Board Review Malignant Hematology Nitin Jain May 17, 2010

1. Board Review Malignant Hematology Nitin Jain May 17, 2010

2. Question 1 (MKSAP 4) • A 67-year-old man comes for a routine physical examination. The patient has hypertension treated with hydrochlorothiazide. On examination, temperature is normal, blood pressure is 140/85 mm Hg, pulse rate is 88/min, and respiration rate is 16/min. The patient has a ruddy complexion. There is no jugular venous distention. Cardiopulmonary examination is normal. The spleen tip is palpable just below the left costal margin. • Laboratory studies • Hematocrit 61% Leukocyte count 11.2 K • Platelet count 405 K Erythropoietin 10 mU/mL • Arterial oxygen saturation 96% • Cytogenetic studies show a JAK2 mutation • Which of the following is the most appropriate treatment? • A. Therapeutic phlebotomy • B. Therapeutic phlebotomy plus anagrelide • C. Therapeutic phlebotomy plus aspirin • D. Therapeutic phlebotomy plus hydroxyurea

3. Myeloproliferative neoplasms (MPN) 2008 WHO classification: MPD (Myeloproliferative disorder) renamed as MPN Classic MPN .

4. Polycythemia vera • Overproduction of erythrocytes • WBC cells and platelets can also be increased • Signs and symptoms • Headache • Pruritus (especially with hot bath) • Erythromelalgia (burning pain in feet/hands with warmth and erythema) • Thrombotic disorders most serious issue (TIA, MI ,Stroke, DVT) • Budd-Chiari syndrome: 50% have underlying PV • Diagnosis: Rule out secondary causes • Smoking, COPD, Sleep Apnea, morbid obesity, high altitude • Renal cell carcinoma, Hepatocellualr carcinoma, uterine fibroids

5. TABLE 4: Diagnostic criteria for polycythemia vera over different time periods

6. JAK2 mutation • First described in 2005 • ~ 100% of PV • 50% ET (essential thrombocythemia) • 50% PMF (primary myelofibrosis) Presence of JAK2 mutation establishes Dx of MPN could be PV / ET / PMF Negative JAK2 rules out PV could be ET/PMF or anything else

7. PV treatment • Phlebotomy all patients • Goal Hct <42% women, <45% men • Aspirin for all patients • Especially erythromelalgia • Hydroxyurea • Age >65 or h/o thrombosis

8. Question 1 (MKSAP 4) A 67-year-old man comes for a routine physical examination. The patient has hypertension treated with hydrochlorothiazide. On examination, temperature is normal, blood pressure is 140/85 mm Hg, pulse rate is 88/min, and respiration rate is 16/min. The patient has a ruddy complexion. There is no jugular venous distention. Cardiopulmonary examination is normal. The spleen tip is palpable just below the left costal margin. Laboratory studies Hematocrit 61% Leukocyte count 11.2 K Platelet count 405 K Erythropoietin 10 mU/mL Arterial oxygen saturation 96% Cytogenetic studies show a JAK2 mutation Which of the following is the most appropriate treatment? A. Therapeutic phlebotomy B. Therapeutic phlebotomy plus anagrelide C. Therapeutic phlebotomy plus aspirin D. Therapeutic phlebotomy plus hydroxyurea

9. Question 2 (MKSAP 32) • A 55-year-old man has a 1-year history of fatigue, daytime hypersomnolence, and frequent nighttime awakenings. The patient has hypertension and a 48-pack-year smoking history. His only medication is lisinopril. • On physical examination, temperature is normal, blood pressure is 135/85 mm Hg, pulse rate is 88/min, and respiration rate is 28/min. BMI is 35. Examination is otherwise unremarkable. • Laboratory studies: Hematocrit 59%, WBC 5.7 K, Platelet count 345 K, Epo 30 mU/mL • Arterial oxygen saturation (on ambient air) 95% • Hematocrit measurements prior to 5 years ago were all normal • Cytogenetic studies are negative for the JAK2 gene mutation • Which of the following is the most likely cause of the patient’s elevated hematocrit? • A. Relative polycythemia • B. High-oxygen–affinity hemoglobin • C. Polycythemia vera • D. Secondary polycythemia • Needs pulse ox with exertion, sleep study

10. Question 3 (MKSAP 18) • A 54-year-old man is evaluated for increased lethargy and vague abdominal symptoms of 2 weeks’ duration. His medical and family histories are noncontributory. He does not smoke and takes no medications. Vitals stable. Arterial oxygen saturation is 99% on ambient air. There is no clubbing or evidence of cyanosis. Cardiopulmonary examination is normal. The abdomen is soft, and there is no hepatosplenomegaly. • Lab studies: Hemoglobin 20.2 g/dL, Platelet count 312, WBC 8.2 k/µL • Erythropoietin 35 mU/mL • Which of the following is the most appropriate next diagnostic test? • A. Ultrasound of the abdomen • B. Echocardiogram • C. JAK2 mutation analysis • D. Erythrocyte mass study

11. Question 4 (MKSAP 21) • A 42-year-old woman who is scheduled to undergo a hysterectomy for endometrial carcinoma comes for a preoperative evaluation. At the time of her initial evaluation, she was also discovered to have thrombocytosis. In addition to menorrhagia, the patient recently developed epistaxis and easy bruising. Her only medications are an oral contraceptive agent and an iron supplement. • Examination is normal. No petechiae, ecchymoses, or splenomegaly. • Laboratory studies: Hemoglobin 11.3, WBC 4.6, platelet count 1,500 K • Platelet function studies: Abnormal platelet aggregation • Cytogenetic studies reveal a JAK2 mutation • Bone marrow examination: Hypercellular marrow with increased megakaryocytes in clusters. • Which of the following is the most appropriate treatment? • Anagrelide beginning 2 days preoperatively • Hydroxyurea beginning the night after surgery • Low-dose aspirin postoperatively • Platelet apheresis preoperatively and hydroxyurea postoperatively

12. Essential thrombocythemia 2008 WHO criteria for diagnosis • Sustained platelet count ≥ 450 K • Bone marrow biopsy showing proliferation of megakaryocytes • Not meeting criteria for others MPNs • Demonstration of JAK2 mutation or other clonal markers (no evidence for reactive thrombocytosis) Diagnosis of ET requires meeting all 4 criteria Important to rule out secondary causes: • Iron deficiency, post-op state, acute inflammatory states • DOES NOT increase thrombosis risk irrespective of degree of elevation

13. Essential thrombocythemia • Thrombosis main risk • Paradoxical bleeding when platelets >1 million (some say >1.5 million) • Acquired vWF deficiency • Treatment: • ASA for all unless bleeding or platelets >1.5 M • Hydroxyurea vs. anagrelide • Used if age >60 / previous thrombosis • Hydroxyurea preferred over anagrelide (NEJM 2006) • Interferon for pregnant patients

14. Question 5 (MKSAP 27) • A 77-year-old man has a 1-year history of increasing fatigue. He has not seen a physician for at least 3 years. Medical and family histories are unremarkable, and he takes no medications. • Vitals stable. Cardiopulmonary examination is normal. The spleen is palpable 6 cm below the left costal margin. • Laboratory studies: Hemoglobin 7.6 g/dL, WBC 11.2 K, Platelet 104 K • Haptoglobin Elevated, Direct Coombs Negative • A bone marrow aspiration reveals a “dry tap.” • A peripheral blood smear and bone marrow biopsy are shown • Cytogenetics: Negative Philadelphia chromosome • Which of the following is the most likely diagnosis? • A. Aplastic anemia • B. Chronic myeloid leukemia • C. Myelofibrosis • D. Pure red cell aplasia

15. Myelofibrosis Normal megakaryocyte Normal megakaryocyte

16. Myelofibrosis • Clonal proliferation of abnormal stromal cells that release fibrosis-promoting cytokines in the bone marrow. • Peripheral blood smear: classic leukoerythroblastic picture of immature granulocytes, nucleated RBCs, dysmorphic erythrocytes (tear-drop cells) • Prefibrotic stage: Leukocytosis, thrombocytosis • Fibrotic stage: pancytopenia • Splenomegaly and hepatomegaly • Bone marrow: Hypercellularity with dysmorphic megakaryocytes and fibrosis • Main risk: transformation to AML • Median survival is 3 to 5 years

17. Myelofibrosis • No real good treatment • Conservative management: Epo, G-CSF, PRBC and platelet transfusion • Allogeneic stem cell transplant: only curative approach • 50% JAK2 mutation positive • Many JAK2 inhibitors in clinical trials

18. Question 6 (MKSAP 15) • A 78-year-old woman has a 3-month history of increasing fatigue. She has no other medical problems and does not take any medications. Vitals normal. The patient appears pale. Examination is unremarkable. • Laboratory studies: • Hemoglobin 7.8 g/dL, Leukocyte count 2.8, ANC 1.2, Platelet count 560 • Erythropoietin 600 mU/mL • Bone marrow examination shows hypercellular marrow with erythroid hyperplasia and dysplasia of the erythroid and granulocyte series. Megakaryocytes are increased with many hypolobulated cells. Iron stores are normal. Cytogenetic studies show deletion of the long arm of chromosome 5 [del(5q-)]. • Which of the following is the most appropriate treatment? • A. Azacitidine • B. Danazol • C. Lenalidomide • D. Granulocyte colony-stimulating factor and recombinant erythropoietin

19. 5q- MDS • Subtype of MDS with interstitial deletion of 5q • Classically seen in older women • Anemia and thromobocytosis: hallmark • Neutropenia less common • Better prognosis (median survival in one study 6.5 yrs compared to 2 yrs for other chromosomal abnormalities) • Rx – lenalidomide (Revlimid) – 2nd generation thalidomide

20. Question 7 (MKSAP 15) • A 25-year-old man is evaluated for the recent onset of fever, fatigue, dyspnea, easy bruising, and bleeding gums. On physical examination, temperature is 38.8 °C (101.8 °F), BP is 105/60 mm Hg, pulse 120/min, and RR is 24/min. Cervical and axillary lymphadenopathy is noted. Cardiopulmonary examination is normal. The liver edge and spleen tip are palpable. Laboratory studies: Hemoglobin 8.5 g/dL, WBC 104 K, ANC 0.6, platelet 17 K, LDH 2200, Uric acid 11.5 mg/dL • CXR: mediastinal mass. Bone marrow: Hypercellular marrow that is replaced with large blasts containing prominent nucleoli and abundant basophilic cytoplasm. The blasts do not contain Auer rods. Sudan black and myeloperoxidase stains are negative; periodic acid-Schiff stain is positive. Blasts are also positive for terminal deoxynucleotidyltransferase (TdT). Immunophenotyping shows CD2, CD3, CD7, and CD38. BCR/ABL translocation is absent. • Which of the following is the most likely diagnosis? • A. Acute lymphoblastic leukemia • B. Acute myeloid leukemia • C. Chronic lymphocytic leukemia • D. Hodgkin lymphoma

21. Acute lymphoblastic leukemia (ALL) • Proliferation of immature lymphoblasts • Constitutes 20% of acute leukemias in adults • Present with lymphocytosis, neutropenia, anemia, and thrombocytopenia • Lymphadenopathy and hepatosplenomegaly common • Central nervous system involvement seen (need for LP) • Bone marrow: increased lymphoblasts (Flow cytometry important)

22. Acute lymphoblastic leukemia (ALL) • Treatment • Induction: prednisone, vincristine, anthracyclines, • L-asparaginase, 6-mercaptopurine, and high- dose cytarabine • Consolidation: high-dose cytarabine • Maintenance: 6-mercaptopurine and methotrexate • Central nervous system prophylaxis: Intrathecal chemotherapy • Philadelphia chromosome positive ALL • Add imatinib/dasatinib to above chemo

23. Question 8 (MKSAP 40) • A 57-year-old woman is brought to the emergency department because of fever and shaking chills of 8 hours’ duration. The patient has a 1-year history of myelodysplastic syndrome treated with azacitidine. On physical examination, temperature is 39.2 °C (102.6 °F), BP 100/70 mm Hg, pulse 110/min, and respiration rate is 20/min. Examination is unremarkable. There is no rash, lymphadenopathy, costovertebral angle tenderness, abdominal tenderness, or splenomegaly. • Laboratory studies: Hemoglobin 10.6 g/dL • WBC 33.6K, Platelet 88 • Chest radiograph is normal. • A peripheral blood smear is shown. • What is the likely diagnosis? • A. Acute lymphoblastic leukemia • B. Acute myeloid leukemia • C. Acute promyelocytic leukemia • D. Chronic myeloid leukemia

24. Acute myelogenous leukemia • Proliferation of immature myeloblasts • By definition: ≥ 20% blasts in bone marrow • Auer rods clinches the Dx • NOTE: <5% blasts normal • 5-19% blasts MDS • Presents with circulating blasts, leukocytosis, neutropenia, anemia, thrombocytopenia (no hepatosplenomegaly, no lymphdenopathy) • FAB Subtype (AML M0-M7): no longer clinically used • Current classification based on cytogenetics and molecular study (FLT3 mutation, NPM1 mutation)

25. Acute myelogenous leukemia • Treatment of AML • Induction: Classically 7+3 • 7 days of cytarabine and 3 days of idarubicin • Consolidation: high dose cytarabine • Unlike ALL, maintenance treatment is not needed

26. Question 9 (MKSAP 34) • An asymptomatic 35-year-old man comes for a routine annual examination. Medical and family histories are unremarkable. Vitals and physical examination normal. • Laboratory studies: Hemoglobin 9.1 g/dL, WBC 2.1, Platelet count 135 • LDH 890 U/L, Uric acid 11.6 mg/dL • Peripheral blood smear: Circulating blasts and promyelocytes • Bone marrow: Hypercellular marrow with 80% myeloblasts and promyelocytes. Cytogenetic studies reveal translocation of chromosomes 15 and 17 [t(15;17)]. • In addition to hydration and allopurinol, which of the following is the most appropriate management at this time? • A. Broad-spectrum antibiotics • B. Chemotherapy • C. Chemotherapy plus all-trans-retinoic acid • D. HLA typing

27. Acute promyelocytic leukemia • AML M3 by FAB • Increased number of myeloblasts and promyelocytes • Presence of t(15;17) leading to PML/RARα fusion gene • Besides pancytopenia, DIC main feature (watch bleeding, DIC panel) • Treatment: all-trans-retinoic acid (ATRA) • Arsenic trioxide • Standard chemotherapy • Some protocols use only ATRA and arsenic (no chemotherapy at all) • ATRA syndrome (Differentiation syndrome) • develops while on ATRA or arsenic • Dyspnea, pulmonary infiltrates, fever • Stop drug, start steroids

28. Question 10 (MKSAP 8) • A 58-year-old man is evaluated for increasing fatigue of 2 months’ duration. Vitals stable. There is no lymphadenopathy. The spleen is palpable 4 cm below the left costal margin. • Laboratory studies: Hemoglobin 12.1 g/dL, WBC 55.2 K, Platelet 105 K • A peripheral blood smear shows an increased number of granulocytic cells in all phases of development but no Auer rods in the blasts. • Bone marrow examination shows hypercellular marrow (80% cellularity) with marked granulocytic hyperplasia, a left shift in the granulocytes, and 3% myeloblasts. Cytogenetic testing reveals a BCR/ABL translocation. • Which of the following is the most appropriate next step in managing this patient? • A. Administration of imatinib • B. HLA typing of the patient and his sister • C. Leukapheresis • D. Observation with monthly follow-up office visits

29. Chronic myelogenous leukemia • Characterized by translocation 9;22 • Leads to juxtaposition of BCR on chr 22 to ABL on chr 9 (BCR-ABL) • Rx – tyrosine kinase inhibitors • First line: Imatinib • Second line: Dasatinib, Nilotinib

30. Question 11 (MKSAP 91) • A 75-year-old woman with chronic lymphocytic leukemia who was previously asymptomatic on no therapy undergoes follow-up evaluation for community-acquired pneumonia for which she was hospitalized. The patient completed a course of antibiotic therapy and currently feels well. She reports no fevers, chills, night sweats, weight loss, abdominal pain, or new lymphadenopathy, and her pulmonary symptoms have resolved. Medical history is significant for a previous episode of pneumonia for which she was hospitalized within the past year. • Exam is normal other than splenomegaly • Laboratory studies: Hemoglobin 11 g/dL, WBC 24 K, with 80% mature-appearing lymphocytes, Platelet count 120 K • IgG: 500 mg/dL • Which of the following is the most appropriate next step in management? • A. Intravenous immune globulin • B. Prophylactic trimethoprim-sulfamethoxazole • C. Splenectomy • D. Repeat blood counts in 1 month

31. Question 12 • A 31-year-old woman is evaluated for painless, bilateral lower extremity edema of 4 weeks’ duration. She denies chest pain, dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. She has hypertension, which has been treated for 2 years with hydrochlorothiazide. At age 5 years, she had acute lymphoblastic leukemia, which was treated with vincristine, doxorubicin, and dexamethasone. She is currently on no medications other than hydrochlorothiazide. • Her blood pressure is 138/92 mm Hg, pulse is 90/min, and respiration rate is 18/min. Her BMI is 27. Her estimated central venous pressure is 10 cm H2O. Cardiac examination reveals a nondisplaced apical impulse, normal heart sounds, and no murmurs or extracardiac sounds. Pulmonary examination is normal. There is bilateral lower extremity edema to the knees. Laboratory results include normal levels of sodium, potassium, blood urea nitrogen, and creatinine. Urinalysis is normal and there is no evidence of proteinuria. • Electrocardiogram demonstrates sinus rhythm (88/min) and left bundle branch block. • Which of the following is the most appropriate management for this patient? • A. Adenosine nuclear perfusion imaging study • B. Bilateral lower extremity venous duplex ultrasound • C. Change hydrochlorothiazide to furosemide • D. Transthoracic echocardiography

32. Hyperleukocytosis and leukostasis • Hyperleukocytosis: Total leukemic cell count > 50K or 100K. • Seen in AML, ALL, CML, CLL • Leukostasis: seen mainly in AML • Need myeloid blasts to clog the arteries • Patient with CLL with WBC count 150K • no concern for leukostasis • lymphocytes are small and easily pass through the blood vessels

33. Thank you! And All the Best