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approach to MPN


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approach to MPN

  1. 1. Diagnostic Approach toMyeloproliferative Neoplasms
  2. 2. 2008 WHO Classification Scheme for Myeloid NeoplasmsAcute Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Atypical Chronic Myeloid Leukemia Juvenile Myelomonocytic Leukemia Myelodysplastic Syndromes MDS/MPN, unclassifiable Chronic Myelogenous Leukemia MDS/MPN Polycythemia Vera Essential Thrombocythemia Primary MyelofibrosisChronic Myeloproliferative Neoplasms Chronic Neutrophilic Leukemia Chronic Eosinophilic Leukemia, NOS Hypereosinophilic Syndrome Mast Cell Disease MPNs, unclassifiable Myeloid neoplasms associated with Myeloproliferative neoplasms PDGFRA rearrangement associated with eosinophilia and Myeloid neoplasms associated with abnormalities of PDGFRA, PDGFRB rearrangement PDGFRB, or FGFR1 Myeloid neoplasms associated with FGFR1 rearrangement (EMS)
  3. 3. • A 55 year-old man presents for routine evaluation• CBC reveals erythrocytosis with mild leukocytosis and thrombocytosis:
  4. 4. What is your differential diagnosis?• Relative erythrocytosis – Secondary to decreased plasma volume – Hemoglobin > 18.5 gm/dL (males) or > 16.5 gm/dL (females) diagnostic for absolute erythrocytosis – Otherwise, measure RBC mass• Absolute erythrocytosis – Polycythemia vera – Secondary erythrocytosis
  5. 5. Differential diagnosis of erythrocytosis
  6. 6. Polycythemia vera – clinical features• May be incidental finding of high Hgb/HCT• Non-specific complaints: HA, weakness, dizziness, excessive sweating• Pruritus – Typically after hot bath/shower or rubbing of skin – Presumed 2/2 mast cell degranulation – histamine, prostaglandins, etc...(unproven) – Consistent with finding that ASA can relieve pruritus in some patients• Erythromelalgia/acral paresthesias – Burning pain/parasthesias in hands/feet accompanied by erythema, pallor, or cyanosis – Thought to be 2/2 microthrombi; associated with thrombocytosis – Responds dramatically to ASA or reduction of plt count to normal
  7. 7. Polycythemia vera – clinical features• Thrombosis (venous or arterial) – Risk factors include age, h/o prior thrombosis, leukocytosis • Extreme thrombocytosis and CV risk factors may also be risk factors (controversial) – Suspect PV in patients with unusual sites of thrombosis, e.g. Budd-Chiari, portal, splenic, or mesenteric vein thrombosis, particularly in women < 45 – Transient visual disturbances (e.g. amaurosis fugax, migraine)• Splenomegaly +/- hepatomegaly
  8. 8. Diagnostic approach to erythrocytosis
  9. 9. Polycythemia VeraDiagnostic Criteria
  10. 10. Polycythemia Vera Course and Prognosis• Median survival is ~ 14 years• Chronic phase may last for years• Progression to: – Myelofibrosis (~10% at 10 years) – AML (1-5% at 10 years)• Thrombosis major source of morbidity and mortality
  11. 11. Polycythemia Vera Treatment• Low dose aspirin indicated for all patients• Phlebotomy: Goal to Hct < 45 (< 42 in females)• Myelosuppression (usually hydroxyurea) – Typically used in patients at high risk for thrombosis (age > 60 or prior h/o thrombosis)• Alpha-interferon (younger high-risk patients)
  12. 12. • A 66 year-old woman presents with headaches and recurrent TIA symptoms• CBC reveals thrombocytosis:
  13. 13. Differential Diagnosis of Thrombocytosis• Reactive (secondary) thrombocytosis – Infection/inflammation – Iron deficiency – Chronicity of thrombocytosis helpful• Primary thrombocytosis – Essential thrombocythemia – (masked) polycythemia vera – Need to exclude CML (BCR-ABL)
  14. 14. Essential Thrombocythemia Clinical Features• Chronic thrombocytosis (often extreme, > 1 x 106/µL)• Many patients are asymptomatic• Vasomotor symptoms: headaches, syncope, visual disturbances, atypical chest pain, erythromelalgia (typically ASA-responsive)• Thrombosis major cause of morbidity and mortality – Both arterial and venous; unusual sites – No clear association with platelet count• Paradoxical increase in bleeding complications – Risk factors/associations: • Extreme thrombocytosis > 1 million (controversial) • Use of ASA > 325 mg/day or other NSAIDs • Acquired VWD• Splenomegaly
  15. 15. Essential Thrombocythemia Diagnostic Criteria• Platelet count ≥ 450,000• JAK2 V617F+ OR no evidence of reactive thrombocytosis• Not meeting WHO criteria for other MPNs (e.g PV, CML)• Megakaryocyte proliferation with large and mature morphology; no or little granulocyte or erythroid proliferation - ALL FOUR CRITERIA ARE “REQUIRED”
  16. 16. Essential Thrombocythemia Bone marrow: Hypercellularity with markedmegakaryocytic hyperplasia
  17. 17. Essential Thrombocythemia Course and Treatment• Survival curves near age-matched controls – Thrombosis major cause of morbidity and mortality – Progression to myelofibrosis in ~5% and AML in ~1-5%• Low dose aspirin indicated for all patients without history of bleeding• Myelosuppresive therapy for high-risk patients (age > 60 OR h/o thrombosis) – Hydroxyurea, anagrelide• Treatment based on platelet count alone is controversial
  18. 18. • A 57 year-old man presents with fatigue, anorexia, and night sweats• He also complains of abdominal discomfort and early satiety• CBC reveals pancytopenia with an abnormal peripheral smearSeg 35, bands 20, metamyelocytes 10, myelocytes 8, promyelocytes 4, blasts 3, teardropRBCs, nRBCs
  19. 19. Primary Myelofibrosis Differential Diagnosis• Reactive myelofibrosis – Marrow infiltration with cancer – Infections (mycobacterial or fungus) – Myelodysplasia• Other MPNs• Work-up – Bone marrow biopsy – Genetic testing for JAK2 V617F and BCR-ABL
  20. 20. Primary myelofibrosis – clinical features• Severe fatigue, weight loss, fevers, night sweats• Splenomegaly, often massive – LUQ discomfort/pain, early satiety• Hepatomegaly – Portal HTN related to HSMG – ascites, varices, UGIB – Portal vein thrombosis• Extramedullary hematopoiesis – Foci can occur in almost any organ• Cytopenias (but can also have leukocytosis, thrombocytosis)• Leukoerythroblastic reaction
  21. 21. Leukoerythroblastic Reaction Triad: • Tear drop RBC • Nucleated RBC • Immature myeloid cells Associated with marrow infiltration • Myelofibrosis • Cancer • Certain infections
  22. 22. Primary Myelofibrosis: Diagnostic Criteria
  23. 23. Primary Myelofibrosis Bone marrow: Megakaryocytic hyperplasia with markedfibrosis
  24. 24. Primary Myelofibrosis Course and Prognosis• Median survival of only 3 years• Bone marrow failure – Progressive cytopenias – RBC transfusion dependence – Susceptibility to infections – Hemorrhage• Evolution to AML
  25. 25. Primary Myelofibrosis Course and PrognosisDIPSS:• Age >65 years: 1 point• Leukocyte count >25,000/microL: 1 point• Hemoglobin <10 g/dL: 2 points• Circulating blast cells ≥1 percent: 1 point• Presence of constitutional symptoms: 1 point DIPSS category Points DIPSS-plus DIPSS-plus points category Low-risk 0 0 0 Intermediate-1 1-2 1 1 Intermediate-2 3-4 2 2-3 High-risk 5-6 3 4-6 Unfavorable karyotype 1 Platelets < 10,000/microL 1 RBC transfusion-dependence 1
  26. 26. Primary Myelofibrosis Course and Prognosis
  27. 27. Primary myelofibrosis – treatment• Supportive care – Transfusions – ESAs – not generally effective in PMF• Hydroxyurea – Can be effective in controlling leukocytosis and/or thrombocytosis – Can ameliorate splenomegaly – Myelosuppression Is limiting factor• Splenectomy – Indicated for severe symptoms related to SMG – May be helpful for improving anemia and/or thrombocytopenia• Splenic irradiation – Considered for poor surgical candidates – Benefits are transient (3-6 months)• BMT – Not an option for many patients
  28. 28. Primary myelofibrosis – treatment• Well tolerated – initial study with higher doses of thalidomide poorly tolerated• 28% with ongoing response – Durable treatment response for anemia and thrombocytopenia, not SMG
  29. 29. JAK2 inhibitors in MPNs Grade 3/4 Grade 3/4 thrombocytopenia anemia INCB018424 20% 23% TG101348 24% 35% CYT387 27% 7% Anemia response by IWG INCB018424 8% TG101348 0% CYT387 50%