Myeloproliferative Diseases Flashcards
What are the myeloproliferative syndromes?
Chronic granulocytic leukemia
Idiopathic myelofibrosis
Primary Thrombocythemia
Polycythemia Rubra Vera
What is the incidence of CML per 100,000?
1-2 (typical of all myelogenous leukemias)
What is the median presentation age of CML?
45-55yrs
Does incidence of CML increase with age?
Yes. 12-30% are >60
What is the ratio of male to female patients with CML?
1.3-1
How are most CML’s diagnoses at presentation?
50% by routine lab tests
85% diagnosed in the chronic phase
What are the etiologic factors associated with chronic granulocytic leukemias?
Idiopathic
Radiation exposure
Chemical exposure
What symptoms are seen in pts. with CML?
Fatigue, weight loss, abdominal fullness, easy bruising or bleeding, abdominal pain
What are the physical findings seen in pts. with CML?
Splenomegally, hepatomegally, sternal tenderness, purpura, retinal hemorrhage, fever, and palpable lymph nodes (pretty rare)
Is uric acid level elevated in CML?
Yes
Do you get a high or low leukocyte alkaline phosphatase score in CML?
Low
Do you see high or low B12 levels with CML?
Elevated
B12 binding protein also elevated. Transcobalamine 1
What are the clinical phases of CML? What are the survival times associated with each?
Chronic phase: 5-6 yrs stabilization
Accelerated phase: 6-9mo median duration
Blast Crisis: 3-6mo survival
What is the name of the abnormal chromosome found in CML? Who discovered it?
Philadelphia. Janet Rowley in 1960
What translocation is seen in the Ph chromosome?
9/22
In how many pts. with CML is the Ph chr found?
95% of pts. Ph chr. is present in 100% of RBCs, WBCs, monocytes, and platelets
What happens as a results of the 9,22 translocation?
Fusion protein Bcr-Abl with tyrosine kinase activity
Which phase of pts. with CML is most likely to have leukemia free survival with BM transplant? Least likely?
Chronic phase most likely to do well. Blast crisis phase pts. most likely to do the worse
What drug is used as a targeted therapy for CML?
Imatinib
What does Imatinib do?
Blocks ATP from binding Bcr-Abl tyrosine kinase.
Imatinib has steady state PK at what dosing?
400-600mg
How is the bioavailibility of imatinib?
98%. It’s rapidly and completely absorbed after oral administration
What is the hematologic response of CML pts. in chronic phase that receive imatinib?
100% rapid response
Is there a 100% hematologic response in pts. with blast crisis myeloid or blast crisis lymphoid CML?
No.
Blast myeloid=56%
Blast lymphoid=70%
What is the overall survival of pts. receiving imatinib for 72mo?
Good, somewhere between 90-100%
What’s the estimated annual rate of treatment failure for CML with imatinib?
Very low. Between 3.3%-7.5% during the first two yrs of treatment and even lower percentages of treatment failures from 3-5yrs
What gives clinical resistance to Imatinib?
Mutation T-3151- BM transplant
What are 2nd generation molecules to treat CML?
Dasatinib and Nilotinib
What hormone is crucial in RBC formation?
Epo
How is Jak2 important in RBC formation?
It’s bound to the EpoR and activated upon Epo binding to the receptor
What pathway is activated with Epo signaling? What does signaling result in?
Signaling of EpoR starts with activation of Jak2, then activation of STAT, Map-kinase, Pi-3 kinase, and AKT. Results in proliferation and differentiation of RBC precursors
What is the mutation found in Jak2 associated with myeloproliferative diseases?
Guanine to thymidine mut. results in substitution of val to phe at codon 617, within the pseudokinase domain of Jak2
Jak2 mutations are found in which diseases?
PV: 95%
ET:50-70%
MF: 40-50%
Can homozygous mutations be found in some pts?
Yes. Pts. with PV can have homozygous Jak2V617F which are the result of recombination and duplication of the mutant allele
What is the median age for idiopathic myelofibrosis (PMF)? Male female ratio? Incidence?
65yrs. 1:1 male to female incidence. 1.4 cases per 100,000
What causes PMF?
Myeloproliferation with granulocytic hyperplasia and megakaryocytosis. Marrow fibrosis with increased collagen types I, III (most), IV, and V
Fibrosis in PMF correlates closely with what?
Increases dysmorphic megakaryocytes in the marrow
Fibrosis in PMF is the result of what?
Cytokines released from abnormal megakaryocytes
What are the clinical symptoms of PMF?
Fatigue, weakness, SOB, palpitations, weight loss, dragging sensations in LUQ, early satiety, pain in L shoulder, bone pain in the lower extremities
What are the physical findings in PMF?
Splenomegally (100%), hepatomegally (75%), muscle wasting, peripheral edema, purpura, bone tenderness, neutrophillic dermatosis
What are the lab findings in PMF?
Early on: thrombocytosis
Bizarre changes in Megs.
Ansiocytosis, poikilocytosis, tear drops Nucleated RBCs and WBCs
WBC elevated
Marrow: increased fibrosis and abnormal megs
Where can fibromatopoietic extra medullary tumors occur in PMF?
Anywhere
What are other symptoms of PMF?
portal HTN, results in ascites, esophageal and gastric varices. Osteosclerosis: proximal femur and humerus, pelvis, vertebral bodies, ribs and skull
What are some therapies for PMF?
androgens, procrit, hydroxyurea, thalidomide, lenalimide
For lenalimide, del 5q31 may achieve what?
Remissions accompanied by marked reduction in numbers of cells bearing marker chr. and JAK2V617F
What is radiation therapy used for in PMF?
Splenic pain, massive spleen enlargement, focal bone pain, and extra medullary tumors
When are splenectomies done in PMF pts?
painful enlargements, excessive transfusions, severe thrombocytopenia, and portal HTN
Can BM transplant cure PMF?
Yes
Why don’t most pts. with PMF have BM transplants?
B/c they are too old or have co-morbidity
Can acute leukemia cause death in idiopathic myelofibrosis?
Yes (25%)
What things can cause secondary thrombocytosis?
trauma, surgery, acute bleeding, Fe deficiency, infection, chronic inflammatory disease, neoplasia, splenectomy
What are Characteristics of secondary thrombocytosis?
Generally have no splenomegally
Extreme platelet elevations don’t r/o secondary thrombocytosis
Platelet morphology and function is normal
Bone marrow megakaryocytes are normal
Thrombosis and bleeding is rare
What are Special cases of secondary Thrombocytosis
Rebound thrombocytosis and splenectomy
What’s associated with rebound thrombocytosis?
Recovery from marrow suppression
May stay elevated for 10-14 days
What would you see in thrombocytosis from splenectomy?
May be greater than 1 million one week after operation. May not return to normal for 2 months
What is the Clinical epidemiology of ET?
It is the least common of the MPDs :0.5 per 100,000 in the U. S. Age at diagnosis is 50-60 years. 1:1 male to female ratio
What are the clinical feats of ET?
Spenomegaly in 40% of patients
Aortic and mitral valvular leaflet thickening or vegetations(similar to non-bacterial thrombotic endocarditis)
Leukemic transformation is less than the other MPDs
Fever, night sweats and weight loss are uncommon.
What are the serum TPO levels in ET?
Serum Thrombopoetin levels are normal or elevated and does not coorelate with the platelet count
Are most forms of secondary thrombocytosis associated with elevated levels of TPO?
Yes
What are major risk factors for thrombosis in pts. with ET?
- previous thrombosis
- advanced age
- associated cardiovascular risk factors(smoking)
What increases the risk for bleeding in pts. with ET?
platetlets >1,500,000
Where are bleeding sites seen in pts. with ET?
Mucosal and GI tract, cutaneous, genitourinary, and post-op
What are Thrombotic complications of ET?
50% of patients have at least one episode in 9 years of followup
Are arterial or venous thrombosis more common in ET?
Arterial thrombosis is more frequent than venous. Venous complications usually of the lower extremities
Where are the arterial sites of thrombosis in ET?
CVA, peripheral vasculitis, coronary artery disease
What are some other complications of ET?
Placental insufficiency spontaneous abortions fetal growth retardation premature deliveries abruptio placenta Budd-Chiari syndrome
What is the treatment of ET?
Hydroxyurea: Cycle specific agent interfering with S phase progression of DNA synthesis
How is hydroxyurea given?
Oral tablet
What are the associated toxicities with hydroxyurea?
leucopenia, anemia, thrombocytopenia
What is another drug treatment of ET?
Anagrelide
What does Anagrelide do?
Interfers with terminal differentiation of megakaryocytes
How is Anagrelide given?
Oral
What are the associated toxicities with Anagrelide?
Thrombocytopenia, congestive heart failure, headaches
What are causes of excess production of Epo?
Cellular hypoxia, Local renal hypoxia.
WHat are causes of secondary polycythemia?
Renal vascular impairment and tumors.
What are epidemiological characteristics of Characteristics of polycythemia rubra vera (PRV)?
2.8/100,000 men
1.3/100,000 women
Commonly presents in 50-60th decade
1.5% risk of leukemic transformation in 18 years
What is the median survival of PRV?
13.9 years
What are symptoms of PRV?
Headache, weakness, pruritis!, dizziness, sweating, visual disturbances, weight loss, parathesias, dyspnea, joint symptoms, epigastric distress
What are the lab findings in PRV?
Hematocrits of 55-65 2/3d have leucocytosis 2/3d have basophilia LAP score and B12 levels elevated in 70% Platelets elevated in ½ patients Marrow hypercellularity Absence of iron stores in most patients
How many PRV pts. have thrombotic events?
1/3d. 3/4th are arterial and 1/4th are venous
What happens with the majority of arterial episodes in PRV?
Ischemic strokes and TIAs
How often is Budd Chiari seen in PRV?
10%, but it is fatal
What is another thrombotic complication of PRV?
Erythromelalgia
What is Erythromelalgia?
warm extremities, painful digits, burning sensation, may lead to necrosis of the digits
What is the therapy for PRV?
Phlebotomy. Take off 500 ml of blood at intervals of 2-4 days and then back off to weekly and then monthly when Hmt stabilizes. And Myelosuppresive agents when platelets or WBC rises or for severe pruritis
What is the key treatment for PRV?
Phlebotomy
What is the spent phase of PRV?
Anemia
Leucocyosis
Marrow fibrosis
Enlarging spleen
At the spent phase, PRV mimics what?
MF
Can you treat ET, PRV and MF with aspirin?
Yep. Use low dose aspirin
