MPD MPN in WHO 2008 Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia Polycythemia vera Primary myelofibrosis Essential thrombocythemia Chronic eosinophilic leukemia, not otherwise specified Mastocytosis Myeloproliferative neoplasm, unclassifiable
MPD MPN in WHO 2008 Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia Polycythemia vera (PV) Primary myelofibrosis (PMF) Essential thrombocythemia (ET) Chronic eosinophilic leukemia, not otherwise specified Mastocytosis Myeloproliferative neoplasm, unclassifiable
Initial Proposal of 3 MPNs 1892, Louis Henri Vaquez : the first case report of PV 1934, Emil Epstein and Alfred Goedel : the first case report of ET 1879, Gustav Hueck : the first case report of PMF Levine RL. Blood 2008;112:2190
JAK2 V617F Mutation ti (2005) Campbell BJ. NEJM 2006;355:2452
JAK2 Mutation for 3 MPNs 1 2 Pre-JAK2 Mutation 3 4 Intensity JAK2 V617F Signaling 5 Levine RL. Blood 2008;112:2190
Contents of This Lecture MPN 국내역학및등록사업결과 MPN 의진단지침 MPN 의치료지침
서구의역학 빈도 : PV > ET» PMF 호발연령 PV and MF (60 대 ) ET (50~60 대및 30 대, 소아에서도발생 ) 남 / 녀비 :PV(1~2) 2), ET (<1), PMF ( 1) 연간발병률 ( 연간십만명당 ): PV (2 명 ), ET (2.53 명 ), PMF (1.46 명 ) 유병률 : 자료가없음 Ania BJ. Am J Hematol 1994;47:89 Mesa RA. Am J Hematol 1999;61:10
심평원등록환자수 4,000 3,500 3,000 170%/4 years Myelofibrosis 2,500 2,000 1,500 1,000 Essential thrombocythemia Polycythemia vera 500 0 2002년 2003년 2004년 2005년 2006년 2007년 상반기
연령별연간환자수 450 400 350 300 250 200 150 PV ET MF 100 50 0 0-9 세 10-19 세 20-29 세 30-39 세 40-49 세 50-59 세 60-69 세 70-79 세 80 세이상
성별연간환자수 1400 M/F ratio 1200 1000 1.5 08 0.8 800 남여 600 400 1.1 200 0 PV ET MF
추정유병률 (/100,000*year) 3.50 3.00 2.50 2.00 1.50 PV ET MF 1.00 0.50 0.00 2002 2003 2004 2005
심평원자료의해석 MPN 환자수는 4 년간 1.7 배로늘어매우빠른증가추세를보임 국내의실제빈도는 ET > PV >> PMF 순이나, 본자료에서는 PV > ET >> PMF 순 : 병명의혼재 [erythrocytosis versus secondary polycythemtia] 정확한 PV 진단방법의부재 질병패턴의서구화 ET 에서 30 대의두번째빈발은없음: 무증상의 ET 환자의조기발견 이과제 성비는외국과유사 추정유병률이서구의발생률과비슷 : (1) 발생률이서구보다실제로 낮을가능성, (2) 낮은진단률
Korean MPN Registry 2006. 3. ~ 2007. 9. 서울 : 경희대학교병원, 서울대학교병원, 서울보훈병원, 순천향대학교병원, 울산의대아산병원, 이대동대문병원 경인 : 가천의대길병원, 분당서울대병원, 인하대학교병원, 중문의대차병원, 한림의대성심병원 원주 : 원주기독병원 대구 : 대구카톨릭대학교병원, 영남대학교병원 전주 : 원광대학교병원 울산 : 울산대학교병원 광주 : 전남대학교병원
1 단계: MPN 및이차성혈구증가증 2 개병원에서 111 명등록 2 단계 :MPN 17 개병원에서 230 명등록 160 141 147 140 120 100 80 60 40 20 14 5 4 28 2 0 PV ET IMF MPDu HES Secondary No CRF
JAK2 V617F rate PV ET PMF Western Up to 98% 23 ~ 57% 35 ~ 74% Korean 79% 59% 43%
PV 진단의변천 Criteria PVSG (1967) WHO (2001) WHO(2008) Major M1: increased red cell mass (>36ml/kg in men, >32ml/kg in women) M2: Normal oxygen saturation (>92%) M3: Splenomegaly; thrombocytosis (>400,000/ L) and leukocytosis (12,000/ L) A1: Elevated red cell mass >25% or Hb > 18.5g/dL (men), 16.5g/dL (women) A2: No cause of secondary erythrocytosis A3: Splenomegaly A4: Clonal abnormality other than Ph or BCR/ABL A5: EEC formation A1: Elevated red cell mass >25% or Hb > 18.5g/dL (men), 16.5g/dL (women) or 17g/dL (men), 15g/dL (women), if increase of 2g/dL from baseline A2: Presence of JAK2 V617F mutation or similar mutation such as JAK2 exon 12 mutation Minor B1: PLT > 400,000/ L B1: BM hypercellularity B2: WBC > 12,000/ L B2: Low serum EPO B3: Marrow panmyelosis B3: EEC formation B4: Low serum EPO Diagnosis M1+M2+M3 A1 + A2 + any A or any two B A1 + A2 + any B or A1 +any two B
PV 환자군의재정립 진단시검사가부족한환자는적어도 6 개월 이상의추적에서도지속적으로혈색소가높 거나, 다른혈액이상이기준에충족하는경 우를선별 추적혈액검사나합병증의데이터가없는 환자들은제외
MPN Registry N=341 Excluded d due to 1) No sufficient data (N=38) 2) Secondary cytosis (N=28) 3) No DNA (N=4) 4) Hypereosinophilic syndrome (N=3) 5) No CRF (N=2) Included patients in this study N=266 JAK2 V617F using allele-specific PCR (N=108) JAK2 V617F using both PCR and sequencing (N=158)
JAK2 V617F (N=266) 140 120 100 80 60 40 60% 85% 20 0 33% 80% ET PV PMF MPDu
JAK2 V617F Mutated Wild type N=187 N=79 P value Sex: Male/female 89/98 47/32 0.076 Age; Mean (SD) 60 (12) 57 (15) 0.021021 Diagnosis; PV/non-PV 99/88 17/62 0.001 CBC: mean (SD) Hemoglobin White blood cells Platelets 16.1 (3.7) 15.972 (7,460) 784 (417) 14.1 (4.1) 11,044 (5,336) 905 (560) 0.000 0.000 0.063 Splenomegaly; (+/-) 65/84 20/44 0.214 Bone marrow (+/-) Increased cellularity Increased mega Increased M:E ratio Fibrosis 112/20 129/5 43/91 13/139 31/17 46/2 23/40 12/58 Vascular a events e (%) Prior to diagnosis During the follow-up All period 52 (28%) 20 (11%) 63 (34%) 17 (22%) 7 (9%) 20 (25%) 0.002 0.775 0.516 0.060 0.285 0.651 0.330
JAK2 V617F Load (N=158) N (%) wild type heterozygote homozygote western ET 53 (75) 17 (24) 1 (1) 0~6 PV 17 (23) 34 (46) 23 (31) 21~71 PMF 8 (80) 2 (20) 9~22 MPDu 1 (33) 1 (33) 1 (33)
혈관합병증의양상 Prior to or at the diagnosis After the diagnosis N= 69 N=27 Thrombosis Cerebral artery Transient ischemia Coronary artery 35 5 3 6 5 4 Peripheral artery Visceral vessel Deep vein 4 3 - - - 2 Bleeding Mucocutaneous Intracranial Muscular or visceral 12 4 3 8 1 1
혈관합병증과 JAK2 변이정도 60 50 40 30 No VE VE 20 10 0 25% 33% 52% < < Wild type Heterozygote Homozygote Bang SM. Thromb Haemost 2009:101;547
요약 1. 한국 MPN 환자의 JAK2 V617F 변이율과변이정도는 서구와유사함 2. JAK2 V617F 는고령과높은혈색소, 백혈구및골수 세포충실도와연관성이높음 3. MPN 진단전이나진단당시혈관합병증의발생은진 단후수치조절과함께감소하고말초동맥이나내장 혈관의혈전은질병조절기에는발생하지않았음 4. 혈관합병증의빈도는 JAK2 V617F homozygote 의경 우 52% 로 hetero/wild type의 33/25% 보다유의하게높았음
Contents t of This Lecture MPN 국내역학및등록사업결과 MPN 의진단지침 MPN 의치료지침
PV 진단지침 2 차성적혈구증가증의감별을위한 serum EPO 검사및 JAK2 V617F 검사를시행 변이양성, 특히 homozygote이면혈색소가진단기준을넘지않더라도우선 PV 를의심 : Hb > 17g/dL (men), 15g/dL (women) 변이음성의 PV 를진단시에는아래기준및다른조건을모두충족시에만진단 ( 가능하면 exon12 mutation 검사도진행 ): Hb >185 18.5g/dL (men), 16.5g/dL (women) 내장정맥의혈전이있는경우, 혈색소수치에상관없이 JAK2 V617F 검사를시행 (21% 에서변이양성 ) Tefferi A. Leukemia 2008:22;14 De Stefano V. J Thrombo Haemost 2007:5;708
ET 진단지침 2 차성혈소판증가증배제 : 철결핍성빈혈, 염증및고형암, PV, PMF, CML and MDS JAK2 V617F 검사를시행 : homozygote이면 PV와 PMF 를반드시감별 변이양성이면혈소판이 45 만이상에서 ET 진단 변이음성이면혈소판이 60 만이상, 한달간지속되면진단 진단시혈색소기준에맞지않더라도병의경과중에지속적으로상승하고, JAK2 변이양성이면 PV로진단변경 (3~15 년추적결과 ) Tefferi A. Leukemia 2008:22;14 Thiele J. Acta Haematol 2005:113;213
PMF 진단지침 진단명부터혼선을거듭하다가 2008 년 idiopathic primary MF (PMF) 로변경됨 여기에 post-pv, post-et and blast phase MF 가추가됨 골수섬유화가 2도이상이면서다음의부진단기준 2개이상이면진단 : (1) leukoerythroblastosis, (2) 혈청 LDH 증가, (3) 빈혈,(4) 비장종대 Prefibrotic stage: 섬유화는 0~1 도이나, megakaryocytic atypism을보임 Tefferi A. Leukemia 2008:22;14 Messa RA. Leuk Res 2007:31;737
Contents t of This Lecture MPN 국내역학및등록사업결과 MPN 의진단지침 MPN 의치료지침
혈전위험도분류 * Hypertension, hypercholesterolemia, diabetes, smoking + family history of premature cardiovascular disease, obesity, microalbuminuria, egfr <60 ml/min
PV 치료원칙
ET 치료원칙
Cervantes F. Blood 2008 Prognosis of PMF *International Working Group for Myelofibrosis Research and Treatment Risk factors Frequency Age > 65 yrs 44.6% Constitutional symptoms 26.4% Hb <10g/dL 35.2% WBC > 25 x 10 9 /L 9.6% PB blasts 1% 36.2% Risk Group No. of risk Proportion of pts Median survival factors (months) Low 0 22% 135 Intermediate-1 1 29% 95 Intermediate-2 2 28% 48 High 3 or more 21% 27
PMF 치료 Conservative Control of splenomegaly Hydroxyurea (40% RR) Low dose melphalan Splenectomy Splenic irradication Correction of anemia Androgen Corticosteroids Danazol (40% RR) Erythropoietin (16~60% RR if low serum EPO) Control of constitutional symptoms Curative Allogeneic transplantation Myeloablative Reduced intensity (RIC) New targeting agents Antiangiogenic agents Signal transduction inhibitors Proteasome inhibitors JAK2 inhibitors Hypomethylating agents HDAC inhibitors Others
증례 ( 여자 /69) 좌측새끼발가락의봉와직염치료중혈소판이 950k 로의뢰됨 과거력: 50 세대퇴경부골절 동반질환 : 고혈압으로 9 년간투약중 동반증상 : 6개월전부터바깥에나가면손가락끝이파래지고주무시는중에는붓고빨갛다
신체검진
추가검사결과 간이나비장비대는없음 CBC: 12,330-14.4-950k 14 4 LD: 382 (100~225) BM aspiration and biopsy: normocellular marrow with increased mature megakaryocytes (cellularity 41-50%) 과거기록검토 : 6년전고관절재수술당시혈소판이최고 717k로상승하였다가수술후 572k로감소함
1. 최종진단을위해필요한검사는? 정답 : JAK2 V617F test 2. 상기검사가양성이라면진단은? 정답 : essential thrombocythemia
3. 증상조절을위한치료법은? 1 Aspirin 2 Anagrelide 3 Hydroxyurea 4 Phlebotomy 5 Weight control 정답 : 1
Seoul National University Soo-Mee Bang M.D. smbang7@snu.ac.kr www. mpn.ecsoft.co.kr