinib?
BM transplant
Dasatinib
Nilotinib
What are the consequences of using dasatinib and nilotinib over imatinib/
they get to remission faster but less studied, both are approved for first line use.
What are the jak2 inhibitors
prv, mf, and tt
Explain the epo, epor, and jak2 relationship
epo and epor are crucial in rbc formatino
jak2 is bound to epor and activated upon epo binding to the receptor
signaling of epor starts with jake2activation.
epor signaling activates stat, mapk, pi3kinase and akt
results in proliferation and differentiation of rbc precursors
What are the three common mutations associated with jak2?
pv, et, and mf in order of decreasing frequency in cml
What is the general characteristic of primary myelofibrosis?
bm has fibrous tissue so bm made in liver and spleen
what is the median age of pmf onset?
65
what are the causes of pmf?
myeloproflieration with granulocytic hyperplasia and megakaryocytosis
marrow fibrosis with increased collagen 1,3,4,5
dysmorphic megakaryocytes
fibrosis is the result of release of cytokines from the abnormal megakaryocytes
What are the clinical symptoms of pmf?
fatigue, weakness, dyspnea, palpitations, weight loss, early satiety, pain in left shoulder, bone pain in lower extrem
what are the physical findings of pmf?
hepatosplenomegaly cachexia peripheral edema purpura bone tenderness neutrophilic dermatosis
what is the primary histopath associated with pmf?
tear drop cells, aniso and poikliocytosis, nucleated rbc and wbcs, marrow has fibrosis
What commonly occurs in many placesi n the body when someone has pmf?
fibrohematopoeitic extramedullary tumors
what are two big symptoms of pmf?
portal htn
and osteosclerosis
what are common therapies in pmf?
androgens, procrit, hydroxyurea, thalidomind, lenalidamide,radiation, splenectomy, bm transplant
What is the least common of the mpds?
essential thrombocytosis
what is the average age of et?
50-60
what are the clinical features of thrombocytosis
fever, night sweats, weight loss, splenomegally, aortic andmitral valvular leaflet thickening or vegetations, leukemic transformation is less than the other mpds
on histo, what do you see in et?
giant plts and massive megakaryocytes
Tell me about the serum thrombopoeitin in et
levels are normal or elevated and doesn’t coorelate with plts count.
what happens with thrombosis and bleeding in et?
50/50 split between the two. half have non-fxn plts, others have overactive plts.
what are the risk factors for thrombosis in et
previous thrombosis, advanced age, cv risk factors ie smoking
what is the risk factor for bleeding with et?
greater than 1500000 plts
what are thrombotic complications of et
50% of patients have at least one peisode in 9 years of follow up
arterial throm is more common
venous complics usually of lower extrem
arterial sites are cva, coronary arter disease
placental insufficiency
budd-chiari syndrome
how do you treat et?
hydroxyurea (interferes with s phase progressino of dna synthesis.
anagrelide
interefers with terminal differentiation of megakaryocytes,
What are the causes of excess production of epo?
cellular hypoxia
local renal hypoxia (ligation, plaques, transplant rejection, pressure of kidney parenchyma)
What are characteristics of polcythemia ruba vera
more common in men, commonly in 50-60.
what are symptoms of polycytehmia vera?
headache, weakness, pruritus, dizziness, sweating, weight loss, more.. rosacea, conjunctival suffusion
what are the lab findings of prv?
hct 55-65 2/3 have leukocytosis 2/3 have basophilia lap score and b12 levesl elevated in 70% of pxs marrow hypercellularity absence of iron stores
what are the thrombotic complications of prv?
1/3 have events
budd-chaiari occurs in 10%
erythrombelalgia (warm extremeties, painful digits, burning senstion)
What are the therapies for prv?
phlebotomy
myelosuppresive agents whe plts and wbc rises
what is the spent phase of prv?
anemia, leucocytosis marrow fibrosis enalrgin spleen, at this stage mimics mf
