Risky Business
Name 2 risk stratification systems for primary myelofibrosis
DIPSS (Dynamic international prognostic scoring system)
MIPSS (Mutation-enhanced IPSS)
A 34 yo Female is referred by her PCP to see a Hematologist for elevated platelet count 550K. She is currently at 14 weeks gestation.
A work up is performed. Iron studies are normal. She carries a JAK2 V617F mutation. She is diagnosed with Essential Thrombocytosis. She has no history of having any type of venous or arterial thrombosis. She has no constitutional B symptoms. What should be started as treatment?
A) ASA
B) ASA + Hydroxyurea
C) Ruxolitinib
D) Phlebotomy
E) Hydroxyurea
A) ASA
100 pt Bonus: What cytoreductive therapy can be given for high risk ET in pregnancy?
a 62 yo M presents to his PCP for fatigue. His CBC shows a hgb 19.7, wbc and platelets are normal. He recently moved to the area and we have no prior lab for comparison. He is referred to Hematology. Epo level 16.2 (normal 2.5-18.2). No smoking history, no prior VTE. He takes HCTZ for HTN, lipitor for hyperlipidemia, androgen replacement for low testosterone, and ibuprofen for headaches. Which of the following is recommended:
A) Phlebotomy
B) Hydroxyurea
C) Discontinue medication
D) Sleep study
E) Bone marrow biopsy
C) Discontinue medication
100 Bonus points: Which medication?
A 54yo M was recently diagnosed with PV. Hgb 19.2, Hct 58%. WBC and platelets are normal. JAK2 V617F positive. The patient has no history of venous or arterial thrombosis. He is started on ASA and intermitted phlebotomy. What is the goal Hemotocrit level for him to be below to optimally reduce his risk of future thrombotic events?
A)40%
B)45%
C)48%
D)52%
E)56%
45%
A randomized study compared patient with JAK2+ PV on phlebotomy to goal <45% vs 45-50%. At median follow up 31 months, risk of death from cardiovascular or thrombotic events was 2.7% vs 9.8%
A 61 yo woman comes in for evaluation of chronic skin rash, intermittent diarrhea, and weight loss. On physical exam there are diffuse reddish—brown macules over the upper chest, back, and thighs. Laboratory studies show the following:
WBC – 17K, Hgb – 13.1, Plt - 155K, Neutr – 22%, Lymph – 40%, Mono – 25%, Eos 13%, Serum tryptase 121 (ref <11.5). Examination of the bone marrow shows dense infiltrates of mast cells that are mostly spindle shaped and express CD117, CD2, and CD25. There is no dysplasia, in increased blasts, or other evidence abnormalities in the marrow. Which of the following genetic aberrations in most likely to be found in this patient?
A)BCR-ABL1 translocation
B)CSF3R T618I mutation
C)FIP1L-PDGFRA rearrangement
D)JAK2 V617F mutation
E)KIT D816V mutation
E) KIT D816V mutation
How do you risk stratify Essential Thrombocythemia?
Very low: No risk factors
Low: JAK2 V617F and <60 yo
Intermediate: Age > 60
High: Hx thrombosis OR JAK2 mut + age >60yo
A 65 yo F is diagnosed with essential thrombocytosis. Work up shows a JAK2 V617F mutation. Bone marrow biopsy with increased megakaryocyte, but no signs of myelofibrosis. She has no personal history of strokes or blood clots. Labs show plt 650K, normal WBC, hgb, ferritin, iron sat. What should be offered as treatment?
A) Phlebotomy
B) Plasmapheresis
C) ASA 81 mg + Hydroxyurea
D) ASA 325 mg daily
E) Observation
C) ASA 81 mg + hydroxyurea
46 yo Male, never smoker, presents to Hematology for new elevated hgb 19. All prior testing wnl. Patient denies any signs/symptoms of sleep apnea and he does not live at a high altitude. He does not use testosterone replacement. JAK2 mutation is negative. Epo level 67 (normal 3-36). Patient reports intermittent left flank pain and hematuria which has been attributed to urinary infections. What would be most helpful in making the diagnosis.
A)BMBx
B)Calreticulin testing
C)Sleep study
D)CT Abdomen
E)Testicular Ultrasound
D) CT Abdomen
A 36 yo premenopausal female presents to see a hematologist for a second opinion for evaluation of her history of having several thrombotic events. She has had 4 different thrombotic events in her life:
2017: 2 arterial thrombotic strokes for which she has minimal residual neurologic deficits
2019: unprovoked DVT/PE 6 years ago
2020: hepatic vein thrombosis 5. S
She has been on treatment with lifelong warfarin since the hepatic vein thrombosis. She has never been on any OCP. Never smoker. She has very heavy menstrual cycles. No family history of thromboses. Never smoker. A full hypercoagulable workup by a prior hematologist was negative. Her labs reveal a plt count 410K and hgb 12. What should be recommended?
A)Switch her to Lovenox 1.5 mg/kg daily
B)Switch her to an Anti-Xa inhibitor
C)Send for JAK2 mutation testing
D)Send for MPL515 mutation testing
E)Continue warfarin
C) Send for JAK2 mutation
Iron deficiency (Heavy menstrual bleeding) can mask underlying PV
Two FDA approved JAK2 inhibitors, Momelotinib and Pacritinib, are capable of improving hemoglobin in patients with Myelofibrosis. These two medications improve anemia in patient with Myelofibrosis by inhibition of which receptor/gene?
A)JAK2
B)CALR
C)MPL
D)ACVR1
E)EPO
D) ACVR1
ACVR1 mediates upregulation of hepcidin
Name at least two of the high risk mutations included in MIPPS risk stratification for Primary Myelofibrosis
ASXL1
EZH2
SRSF2
IDH 1/2
A 74 yo female is currently on treatment with ruxolitinib for Primary Myelofibrosis that was diagnosed 9 months ago. At baseline she had anemia and thrombocytopenia (100K), splenomegaly, and constitutional symptoms including fever and night sweats. Molecular testing revealed an ASXL1 mutation. She is not considered a viable allogeneic transplant candidate. She has responded to ruxolitinib with decreased spleen size and improvement of her blood counts. Recently, she presents with worsening back pain. An MRI is ordered that reveals extramedullary hematopoiesis at the L1 vertebrae. What should be done at this time?
a)Switch her therapy to pacritinib
b)Add hydrea to her therapy
c)Stop ruxolitinib and start lenalidomide
d)Refer to Neurosurgery
e)Refer to Radiation Oncology
A) Refer to Radiation Oncology
A 24 yo male presents to see Hematology for erythrocytosis. Baseline hgb 20. WBC and platelets are normal.He has 3 siblings with the same finding. No smoking history. Epo is low (1). JAK.2 nutation in negative. He has no cardiac, pulmonary, or renal comorbidities. He is found to have normal hgb oxygen affinities. CT C/A/P and TEE with bubble are normal. The patient is not taking exogenous testosterone and his wife mentions that he never snores. What is the more likely diagnosis?
A)EPO secreting tumor
B)Polycythemia Vera
C)Secondary erythrocytosis
D)EPOR mutation
E)Sleep apnea
D) EPOR mutation
Primary familial and congenital polycythemia (PFCP)
A 52 yo woman with a history of HTN is evaluated because of a 3-day history of progressively worsening pain of the RUQ of the abdomen. She has no history of cirrhosis or liver disease. Medications include lisinopril and estrogen/progesterone hormone replacement. Her sister was diagnosed with DVT after a femur fracture at age 47. On exam patient appears jaundiced with abdominal distention. Labs show Hgb 10/8, plt 104K, Alt 1200, AST 1880. Abdominal ultrasound shows a hepatic vein thrombosis. Which of the following lab tests will most likely identify this patient’s underlying predisposition to hepatic vein thrombosis?
A)Factor V Leiden
B)JAK2 V617F mutation
C)Lupus anticoagulant
D)Peripheral blood flow cytometry
E)Prothrombin gene mutation
B)JAK2 V617F mutation
CALR is a gene that encodes for calreticulin and a somatic mutation is found in some MPNs. Which of the following is ture?
A) Over 50% of patients with PV carry a CALR mutation
B) JAK2 mutations and CALR mutations occur simultaneously in 40% of patients with ET
C) Patients with MPNs with a CALR mutations have a more favorable prognosis compared to those patients who have a JAK2 mutations
D) CALR mutations occur more frequently in patients with PV compared to patients who have ET
E) Patients with an MPN with CALR mutation have a higher risk of developing thrombosis compared to patients who harbor a JAK2 mutation
C) Patients with MPNs with a CALR mutations have a more favorable prognosis compared to those patients who have a JAK2 mutations
A 56 yo post-menopausal female with no PMH is referred over to see a Hematologist as her hemoglobin was recently found to be 16.2. She has no history of smoking and no signs or symptoms of sleep apnea. She has read on the internet that Polycythemia Vera can cause elevated hemoglobin level and she is concerned that this is what she has. She asks the Hematologist if she should be tested. What should be recommended?
A)No testing is needed. The hemoglobin cut off for PV is >16.5
B)No testing is needed. The hemoglobin cut off for PV is >17.0
C)No testing is needed. The hemoglobin cut off for PV is >17.5
D)Testing is needed. The hemoglobin cut off for PV is >16.0
Testing is needed. The hemoglobin cut off for PV is >15.5
D) Testing is needed. The hemoglobin cut off for PV is >16.0
Males >16.5
Females >16.0
A 42yo M presents to see a Hematologist for newly found eosinophilia. The patient has had significant pruritus for the past 6 months. His PCP ordered a CBC w diff and noticed that his eosinophil count was very high. Eosinophil percentage over 29% witht an absolute count of 2500.
He is not taking any medications, denies having any fever, rashes or recent international travel. Bone marrow biopsy was done. Pathologic analysis of the specimen reveals Hypereosiophilic syndrome. Molecular testing reveals a 5q31-33 breakpoint. FISH testing reveals a PDGFR-B rearrangement but no abnormality is seen in FIP1L1-PDGFRA. What therapy should be offered?
A)Imatinib 100-400 mg daily
B)Mepolizumab
C)Observation
D)Pegylated interferon
E)Ruxolitinib
A) Imatinib 100-400 mg daily
Start with 100 mg, if inadequate response, increase to 400 mg
A 32 yo male presents to see a Hematologist for evaluation of erythrocytosis. He emigrated from Russia 8 years ago and has not been seeing his PCP routinely. He recently presented for a routine visit and labs reveal hgb 19, hct 57%, rest of CBC w diff iw wnl.
Additional work up:
JAK2 mutation: Negative
Epo level: 22 (normal 3.7 – 16)
BMBx: 65% cellularity, normal trilineage hematopoeisis, no evidence of MPN, lymphoma, or leukemia.
What is the most likely diagnosis:
A)Polycythemia Vera
B)Reactive thrombocytosis
C)MPN NOS
D)Occult malignancy
E)Chuvash Polycythemia
E) Chuvash Polycythemia
100 pt Bonus: What gene is mutated in this disease?
Which of the following patients with Essential Thrombocytoisis has the lowest risk of developing a thrombotic event?
A)A 65 yo male with a Carlreticulin mutation
B)28 yo male with a Jak2 mutation with no known cardiovascular risk factors
C)56 yo female with no mutation in JAK2, calreticulin, or MLP515 mutation. She has a history of recurrent DVTs
D)59 yo male with an MLP515 mutation and no known cardiovascular risk factors
E)None
A) A 65 yo male with a Carlreticulin mutation
Chronic Neutrophilic Leukemia (CNL) is a disorder characterized by mature granulocytic proliferation in the bone marrow. These granulocytes can infiltrate into the organs leading to hepatosplenomegaly. Which of the following mutations is found in over 90% of CNL patients?
A)KIT D816V
B)Calreticulin
C)JAK2
D)CSF3R
E)MPL
D) CSF3R
A 66yo female is referred over to Hematology by her PCP for abnormal blood work:
WBC 32K, Hgb 9.2, plt 175K
No prior labs to compare. She reports a 3 month history of pruritus and drenching night sweats. Exam shows splenomegaly without lymphadenopathy.
A BMBx is performed. Pathology shows 6% blasts with significant myelofibrosis. Further molecular testing reveals patient does not have a JAK2, MPL, or calreticulin mutations. Based on DIPSS, how would her Primary myelofibrosis be classified?
A) Low risk
B) Intermediate-1 risk
C) Intermediate-2 risk
D) High risk
E) Very high risk
D) High risk
Age>65
WBC>25K
Hgb<10 (2pts)
Constitutional symptoms
Circulating blasts >1%
A 76 yo M has a long-standing history of PV. In the last year, his disease has been much more difficult to control. Despite undergoing weekly phlebotomy and hydrea 1000 mg daily, his Hct remains >52 and he has developed painful splenomegaly.
Unfortunately, he has developed dose-limiting toxicity to hydrea. When the dose is increased to >1000 mg daily, he develops marked fatigue, painful hand ulcers, and neuropathy. His performance status has suffered and he implores his Hematologist to discontinue hydrea. The patient is then started on Ropeginterferon alpha. Unfortunately he develops severe depression and it is stopped. He has no history of DVT, PE, or stroke. He is on ASA 81 mg daily. What should be recommended?
A)Increase phlebotomy frequency to 3x/week
B)Start imatinib
C)Increase aspirin to 325 mg daily
D)Start ruxolitinib
E)Start plasmapheresis
D) Start Jakafi
RESPONSE Study
21% of patient experienced a reduction in need for phlebotomy and reduced spleen size vs 1% who received best available therapy
A 52 yo male with no PMH presents to the ED with right-sided flank pain and dyspnea. He undergoes an extensive work up. His room air oxygen is 95% but decreases to 70% with ambulation. Cardiology was consulted. EKG, TTE, and troponin are normal. Microscopic intrapulmonary shunting is suspected.
Hgb is 19.2, rest of CBC wnl. Physical exam shows no hepatosplenomegaly but he does have telangiectasias thought his whole body which the patient states started around 8 months ago. Patient reports neuropathy. CTPA negative. CT A/P shows a perinephric 14 cm fluid collection. JAK2 mutation negative. B12 wnl. SPEP shows M-spike 0.6 g/dL IgG kappa. The perinephric fluid is negative for infection or malignant cells. What is the most likely diagnosis?
A)Reactive erythrocytosis
B)Polycythemia vera
C)Occult PE
D)TEMPI syndrome
E) Plasma cell dyscrasia NOS
D) TEMPI Syndrome
T = telangiectasia
E = erythrocytosis/elevated epo
M = M-spike
P = Perinephric fluid
I = intrapulmonary shunting
An otherwise healthy 39 yo female comes for evaluation because of a 3-month history of easy bruising, frequent epistaxis, and heavy menstrual bleeding. She takes not medications. Vital signs are wnl. Physical exam shows multiple ecchymoses at various stages of healing. No petechiae.
WBC 9400, Hgb 12.7, plt 1350000
Molecular testing shows a mutation in CALR.
Which of the following is the next more appropriate test to determine the cause of this patient’s bleeding?
A)Antithrombin
B)Factor X activity
C)Fibrinogen
D)INR
E)Von Willebrand factor:ristocetin cofactor
E)Von Willebrand factor:ristocetin cofactor
A 22 yo male presents to his PCP for evaluation of several symptoms. Over the past 2 years, he has developed hyperflexible joints, dysautonomia, dizziness, chronic pain, syncope, and IBS. He is referred to a variety of specialists. Ehlers-Danlos syndrome and POTS have been ruled out. The most problematic symptoms for him have been an allergic-like syndrome with skin itching, flushing, hives and anaphylaxis. A hematologist if consulted. Serum tryptase is markedly elevated at 450 ng/dL. A bone marrow biopsy is done and shows normal morphology, immunophenotype, and cytogenetics. KIT is wildtype. What is the most likely diagnosis?
A)Primary mast cell activation syndrome
B)Systemic mastocytosis
C)Mast cell leukemia
D)Smoldering systemic mastocytosis
E)Hereditary alpha tryptasemia syndrome
E) Hereditary alpha trypasemia syndrome
Caused by duplications or triplications in the TPSAB1 gene.