Polycythemai vera and Essential Thrombocytosis

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Slide ประกอบการบรรยายเรื่อง PV&ET โดย อ.อภิชัย ในการประชุมกลางปี สมาคมโลหิตวิทยาแห่งประเทศไทย พ.ศ.2552

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Polycythemai vera and Essential Thrombocytosis

  1. 1. Apichai Leelasiri, M.D. FACP Hematology Division Department of Medicine Phramongkutklao Hospital and College of Medicine How I Treat Polycythemia Vera & Essential Thrombocythemia
  2. 2. ชายอายุ 76 ปี ข้าราชการบำนาญ <ul><li>อาการสำคัญ & แน่นหน้าอกเวลาทำงาน ปวดศีรษะ หน้าแดง 1 เดือน </li></ul><ul><li>ประวัติปัจจุบัน เหนื่อยง่าย เบื่ออาหาร 6 เดือน น้ำหนักลด 10 กก . ใน 1 ปี อุจจาระปัสสาวะปกติ ไม่คันตามตัว </li></ul><ul><li>ประวัติอดีต เป็น HTN, dyslipidemia และ hyperuricemia 20 ปี </li></ul><ul><li>ตรวจร่างกาย BP 140/80 mmHg, PR 76/min </li></ul><ul><li>red face, no lymphadenopathy </li></ul><ul><li>spleen just palpable </li></ul>
  3. 4. Investigations <ul><li>CBC: Hct 71%, Hb 23.3 g/dL , WBC 12.8 x 10 9 /L, PMN </li></ul><ul><li>89%, band 2%, L 5%, M 2%, E 2%, Platelet 349 x 10 9 /L, </li></ul><ul><li>ESR 1 mm/hr, reticulocyte 1.1 % </li></ul><ul><li>FPG 90 mg/dL, BUN 20.6 mg/dL, Cr 1.14 mg/dL, TB 0.97 </li></ul><ul><li>mg/dL, AP 129 U/L, AST 48 U/L, GPT 22 U/L, albumin </li></ul><ul><li>3.6 g/dL, globulin 2.9 g/dL, uric acid 4.9 mg/dL, TG 105 </li></ul><ul><li>mg/dL, cholesterol 258 g/dL </li></ul><ul><li>EKG: NSR 65/min, LAE, LVH, nonspecific lateral ST </li></ul><ul><li>depression, inferior ST elevation </li></ul>
  4. 5. Further Investigations <ul><li>PBS </li></ul><ul><li>Bone marrow aspiration Bx: panmyelosis </li></ul><ul><li>Cytogenetics: 46, XY </li></ul><ul><li>Pulse oximeter: O 2 sat 96.8% </li></ul><ul><li>U/S: mild splenomegaly, small gall stone, enlarged prostate </li></ul><ul><li>RBC mass: 57.8 ml/kg (22.9-36.9) </li></ul><ul><li>Plasma volume: 34.8 ml/kg (38.2-57.8) </li></ul><ul><li>Blood for JAK2 mutation: not done @2543 </li></ul>
  5. 12. Provisional Dx Polycythemia vera
  6. 13. Management: Point of Discussion <ul><li>จะเริ่มรักษาเมื่อใด </li></ul><ul><li>จะต้องทำ blood letting ทันทีหรือไม่ ปริมาณและความถี่ ถ้าทำต้องให้ IV fluid ร่วมด้วยหรือไม่ </li></ul><ul><li>ต้องให้ cytoreductive ร่วมด้วยหรือไม่ </li></ul><ul><ul><li>Hydroxyurea </li></ul></ul><ul><ul><li>Busulfan </li></ul></ul><ul><ul><li>IFN alpha </li></ul></ul><ul><ul><li>32 P </li></ul></ul><ul><li>Aim ให้ Hct อยู่ในระดับใด </li></ul><ul><li>ต้องให้ antiplatelet ร่วมด้วยหรือไม่ </li></ul>ยาชนิดใดเหมาะสมที่สุด
  7. 14. Management <ul><li>Blood letting 1 unit </li></ul><ul><li>Hydroxyurea (500 mg) 1 x 3 x 2 weeks </li></ul><ul><li>F/U 2 weeks -> Hct 59%, WBC 3.4 x 10 9 /L, PMN 66%, L 32%, E 1%, platelet 209 x 10 9 /L -> ↓ Hydroxyurea 1 x 1 x 4 weeks </li></ul><ul><li>F/U 4 weeks -> Hct 45%, WBC 3.8 x 10 9 /L, PMN 49%, L 37%, M 11%, E 2%, B 1%, platelet 168 x10 9 /L </li></ul><ul><li>Now on HU 1 x 3/week: last F/U (9 + years) Hct 45%, WBC 11.5 x 10 9 /L, platelet 264 x 10 9 /L </li></ul>
  8. 15. PV: S/S <ul><li>Median age at Dx ~ 60 yrs </li></ul><ul><li>M:F 1.2:1 </li></ul><ul><li>↑ RBC mass -> HTN, venous & arterial thrombosis </li></ul><ul><li>Cerebral, mesenteric, portal, splenic, hepatic vein thrombosis </li></ul><ul><li>Hyperviscosity: headache, vertigo, visual disturbance, erythromelalgia </li></ul>
  9. 16. PV: S/S <ul><li>Plethora, red ruddy cyanosis </li></ul><ul><li>Aquagenic pruritus </li></ul><ul><li>Acquired vWD type II in pts with Plt > 1M </li></ul><ul><li>Metabolic: gouty attack </li></ul><ul><li>Splenomegaly 70% </li></ul><ul><li>Hepatomegaly 40% </li></ul>
  10. 17. PV: Lab <ul><li>CBC: Hct > 50%, WBC & plt ↑, basophil & eosinophil ↑ </li></ul><ul><li>PBS: aggregation of platelet, giant & pale-staining </li></ul><ul><li>MCV, MCH ↓, serum EPO ↓ </li></ul><ul><li>O 2 sat > 92%, U/S: splenomegaly </li></ul><ul><li>Blood for JAK2 mutation </li></ul><ul><li>Bone marrow: panmyelosis </li></ul>
  11. 18. JAK2 Gene <ul><li>9p -> JAK2 protein (cytoplasmic tyrosine kinase)-> binding to intracellular portion of EPOR, MPL, IL-3R, G-CSFR </li></ul><ul><li>7 domains (JH1-JH7) </li></ul><ul><ul><li>JH1: kinase activity </li></ul></ul><ul><ul><li>JH2: psedokinase domain </li></ul></ul><ul><ul><li>JH6, JH7: binding to cytokine receptor </li></ul></ul>
  12. 19. JAK2 Domains Levine RL and Gilliland DG. Blood 2008; 112: 2190-2198
  13. 20. JAK2: Wild-type & V617F Campbell PJ and Green AR. N Engl J Med 2006; 355: 2452-2466
  14. 21. Homozygosity of JAK2V617F Campbell PJ and Green AR. N Engl J Med 2006; 355: 2452-2466
  15. 22. JAK2 Gene Mutation <ul><li>Acquired, gain-of-function mutation </li></ul><ul><li>Specific for myeloid malignancies </li></ul><ul><li>1849, exon 14 @ JH2 domain: G->T </li></ul><ul><li>617: valine->phenylalanine (JAK2V671F) </li></ul><ul><li>Other mutation: @ exon12: 2% of PV </li></ul>
  16. 23. JAK2V617F <ul><li>Disease Frequency </li></ul><ul><li>Polycythemia vera > 95% </li></ul><ul><li>Essential thrombocythemia ~60% </li></ul><ul><li>Primary myelofibrosis ~60% </li></ul><ul><li>MPN, unclassifiable ~20% </li></ul><ul><li>Refractory anemia with ringed sideroblasts ~50% </li></ul><ul><li>and thrombocytosis (RARS-T) </li></ul>Vannucchi AM, et al. CA Cancer J Clin 2009; 59: 171-191
  17. 24. PV: Major Minor Criteria Dx Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65
  18. 25. Clinical & Laboratory Criteria for Dx of PV* (Pre-JAK2V617F era) <ul><li>↑ RBC mass > 25% above mean predicted value </li></ul><ul><li>Normal O2 saturation > 92% </li></ul><ul><li>Splenomegaly </li></ul><ul><li>Platelet > 400 x 10 9 /L and WBC > 12 x 10 9 /L </li></ul><ul><li>BM hypercellularity associated with clustered mature megakaryocytes with hyperlobulated nuclei and absent iron stores </li></ul><ul><li>Low serum EPO < 3.0 U/L </li></ul><ul><li>Erythroid colony formation in the absence of exogenous EPO </li></ul>* Criterion 1+ any 3 additional criteria Hoffman R. Hematology Basic Principles and Practice 3 rd edition, 2000
  19. 26. Diagnostic Criteria of PV by PVSG (Pre-JAK2V617F era) <ul><li>Major </li></ul><ul><li>Hct ↑ + RBC mass ↑ </li></ul><ul><ul><li>> 36 mL/kg in men </li></ul></ul><ul><ul><li>> 32 mL/kg in women </li></ul></ul><ul><li>O 2 sat > 92% </li></ul><ul><li>Splenomegaly </li></ul><ul><li>Minor </li></ul><ul><li>WBC > 12 x10 9 /L </li></ul><ul><li>Platelet > 400 x 10 9 /L </li></ul><ul><li>Neutrophil AP > 100 score </li></ul><ul><li>Serum B12 > 900 pg/mL or unbounded B12 binding capacity > 2,200 pg/mL </li></ul><ul><li>Criteria Dx </li></ul><ul><li>All 3 major or </li></ul><ul><li>2 major + 2 minor </li></ul>
  20. 27. PV @ PMK: Pre-JAK2 era <ul><li>1982-1998 </li></ul><ul><li>Baseline Hct > 50% </li></ul><ul><ul><li>WBC > 12 x 10 9 /L or platelet > 400 x 10 9 /L </li></ul></ul><ul><ul><li>Bone marrow: panmyelosis </li></ul></ul><ul><ul><li>Splenomegaly </li></ul></ul><ul><ul><li>RBC mass > 36 mL/kg in men or > 32 mL/kg in women </li></ul></ul>Leelasiri, et al. 1999
  21. 28. PV @ PMK: Pre-JAK2 era <ul><li>41 pts, M:F 26:15 </li></ul><ul><li>Median age of Dx 57 years </li></ul><ul><li>Median duration of symptoms 4 months </li></ul><ul><li>Presenting symptom </li></ul><ul><ul><li>Cerebrovascular 25 pts (61%) </li></ul></ul><ul><ul><li>Myocardial ischemia or infarction 8 pts (20%) </li></ul></ul><ul><ul><li>Peripheral vascular insufficiency 5 pts (12%) </li></ul></ul>Leelasiri, et al. 1999
  22. 29. PV @ PMK: Pre-JAK2 era (N=41) <ul><li>Splenomegaly 16 pts (39%) </li></ul><ul><li>Hepatomegaly 2 pts (5%) </li></ul><ul><li>Hepatosplenomegaly 18 pts (44%) </li></ul><ul><li>Mean Hct 63 + 9% </li></ul><ul><li>WBC 22.3 + 12.0 x 10 9 /L </li></ul><ul><li>Platelet 643.0 + 275.5 x 10 9 /L </li></ul><ul><li>RBC mass 48 + 20 mL/kg </li></ul>Leelasiri, et al. 1999
  23. 30. PV @ PMK: Pre-JAK2 era (N=41) <ul><li>Initial Rx with blood letting 36 pts </li></ul><ul><ul><li>Median no. of blood letting 3 </li></ul></ul><ul><li>Rx busulfan (BU) 18 pts </li></ul><ul><li>Rx hydroxyurea (HU) 14 pts </li></ul><ul><li>Rx BU & HU 5 pts </li></ul><ul><li>Rx IFN alpha 5 pts </li></ul><ul><li>Rx 32 P 4 pts </li></ul>Leelasiri, et al. 1999
  24. 31. PV @ PMK: Pre-JAK2 era (N=41) <ul><li>Median F/U duration 854.5 days </li></ul><ul><li>Alive 22 pts </li></ul><ul><li>Died 2 pts </li></ul><ul><ul><li>AML 1 pt </li></ul></ul><ul><ul><li>GI bleeding 1 pt </li></ul></ul><ul><li>Mean last Hct 45 + 10% </li></ul><ul><li>WBC 12.9 + 11.1 x 10 9 /L </li></ul><ul><li> platelet 398.1 + 205.1 x 10 9 /L </li></ul>Leelasiri, et al. 1999
  25. 32. PV: DDx <ul><li>Secondary erythrocytosis </li></ul><ul><ul><li>Renal cell cancer, hepatoma </li></ul></ul><ul><ul><li>EPO, androgen Rx, herbal medicine (ginseng) </li></ul></ul><ul><ul><li>Chronic hypoxemia </li></ul></ul><ul><ul><ul><li>COPD, cyanotic heart disease </li></ul></ul></ul><ul><ul><ul><li>ASD or VSD with reverse shunt </li></ul></ul></ul><ul><li>Relative erythrocytosis </li></ul><ul><ul><li>Normal RBC mass, reduced plasma volume </li></ul></ul><ul><ul><li>HTN, obesity, stress </li></ul></ul>
  26. 33. Staging of PV <ul><li>Prodromal phase: borderline or mild ↑ in RBC </li></ul><ul><li>Overt polycythemic phase: definite ↑ in RBC </li></ul><ul><li>Spent or post-polycythemic myelofibrosis phase (PPMF): </li></ul><ul><ul><li>decrease in RBC </li></ul></ul><ul><ul><li>progressive anemia & splenomegaly </li></ul></ul><ul><ul><li>low-grade fever from marrow fibrosis and extramedullary hematopoiesis </li></ul></ul><ul><ul><li>AML transformation </li></ul></ul>
  27. 34. Management of PV <ul><li>Risk stratification </li></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>H/O thrombosis </li></ul></ul><ul><ul><li>Cardiovascular risk factors </li></ul></ul><ul><ul><ul><li>HTN </li></ul></ul></ul><ul><ul><ul><li>DM </li></ul></ul></ul><ul><ul><ul><li>Dyslipidemia </li></ul></ul></ul><ul><ul><ul><li>Smoking </li></ul></ul></ul><ul><ul><ul><li>Alteration of hemostatic factors </li></ul></ul></ul>
  28. 35. Risk-Stratification in Polycythemia vera * HTN, DM, dyslipidemia, smoking, alteration of hemostatic factors ** Platelet > 1,500 x 10 9 /L Risk Category Age > 60 years or History of Thrombosis Generic Cardiovascular Risk Factors* Low No No Intermediate** No Yes High Yes Not applicable
  29. 36. Management of Polycythemia vera by Risk factors * Anagrelide or IFN alpha may be used with phlebotomy in selected cases Risk Category Risk Factors Management Low Age < 60 and no prior cardiovascular event Phlebotomy + low dose aspirin Intermediate* Generic cardiovascular risk factors High Age > 60 and/or prior cardiovascular events Myelosuppression + phlebotomy + low dose aspirin
  30. 37. Management of PV <ul><li>Blood letting 300-350 ml: target Hct 45% in men, 42% in women </li></ul><ul><ul><li>OD or every other day or 1-2/week </li></ul></ul><ul><li>ASA 40-100 mg/d (81 mg) if platelet < 1-1.5 M </li></ul><ul><li>Myelosuppressive Rx </li></ul><ul><ul><li>Busulfan (myleran), Melphalan, 32 P </li></ul></ul><ul><ul><li>Hydroxyurea 15-30 mg/kg/d aim Hct < 45%, plt < 400 x 10 9 /L </li></ul></ul><ul><ul><li>Anagrelide </li></ul></ul><ul><ul><li>Interferon alpha </li></ul></ul>
  31. 38. Busulfan in PV <ul><li>4 mg/d x 1 week then 2 mg/d x 3 weeks then 2 mg AD until max. response (~ 3 mos.) and stop </li></ul><ul><li>If relapse, restart </li></ul><ul><li>Can use melphalan in stead of busulfan @ the same dose </li></ul>
  32. 39. IFN alpha in PV <ul><li>Age < 40, pregnancy, severe pruritus, intolerable to HU </li></ul><ul><li>3 MU SQ x 3 /week up to 5 MU SQ/d </li></ul><ul><li>Single agent or with phlebotomy </li></ul><ul><li>50% CR , 21% intolerable </li></ul><ul><li>When count plateau, decrease to 3 times/week or less </li></ul><ul><li>Pegasys (alpha-2a) 135 or 180 μ g or Peg-intron (alpha-2b) 50, 80 or 100 μ g SQ weekly </li></ul>
  33. 40. 32 P in PV <ul><li>2.7 mCi/m 2 IV (max. 5 ) q 3 mos. </li></ul>
  34. 41. Other Management of PV <ul><li>Cyproheptadine </li></ul><ul><li>Cimitidine </li></ul><ul><li>Erythromelalgia: low-dose ASA </li></ul><ul><li>Gouty arthritis or uric acid excretion > 1,100 mg/d -> allopurinol 300 mg/d </li></ul>Severe pruritus
  35. 42. PV: Observation <ul><li>After disease is stabilized, check CBC q 1-3 mos. Depending on clinical and pt anxiety </li></ul>
  36. 44. หญิงโสดอายุ 23 ปี แอร์โฮสเตท ภูมิลำเนา ระยอง <ul><li>อาการสำคัญ & ทราบว่ามีเกร็ดเลือดสูง ~ 1.4 ล้าน ตั้งแต่ 9 เดือนก่อน </li></ul><ul><li>ประวัติปัจจุบัน ได้รับการตรวจไขกระดูกเมื่อ 8 เดือนก่อน แพทย์วินิจฉัย </li></ul><ul><li>ET แต่ยังไม่ได้รับการรักษา แพทย์ตรวจเลือดเป็นระยะ เกร็ดเลือดเพิ่มขึ้นเรื่อยๆเป็น 1.9->2.1->2.3-> </li></ul><ul><li>2.6 ล้าน เคยปวดศีรษะบ่อย แต่ขณะนี้ปกติ ไม่เหนื่อย </li></ul><ul><li>ง่าย ไม่มีจ้ำเขียวง่าย ประจำเดือนปกติ </li></ul><ul><li>ประวัติอดีต เป็น homozygous Hb E </li></ul><ul><li>ประวัติครอบครัว เป็นบุตรคนเดียว </li></ul>
  37. 45. การตรวจร่างกาย <ul><li>VS BP 110/70 mmHg, PR 52/min </li></ul><ul><li>HEENT mildly pale, no jaundice </li></ul><ul><li>Chest </li></ul><ul><li>Heart </li></ul><ul><li>Abdomen liver, spleen not palpable </li></ul><ul><li>Ext no edema </li></ul><ul><li>LN not palpable </li></ul>unremarkable
  38. 48. Initial Investigation <ul><li>CBC Hct 35%, Hb 11.3 g/dL, WBC </li></ul><ul><li>12.6 x 10 9 /L, PMN 70%, L 25%, M 4%, E 1%, platelet 2,375 x 10 9 /L , MCV 62.1 fL, MCH 20 pg MCHC 32.2 g/Dl, RDW 16.8% </li></ul><ul><li>Blood chemistries normal </li></ul>
  39. 49. Further Investigation <ul><li>PBS </li></ul><ul><li>Bone marrow exam, Bx and </li></ul><ul><li>Cytogenetics: 46, XX </li></ul><ul><li>U/S abdomen: not done </li></ul><ul><li>Platelet function test: not done </li></ul>
  40. 55. Management <ul><li>จะรักษาผู้ป่วยเมื่อใดหรือจะ F/U CBC ต่อไปอีก </li></ul><ul><li>จะเริ่มรักษาด้วยยาชนิดใด </li></ul><ul><ul><li>Anagrelide </li></ul></ul><ul><ul><li>Hydroxyurea </li></ul></ul><ul><ul><li>Busulfan </li></ul></ul><ul><ul><li>IFN alpha </li></ul></ul><ul><li>ต้องทำ plateletpheresis หรือไม่ </li></ul><ul><li>Aim ให้เกร็ดเลือดอยู่ประมาณเท่าใด </li></ul><ul><li>เนื่องจากผู้ป่วยอายุน้อย จะพิจารณาทำ HSCT หรือไม่ </li></ul>
  41. 56. Managment <ul><li>Intron A 5 mu SQ x 2/week x 3 weeks </li></ul><ul><li> ↓ </li></ul><ul><li>platelet 2,375 x 10 9 /L -> 1,494 x 10 9 /L </li></ul><ul><li> ↓ </li></ul><ul><li>Intron A 5 mu SQ x 2/week x 6 weeks </li></ul><ul><li> ↓ </li></ul><ul><li>platelet 1,419 x 10 9 /L </li></ul><ul><li> ↓ </li></ul><ul><li>Intron A 5 mu SQ x 2/week x 5 weeks + anagrelide 1x3 </li></ul><ul><li> ↓ </li></ul><ul><li>plalelet 273 x 10 9 /L </li></ul><ul><li>Now (~ 4 years) on anagrelide 2 x 2 last F/U platelet 316 x 10 9 /L </li></ul>
  42. 57. ET @ PMK <ul><li>Criteria Dx </li></ul><ul><ul><li>Persistent thrombocytosis > 600 x 10 9 /L at least 1 month </li></ul></ul><ul><ul><li>No underlying disease of thrombocytosis </li></ul></ul><ul><ul><li>Ph chromosome negative </li></ul></ul><ul><ul><li>Exclusion of other MPNs </li></ul></ul><ul><li>1992-1998 </li></ul><ul><li>15 pts M:F 10:5 </li></ul><ul><li>Mean age @ Dx 54.5 years </li></ul>Numbenjapol, et al. 2000
  43. 58. ET @ PMK (N=15) <ul><li>Presenting symptoms </li></ul><ul><ul><li>Asymptomatic 40% </li></ul></ul><ul><ul><li>Bleeding 40% </li></ul></ul><ul><ul><li>Vascular thrombosis 20% </li></ul></ul><ul><li>Splenomegaly 26.7% </li></ul><ul><li>Hepatomegaly 20% </li></ul><ul><li>Hepatosplenomegaly 13.3% </li></ul><ul><li>No organomegaly 40% </li></ul>Numbenjapol, et al. 2000
  44. 59. ET @ PMK (N=15) <ul><li>Initial mean Hct 34.3 + 10.1% </li></ul><ul><li> WBC 19.4 + 12.8 x 10 9 /L </li></ul><ul><li>Platelet 1,573.6 + 1,116.4 x 10 9 /L </li></ul><ul><li>Initial Rx IFN alpha 6 pts </li></ul><ul><ul><ul><li>Switched to HU or BU 4 pts </li></ul></ul></ul><ul><li>Initial Rx HU or BU 7 pts </li></ul><ul><li>No Rx 2 pts </li></ul><ul><li>Mean duration of F/U 621.7 + 708 days </li></ul><ul><ul><li>Last F/U mean platelet 543.1 + 252.8 x 10 9 /L </li></ul></ul>Numbenjapol, et al. 2000
  45. 60. ET: S/S <ul><li>Median age at Dx ~ 60 yrs </li></ul><ul><li>M:F 2:1 </li></ul><ul><li>Asymptomatic </li></ul><ul><li>Thrombosis, bleeding </li></ul><ul><li>Vasomotor: headache, vertigo, syncope </li></ul><ul><li>Livedo reticularis </li></ul><ul><li>Erythromelalgia </li></ul><ul><li>Visual disturbance </li></ul>
  46. 61. ET: S/S <ul><li>Thrombosis: retinal artery & vein, coronary, pulmonary, digital artery </li></ul><ul><li>Raynaud phenomenon </li></ul><ul><li>Digital ischemia </li></ul><ul><li>Splenomegaly 25-48% </li></ul>
  47. 62. ET: WHO 2008 Criteria Dx All 4 criteria must be met Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65
  48. 63. Diagnostic Criteria of ET by PVSG (Pre-JAK2V617F era) <ul><li>Sustained platelet > 600 x 10 9 /L </li></ul><ul><li>No conditions associated with 2 0 thrombocytosis </li></ul><ul><li>Normal serum ferritin or stainable iron in marrow Bx </li></ul><ul><li>Normal Hct and MCV or normal RBC mass </li></ul><ul><li>Cytogenetics without t (9;22) and no evidence of BCR-ABL gene rearrangement </li></ul><ul><li>Marrow fibrosis < 1/3 of the cross-sectional area on Bx, without both splenomegaly and leukoerythroblastic changes </li></ul><ul><li>No morphologic or cytogenetic evidence of MDS </li></ul>
  49. 64. ET: DDx <ul><li>Secondary thrombocytosis </li></ul><ul><ul><li>Infection, inflammation, malignancy </li></ul></ul><ul><ul><li>Iron deficiency, hemolysis, acute blood loss </li></ul></ul><ul><li>Other causes </li></ul><ul><ul><li>CML, PV, PMF : so cytogenetics is needed </li></ul></ul><ul><ul><li>5q- syndrome </li></ul></ul>
  50. 65. ET: Lab <ul><li>CBC, PBS </li></ul><ul><li>Bone marrow exam, cytogenetics </li></ul><ul><li>Blood for JAK2 mutation </li></ul><ul><li>Serum TPO not help in Dx </li></ul>
  51. 69. Atypical Megakaryocytes
  52. 70. Atypical and Micromegakaryocytes
  53. 71. Risk-Stratification in Essential Thrombocythemia * HTN, DM, dyslipidemia, smoking, alteration of hemostatic factors ** Platelet > 1,500 x 10 9 /L Risk Category Age > 60 years or History of Thrombosis Generic Cardiovascular Risk Factors* Low No No Intermediate** No Yes High Yes Not applicable
  54. 72. Management of Essential Thrombocythemia by Risk factors * anagrelide, HU or IFN alpha may be used in stead of observation Risk Category Risk Factors Management Low Age < 60 and no prior cardio vascular event Nil or low-dose aspirin (no consensus) Intermediate* Generic cardiovascular risk factors Low-dose aspirin (no consensus) High Age > 60 and/or prior cardio vascular events Myelosuppression + low-dose aspirin
  55. 73. ET: Rx <ul><li>Thrombocytosis or bleeding or platelet > 1,500 x10 9 /L or age > 60 </li></ul><ul><ul><li>1 st line: HU, IFN alpha (in pregnancy) </li></ul></ul><ul><ul><li>2 nd line: anagrelide or IFN alpha in pts intolerable to HU </li></ul></ul><ul><ul><li>3 rd : busulfan or melphalan </li></ul></ul><ul><li>Low-dose ASA in pts with no contraindications </li></ul>
  56. 74. ET: ASA <ul><li>81-325 mg/d </li></ul><ul><li>Good for erythromelalgia or possible reduction in risk of thrombosis </li></ul><ul><li>Do not use if plt. > 1,000-1,500 x 10 9 /L </li></ul>
  57. 75. ET: Hydroxyurea <ul><li>500 mg/cap, 2-3 caps/d </li></ul><ul><li>Goal: plt. < 400 x 10 9 /L , keeping ANC > 1 x 10 9 /L or WBC > 3 x10 9 /L </li></ul><ul><li>CBC weekly until plt. count plateau then monthly </li></ul><ul><li>Side effects: nail discoloration, leg ulcers, aphthous ulcer </li></ul>
  58. 81. ET: Anagrelide ( 1) <ul><li>Inhibits differentiation, no effect on WBC, splenic size </li></ul><ul><li>0.5 mg/tab, starting 1x4 </li></ul><ul><li>Give cautiously if Cr > 2 mg/dl, AST > 1.5 x upper limit </li></ul><ul><li>AEs: fluid retention, edema, dizziness, headache, postural hypotension, palpitation, tachycardia, arrhythmias, CHF </li></ul><ul><li>Avoid if having cardiovascular disease </li></ul><ul><li>Total dose not exceed 3 mg/d </li></ul>
  59. 82. ET: Anagrelide ( 2) <ul><li>Check CBC, Cr, LFT weekly when plt. stabilizes CBC monthly, LFT, Cr every 3 months </li></ul><ul><li>Target plt. < 400-600 x 10 9 /L </li></ul><ul><li>Time to 50% plt. r eduction 11 days (in PV 15 days) </li></ul><ul><li>15% pts. can not tolerate anagrelide </li></ul><ul><li>No leukemogenesis, carcinogenesis but can cross placenta causing neonatal thrombocytopenia </li></ul>
  60. 83. ET: IFN alpha <ul><li>5 MU SQ/d then 2.5 MU/d or 3 MU x 3 /week </li></ul><ul><li>When counts plateau give < 3 times/week </li></ul><ul><li>20% pts can not tolerate IFN alpha because of side effects </li></ul>
  61. 84. ET: Busulfan <ul><li>2 mg/tab </li></ul><ul><li>4 mg/d x 1 week then 2 mg/d x 3 weeks then 2 mg AD until maximal sustained response ~ 3 mos. and stop </li></ul>
  62. 85. Role of HSCT in MPNs
  63. 86. <ul><li>Number of patients studied 104 </li></ul><ul><li>Patient age, ( years ) , range ( median ) 18-70 ( 49 ) </li></ul><ul><li>Patient sex, M / F 57/47 </li></ul><ul><li>Disease duration, ( months ) , range ( median ) 2-31 ( 15 ) </li></ul><ul><li>Primary diagnosis </li></ul><ul><li>CIMF 62 </li></ul><ul><li>ET with myelofibrosis 18 </li></ul><ul><li>PV with myelofibrosis 12 </li></ul><ul><li>Myelofibrosis with increased blasts 7 </li></ul><ul><li>Other 5 </li></ul>HSCT in MPNs Kerbauy DM, et al. Biol Blood Marrow Transplant 2007: 13: 355-65
  64. 87. Impact of P rimary D iagnosis on T ransplantation O utcome Kerbauy DM, et al. Biol Blood Marrow Transplant 2007: 13: 355-65
  65. 88. <ul><li>Causes of Death N o. of Patients </li></ul><ul><li>Progressive disease/relapse 8 </li></ul><ul><li>Nonrelapse causes 33 </li></ul><ul><li>Pneumonia/pulmonary failure 12 </li></ul><ul><li>MOF/HUS/TTP 5 </li></ul><ul><li>Invasive aspergillosis + GVHD 7 </li></ul><ul><li>GVHD 6 </li></ul><ul><li>Miscellaneous 3 </li></ul>Causes of Death (N=104) Kerbauy DM, et al. Biol Blood Marrow Transplant 2007: 13: 355-65
  66. 89. Thank you for Attention
  67. 91. ET & PV: Consideration <ul><li>Risks of the disease itself </li></ul><ul><li>Risks of the proposed Rx </li></ul><ul><li>Risk category of patient : low, intermediate, high </li></ul>
  68. 92. Risks from ET <ul><li>Thrombosis </li></ul><ul><li>Major hemorrhage </li></ul><ul><li>Conversion to leukemia (up to 4% ) </li></ul><ul><li>Conversion to myelofibrosis (up to 6% ) </li></ul>
  69. 93. ET: Risks for Thrombosis <ul><li>Age </li></ul><ul><li>Prior thrombosis </li></ul><ul><li>Smoking </li></ul><ul><li>Obesity </li></ul>
  70. 94. ET: Risks for Leukemia <ul><li>Rx with chlorambucil </li></ul><ul><li>32 P </li></ul><ul><li>Melphalan </li></ul>
  71. 95. Management of ET <ul><li>Observation </li></ul><ul><li>ASA </li></ul><ul><li>Hydroxyurea </li></ul><ul><li>Anagrelide </li></ul><ul><li>IFN alpha </li></ul><ul><li>Busulfan </li></ul><ul><li>32 P </li></ul>
  72. 96. ET: Observation <ul><li>CBC q 3 months </li></ul><ul><li>May vary depending on clinical & pt. anxiety </li></ul>
  73. 97. ET: 32 P <ul><li>2.7-2.9 mCi/m 2 (max. 5 ) per dose </li></ul><ul><li>Can repeat after 3 mos. </li></ul>
  74. 98. High Risk ET <ul><li>Age > 60 or </li></ul><ul><li>Any age with thrombosis </li></ul><ul><li>Rx hydroxyurea </li></ul><ul><li>Alternatives: anagrelide, IFN alpha </li></ul>
  75. 99. Intermediate-Risk ET <ul><li>Age < 60 </li></ul><ul><li>Have not had thrombosis but plt. > 1-1.5 M or </li></ul><ul><li>Have significant CVS risk factors </li></ul><ul><li>Rx low-dose ASA if plt. < 1.5 M </li></ul><ul><li>Can be observed or Rx with anagrelide, HU or IFN alpha </li></ul><ul><li>Should also Rx CVS risk factors </li></ul>
  76. 100. Low-Risk ET <ul><li>Age < 60 </li></ul><ul><li>Have not had thrombosis and </li></ul><ul><li>Platelet < 1.5 M </li></ul><ul><li>Rx observe or low-dose ASA </li></ul>
  77. 109. WHO 2008 Classification Myeloproliferative Neoplasms <ul><li>Chronic myelogenous leukemia (CML), BCR-ABL1 positive </li></ul><ul><li>Polycythemia vera (PV) </li></ul><ul><li>Essential thrombocythemia (ET) </li></ul><ul><li>Primary myelofibrosis (PMF) </li></ul><ul><li>Chronic neutrophilic leukemia (CNL) </li></ul><ul><li>Chronic eosinophilic leukemia, not otherwise classified (CEL-NOS) </li></ul><ul><li>Mastocytosis </li></ul><ul><li>Myeloproliferative neoplasm, unclassifiable (MPN-u) </li></ul>Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65
  78. 110. Stem Cell Differentiation Campbell PJ and Green AR. N Engl J Med 2006; 355: 2452-2466
  79. 111. Pre-JAK2 Mutation Levine RL and Gilliland DG. Blood 2008; 112: 2190-2198
  80. 112. Genetic Disease Frequency abnormality <ul><li>BCR-ABL Chronic myelogenous leukemia ~99% </li></ul><ul><li>JAK2 exon 12 Polycythemia vera ~2% </li></ul><ul><li>MPLW515L/K Primary myelofibrosis ~8% </li></ul><ul><li>Essential thrombocythemia ~8% </li></ul><ul><li>Involving PDGFRA Myeloid neoplasms with eosinophilia unknown </li></ul><ul><li>Mast cell disease unknown </li></ul><ul><li>Involving PDGFRB Myeloid neoplasms with eosinophilia unknown </li></ul><ul><li>Involving FGRR1 Myeloid neoplasms with eosinophilia unknown </li></ul><ul><li>Involving KIT (D816V Mast cell disease unknown </li></ul><ul><li>as the most frequent) </li></ul>Vannucchi AM, et al. CA Cancer J Clin 2009; 59: 171-191
  81. 113. PMF (Primary myelofibrosis) <ul><li>Median age at Dx ~ 65 yrs </li></ul><ul><li>M:F 1:1 </li></ul><ul><li>Fatigue, anemic S/S </li></ul><ul><li>Hypercatabolism: weight loss, night sweats </li></ul><ul><li>Abdominal discomfort: splenomegaly (slight to massive), splenic infarction, early satiety </li></ul><ul><li>Extramedullary hematopoiesis </li></ul>
  82. 114. PMF: Lab <ul><li>CBC: leukoerythroblastic blood picture, tear drop cells, basophils, eosinophils ↑ </li></ul><ul><li>BM: dry tap from marrow fibrosis </li></ul><ul><ul><li>Early stage: cellular marrow (prefibrotic) </li></ul></ul><ul><ul><li>Atypical and micromegakaryocytes </li></ul></ul><ul><li>Cytogenetics </li></ul><ul><li>Blood for JAK2 mutation </li></ul>
  83. 115. PMF: Clinical Course <ul><li>Median survival 3-7 yrs </li></ul><ul><li>Factors for survival </li></ul><ul><ul><li>Age > 70, hypercatabolic </li></ul></ul><ul><ul><li>Hb < 10, WBC < 4 or > 30 x 10 9 /L, plt < 100 x 10 9 /L </li></ul></ul><ul><ul><li>Cytogenetics </li></ul></ul><ul><li>Cause of death: infection, bleeding, thromboembolism, portal HTN, CHF, AML </li></ul>
  84. 116. PMF: Rx <ul><li>PRCTx </li></ul><ul><li>HU 20-30 mg/kg/d </li></ul><ul><li>Busulfan, melphalan or IFN alpha </li></ul><ul><li>Splenic RT in painful splenic infarction </li></ul><ul><li>Allogeneic HSCT (RIC) </li></ul>
  85. 117. PMF: Major Minor Criteria Dx All 3 major + 2 minor Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65
  86. 118. Levine RL and Gilliland DG. Blood 2008; 112: 2190-2198
  87. 119. Vannucchi AM, et al. CA Cancer J Clin 2009; 59: 171-191

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