Polycythemai vera and Essential Thrombocytosis

Apichai Leelasiri, M.D. FACP Hematology Division Department of Medicine Phramongkutklao Hospital and College of Medicine How I Treat Polycythemia Vera & Essential Thrombocythemia

ชายอายุ 76 ปี ข้าราชการบำนาญ อาการสำคัญ & แน่นหน้าอกเวลาทำงาน ปวดศีรษะ หน้าแดง 1 เดือน ประวัติปัจจุบัน เหนื่อยง่าย เบื่ออาหาร 6 เดือน น้ำหนักลด 10 กก . ใน 1 ปี อุจจาระปัสสาวะปกติ ไม่คันตามตัว ประวัติอดีต เป็น HTN, dyslipidemia และ hyperuricemia 20 ปี ตรวจร่างกาย BP 140/80 mmHg, PR 76/min red face, no lymphadenopathy spleen just palpable

Investigations CBC: Hct 71%, Hb 23.3 g/dL , WBC 12.8 x 10 9 /L, PMN 89%, band 2%, L 5%, M 2%, E 2%, Platelet 349 x 10 9 /L, ESR 1 mm/hr, reticulocyte 1.1 % FPG 90 mg/dL, BUN 20.6 mg/dL, Cr 1.14 mg/dL, TB 0.97 mg/dL, AP 129 U/L, AST 48 U/L, GPT 22 U/L, albumin 3.6 g/dL, globulin 2.9 g/dL, uric acid 4.9 mg/dL, TG 105 mg/dL, cholesterol 258 g/dL EKG: NSR 65/min, LAE, LVH, nonspecific lateral ST depression, inferior ST elevation

Further Investigations PBS Bone marrow aspiration Bx: panmyelosis Cytogenetics: 46, XY Pulse oximeter: O 2 sat 96.8% U/S: mild splenomegaly, small gall stone, enlarged prostate RBC mass: 57.8 ml/kg (22.9-36.9) Plasma volume: 34.8 ml/kg (38.2-57.8) Blood for JAK2 mutation: not done @2543

Provisional Dx Polycythemia vera

Management: Point of Discussion จะเริ่มรักษาเมื่อใด จะต้องทำ blood letting ทันทีหรือไม่ ปริมาณและความถี่ ถ้าทำต้องให้ IV fluid ร่วมด้วยหรือไม่ ต้องให้ cytoreductive ร่วมด้วยหรือไม่ Hydroxyurea Busulfan IFN alpha 32 P Aim ให้ Hct อยู่ในระดับใด ต้องให้ antiplatelet ร่วมด้วยหรือไม่ ยาชนิดใดเหมาะสมที่สุด

Management Blood letting 1 unit Hydroxyurea (500 mg) 1 x 3 x 2 weeks 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 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 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

PV: S/S Median age at Dx ~ 60 yrs M:F 1.2:1 ↑ RBC mass -> HTN, venous & arterial thrombosis Cerebral, mesenteric, portal, splenic, hepatic vein thrombosis Hyperviscosity: headache, vertigo, visual disturbance, erythromelalgia

PV: S/S Plethora, red ruddy cyanosis Aquagenic pruritus Acquired vWD type II in pts with Plt > 1M Metabolic: gouty attack Splenomegaly 70% Hepatomegaly 40%

PV: Lab CBC: Hct > 50%, WBC & plt ↑, basophil & eosinophil ↑ PBS: aggregation of platelet, giant & pale-staining MCV, MCH ↓, serum EPO ↓ O 2 sat > 92%, U/S: splenomegaly Blood for JAK2 mutation Bone marrow: panmyelosis

JAK2 Gene 9p -> JAK2 protein (cytoplasmic tyrosine kinase)-> binding to intracellular portion of EPOR, MPL, IL-3R, G-CSFR 7 domains (JH1-JH7) JH1: kinase activity JH2: psedokinase domain JH6, JH7: binding to cytokine receptor

JAK2 Domains Levine RL and Gilliland DG. Blood 2008; 112: 2190-2198

JAK2: Wild-type & V617F Campbell PJ and Green AR. N Engl J Med 2006; 355: 2452-2466

Homozygosity of JAK2V617F Campbell PJ and Green AR. N Engl J Med 2006; 355: 2452-2466

JAK2 Gene Mutation Acquired, gain-of-function mutation Specific for myeloid malignancies 1849, exon 14 @ JH2 domain: G->T 617: valine->phenylalanine (JAK2V671F) Other mutation: @ exon12: 2% of PV

JAK2V617F Disease Frequency Polycythemia vera > 95% Essential thrombocythemia ~60% Primary myelofibrosis ~60% MPN, unclassifiable ~20% Refractory anemia with ringed sideroblasts ~50% and thrombocytosis (RARS-T) Vannucchi AM, et al. CA Cancer J Clin 2009; 59: 171-191

PV: Major Minor Criteria Dx Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65

Clinical & Laboratory Criteria for Dx of PV* (Pre-JAK2V617F era) ↑ RBC mass > 25% above mean predicted value Normal O2 saturation > 92% Splenomegaly Platelet > 400 x 10 9 /L and WBC > 12 x 10 9 /L BM hypercellularity associated with clustered mature megakaryocytes with hyperlobulated nuclei and absent iron stores Low serum EPO < 3.0 U/L Erythroid colony formation in the absence of exogenous EPO * Criterion 1+ any 3 additional criteria Hoffman R. Hematology Basic Principles and Practice 3 rd edition, 2000

Diagnostic Criteria of PV by PVSG (Pre-JAK2V617F era) Major Hct ↑ + RBC mass ↑ > 36 mL/kg in men > 32 mL/kg in women O 2 sat > 92% Splenomegaly Minor WBC > 12 x10 9 /L Platelet > 400 x 10 9 /L Neutrophil AP > 100 score Serum B12 > 900 pg/mL or unbounded B12 binding capacity > 2,200 pg/mL Criteria Dx All 3 major or 2 major + 2 minor

PV @ PMK: Pre-JAK2 era 1982-1998 Baseline Hct > 50% WBC > 12 x 10 9 /L or platelet > 400 x 10 9 /L Bone marrow: panmyelosis Splenomegaly RBC mass > 36 mL/kg in men or > 32 mL/kg in women Leelasiri, et al. 1999

PV @ PMK: Pre-JAK2 era 41 pts, M:F 26:15 Median age of Dx 57 years Median duration of symptoms 4 months Presenting symptom Cerebrovascular 25 pts (61%) Myocardial ischemia or infarction 8 pts (20%) Peripheral vascular insufficiency 5 pts (12%) Leelasiri, et al. 1999

PV @ PMK: Pre-JAK2 era (N=41) Splenomegaly 16 pts (39%) Hepatomegaly 2 pts (5%) Hepatosplenomegaly 18 pts (44%) Mean Hct 63 + 9% WBC 22.3 + 12.0 x 10 9 /L Platelet 643.0 + 275.5 x 10 9 /L RBC mass 48 + 20 mL/kg Leelasiri, et al. 1999

PV @ PMK: Pre-JAK2 era (N=41) Initial Rx with blood letting 36 pts Median no. of blood letting 3 Rx busulfan (BU) 18 pts Rx hydroxyurea (HU) 14 pts Rx BU & HU 5 pts Rx IFN alpha 5 pts Rx 32 P 4 pts Leelasiri, et al. 1999

PV @ PMK: Pre-JAK2 era (N=41) Median F/U duration 854.5 days Alive 22 pts Died 2 pts AML 1 pt GI bleeding 1 pt Mean last Hct 45 + 10% WBC 12.9 + 11.1 x 10 9 /L platelet 398.1 + 205.1 x 10 9 /L Leelasiri, et al. 1999

PV: DDx Secondary erythrocytosis Renal cell cancer, hepatoma EPO, androgen Rx, herbal medicine (ginseng) Chronic hypoxemia COPD, cyanotic heart disease ASD or VSD with reverse shunt Relative erythrocytosis Normal RBC mass, reduced plasma volume HTN, obesity, stress

Staging of PV Prodromal phase: borderline or mild ↑ in RBC Overt polycythemic phase: definite ↑ in RBC Spent or post-polycythemic myelofibrosis phase (PPMF): decrease in RBC progressive anemia & splenomegaly low-grade fever from marrow fibrosis and extramedullary hematopoiesis AML transformation

Management of PV Risk stratification Age H/O thrombosis Cardiovascular risk factors HTN DM Dyslipidemia Smoking Alteration of hemostatic factors

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

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

Management of PV Blood letting 300-350 ml: target Hct 45% in men, 42% in women OD or every other day or 1-2/week ASA 40-100 mg/d (81 mg) if platelet < 1-1.5 M Myelosuppressive Rx Busulfan (myleran), Melphalan, 32 P Hydroxyurea 15-30 mg/kg/d aim Hct < 45%, plt < 400 x 10 9 /L Anagrelide Interferon alpha

Busulfan in PV 4 mg/d x 1 week then 2 mg/d x 3 weeks then 2 mg AD until max. response (~ 3 mos.) and stop If relapse, restart Can use melphalan in stead of busulfan @ the same dose

IFN alpha in PV Age < 40, pregnancy, severe pruritus, intolerable to HU 3 MU SQ x 3 /week up to 5 MU SQ/d Single agent or with phlebotomy 50% CR , 21% intolerable When count plateau, decrease to 3 times/week or less Pegasys (alpha-2a) 135 or 180 μ g or Peg-intron (alpha-2b) 50, 80 or 100 μ g SQ weekly

32 P in PV 2.7 mCi/m 2 IV (max. 5 ) q 3 mos.

Other Management of PV Cyproheptadine Cimitidine Erythromelalgia: low-dose ASA Gouty arthritis or uric acid excretion > 1,100 mg/d -> allopurinol 300 mg/d Severe pruritus

PV: Observation After disease is stabilized, check CBC q 1-3 mos. Depending on clinical and pt anxiety

หญิงโสดอายุ 23 ปี แอร์โฮสเตท ภูมิลำเนา ระยอง อาการสำคัญ & ทราบว่ามีเกร็ดเลือดสูง ~ 1.4 ล้าน ตั้งแต่ 9 เดือนก่อน ประวัติปัจจุบัน ได้รับการตรวจไขกระดูกเมื่อ 8 เดือนก่อน แพทย์วินิจฉัย ET แต่ยังไม่ได้รับการรักษา แพทย์ตรวจเลือดเป็นระยะ เกร็ดเลือดเพิ่มขึ้นเรื่อยๆเป็น 1.9->2.1->2.3-> 2.6 ล้าน เคยปวดศีรษะบ่อย แต่ขณะนี้ปกติ ไม่เหนื่อย ง่าย ไม่มีจ้ำเขียวง่าย ประจำเดือนปกติ ประวัติอดีต เป็น homozygous Hb E ประวัติครอบครัว เป็นบุตรคนเดียว

การตรวจร่างกาย VS BP 110/70 mmHg, PR 52/min HEENT mildly pale, no jaundice Chest Heart Abdomen liver, spleen not palpable Ext no edema LN not palpable unremarkable

Initial Investigation CBC Hct 35%, Hb 11.3 g/dL, WBC 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% Blood chemistries normal

Further Investigation PBS Bone marrow exam, Bx and Cytogenetics: 46, XX U/S abdomen: not done Platelet function test: not done

Management จะรักษาผู้ป่วยเมื่อใดหรือจะ F/U CBC ต่อไปอีก จะเริ่มรักษาด้วยยาชนิดใด Anagrelide Hydroxyurea Busulfan IFN alpha ต้องทำ plateletpheresis หรือไม่ Aim ให้เกร็ดเลือดอยู่ประมาณเท่าใด เนื่องจากผู้ป่วยอายุน้อย จะพิจารณาทำ HSCT หรือไม่

Managment Intron A 5 mu SQ x 2/week x 3 weeks ↓ platelet 2,375 x 10 9 /L -> 1,494 x 10 9 /L ↓ Intron A 5 mu SQ x 2/week x 6 weeks ↓ platelet 1,419 x 10 9 /L ↓ Intron A 5 mu SQ x 2/week x 5 weeks + anagrelide 1x3 ↓ plalelet 273 x 10 9 /L Now (~ 4 years) on anagrelide 2 x 2 last F/U platelet 316 x 10 9 /L

ET @ PMK Criteria Dx Persistent thrombocytosis > 600 x 10 9 /L at least 1 month No underlying disease of thrombocytosis Ph chromosome negative Exclusion of other MPNs 1992-1998 15 pts M:F 10:5 Mean age @ Dx 54.5 years Numbenjapol, et al. 2000

ET @ PMK (N=15) Presenting symptoms Asymptomatic 40% Bleeding 40% Vascular thrombosis 20% Splenomegaly 26.7% Hepatomegaly 20% Hepatosplenomegaly 13.3% No organomegaly 40% Numbenjapol, et al. 2000

ET @ PMK (N=15) Initial mean Hct 34.3 + 10.1% WBC 19.4 + 12.8 x 10 9 /L Platelet 1,573.6 + 1,116.4 x 10 9 /L Initial Rx IFN alpha 6 pts Switched to HU or BU 4 pts Initial Rx HU or BU 7 pts No Rx 2 pts Mean duration of F/U 621.7 + 708 days Last F/U mean platelet 543.1 + 252.8 x 10 9 /L Numbenjapol, et al. 2000

ET: S/S Median age at Dx ~ 60 yrs M:F 2:1 Asymptomatic Thrombosis, bleeding Vasomotor: headache, vertigo, syncope Livedo reticularis Erythromelalgia Visual disturbance

ET: S/S Thrombosis: retinal artery & vein, coronary, pulmonary, digital artery Raynaud phenomenon Digital ischemia Splenomegaly 25-48%

ET: WHO 2008 Criteria Dx All 4 criteria must be met Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65

Diagnostic Criteria of ET by PVSG (Pre-JAK2V617F era) Sustained platelet > 600 x 10 9 /L No conditions associated with 2 0 thrombocytosis Normal serum ferritin or stainable iron in marrow Bx Normal Hct and MCV or normal RBC mass Cytogenetics without t (9;22) and no evidence of BCR-ABL gene rearrangement Marrow fibrosis < 1/3 of the cross-sectional area on Bx, without both splenomegaly and leukoerythroblastic changes No morphologic or cytogenetic evidence of MDS

ET: DDx Secondary thrombocytosis Infection, inflammation, malignancy Iron deficiency, hemolysis, acute blood loss Other causes CML, PV, PMF : so cytogenetics is needed 5q- syndrome

ET: Lab CBC, PBS Bone marrow exam, cytogenetics Blood for JAK2 mutation Serum TPO not help in Dx

Atypical and Micromegakaryocytes

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

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

ET: Rx Thrombocytosis or bleeding or platelet > 1,500 x10 9 /L or age > 60 1 st line: HU, IFN alpha (in pregnancy) 2 nd line: anagrelide or IFN alpha in pts intolerable to HU 3 rd : busulfan or melphalan Low-dose ASA in pts with no contraindications

ET: ASA 81-325 mg/d Good for erythromelalgia or possible reduction in risk of thrombosis Do not use if plt. > 1,000-1,500 x 10 9 /L

ET: Hydroxyurea 500 mg/cap, 2-3 caps/d Goal: plt. < 400 x 10 9 /L , keeping ANC > 1 x 10 9 /L or WBC > 3 x10 9 /L CBC weekly until plt. count plateau then monthly Side effects: nail discoloration, leg ulcers, aphthous ulcer

ET: Anagrelide ( 1) Inhibits differentiation, no effect on WBC, splenic size 0.5 mg/tab, starting 1x4 Give cautiously if Cr > 2 mg/dl, AST > 1.5 x upper limit AEs: fluid retention, edema, dizziness, headache, postural hypotension, palpitation, tachycardia, arrhythmias, CHF Avoid if having cardiovascular disease Total dose not exceed 3 mg/d

ET: Anagrelide ( 2) Check CBC, Cr, LFT weekly when plt. stabilizes CBC monthly, LFT, Cr every 3 months Target plt. < 400-600 x 10 9 /L Time to 50% plt. r eduction 11 days (in PV 15 days) 15% pts. can not tolerate anagrelide No leukemogenesis, carcinogenesis but can cross placenta causing neonatal thrombocytopenia

ET: IFN alpha 5 MU SQ/d then 2.5 MU/d or 3 MU x 3 /week When counts plateau give < 3 times/week 20% pts can not tolerate IFN alpha because of side effects

ET: Busulfan 2 mg/tab 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

Number of patients studied 104 Patient age, ( years ) , range ( median ) 18-70 ( 49 ) Patient sex, M / F 57/47 Disease duration, ( months ) , range ( median ) 2-31 ( 15 ) Primary diagnosis CIMF 62 ET with myelofibrosis 18 PV with myelofibrosis 12 Myelofibrosis with increased blasts 7 Other 5 HSCT in MPNs Kerbauy DM, et al. Biol Blood Marrow Transplant 2007: 13: 355-65

Impact of P rimary D iagnosis on T ransplantation O utcome Kerbauy DM, et al. Biol Blood Marrow Transplant 2007: 13: 355-65

Causes of Death N o. of Patients Progressive disease/relapse 8 Nonrelapse causes 33 Pneumonia/pulmonary failure 12 MOF/HUS/TTP 5 Invasive aspergillosis + GVHD 7 GVHD 6 Miscellaneous 3 Causes of Death (N=104) Kerbauy DM, et al. Biol Blood Marrow Transplant 2007: 13: 355-65

ET & PV: Consideration Risks of the disease itself Risks of the proposed Rx Risk category of patient : low, intermediate, high

Risks from ET Thrombosis Major hemorrhage Conversion to leukemia (up to 4% ) Conversion to myelofibrosis (up to 6% )

ET: Risks for Thrombosis Age Prior thrombosis Smoking Obesity

ET: Risks for Leukemia Rx with chlorambucil 32 P Melphalan

Management of ET Observation ASA Hydroxyurea Anagrelide IFN alpha Busulfan 32 P

ET: Observation CBC q 3 months May vary depending on clinical & pt. anxiety

ET: 32 P 2.7-2.9 mCi/m 2 (max. 5 ) per dose Can repeat after 3 mos.

High Risk ET Age > 60 or Any age with thrombosis Rx hydroxyurea Alternatives: anagrelide, IFN alpha

Intermediate-Risk ET Age < 60 Have not had thrombosis but plt. > 1-1.5 M or Have significant CVS risk factors Rx low-dose ASA if plt. < 1.5 M Can be observed or Rx with anagrelide, HU or IFN alpha Should also Rx CVS risk factors

Low-Risk ET Age < 60 Have not had thrombosis and Platelet < 1.5 M Rx observe or low-dose ASA

WHO 2008 Classification Myeloproliferative Neoplasms Chronic myelogenous leukemia (CML), BCR-ABL1 positive Polycythemia vera (PV) Essential thrombocythemia (ET) Primary myelofibrosis (PMF) Chronic neutrophilic leukemia (CNL) Chronic eosinophilic leukemia, not otherwise classified (CEL-NOS) Mastocytosis Myeloproliferative neoplasm, unclassifiable (MPN-u) Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65

Stem Cell Differentiation Campbell PJ and Green AR. N Engl J Med 2006; 355: 2452-2466

Pre-JAK2 Mutation Levine RL and Gilliland DG. Blood 2008; 112: 2190-2198

Genetic Disease Frequency abnormality BCR-ABL Chronic myelogenous leukemia ~99% JAK2 exon 12 Polycythemia vera ~2% MPLW515L/K Primary myelofibrosis ~8% Essential thrombocythemia ~8% Involving PDGFRA Myeloid neoplasms with eosinophilia unknown Mast cell disease unknown Involving PDGFRB Myeloid neoplasms with eosinophilia unknown Involving FGRR1 Myeloid neoplasms with eosinophilia unknown Involving KIT (D816V Mast cell disease unknown as the most frequent) Vannucchi AM, et al. CA Cancer J Clin 2009; 59: 171-191

PMF (Primary myelofibrosis) Median age at Dx ~ 65 yrs M:F 1:1 Fatigue, anemic S/S Hypercatabolism: weight loss, night sweats Abdominal discomfort: splenomegaly (slight to massive), splenic infarction, early satiety Extramedullary hematopoiesis

PMF: Lab CBC: leukoerythroblastic blood picture, tear drop cells, basophils, eosinophils ↑ BM: dry tap from marrow fibrosis Early stage: cellular marrow (prefibrotic) Atypical and micromegakaryocytes Cytogenetics Blood for JAK2 mutation

PMF: Clinical Course Median survival 3-7 yrs Factors for survival Age > 70, hypercatabolic Hb < 10, WBC < 4 or > 30 x 10 9 /L, plt < 100 x 10 9 /L Cytogenetics Cause of death: infection, bleeding, thromboembolism, portal HTN, CHF, AML

PMF: Rx PRCTx HU 20-30 mg/kg/d Busulfan, melphalan or IFN alpha Splenic RT in painful splenic infarction Allogeneic HSCT (RIC)

PMF: Major Minor Criteria Dx All 3 major + 2 minor Swerdlow SH, et al, eds. Lyon, France. IARC Press; 2008: 18-65

Levine RL and Gilliland DG. Blood 2008; 112: 2190-2198

Vannucchi AM, et al. CA Cancer J Clin 2009; 59: 171-191

Polycythemai vera and Essential Thrombocytosis

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