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1 대한내과학회지 : 제 90 권제 4 호 특집 (Special Review) - 골수증식종양 : 진단과치료의발전 진성적혈구증가증 / 본태성혈소판증가증치료의발전 건국대학교의학전문대학원종양혈액내과학교실 김성용 Advances in Treatment for Polycythemia Vera and Essential Thrombocythemia Sung-Yong Kim Division of Hemato-Oncology, Department of Internal Medicine, KonKuk University School of Medicine, Seoul, Korea Although there have been substantial advances in confirming diagnoses and defining the molecular characteristics of polycythemia vera (PV) and essential thrombocythemia (ET), treatments for these conditions remain elementary. The main goal is still mainly focused on reducing the risk of thrombosis. The prevention of hemorrhage, leukemia transformation, and progression to myelofibrosis has yet to be established. To reduce the risk of thrombosis, risk-adapted treatment is recommended. Phlebotomy is the most important and effective treatment modality for patients with erythrocytosis, while cytoreduction using hydroxyurea, busulfan, or interferon-α is an ancillary treatment for patients at high risk for thrombosis. Anagrelide is used to decrease platelet counts in patients with thrombocytosis by inhibiting the maturation of platelets from megakaryocytes. Recent trials have shown that ruxolitinib, a Janus kinase (JAK) inhibitor, has clinical benefits in patients with polycythemia vera who show an inadequate response, or unacceptable side effects, to therapeutic doses of hydroxyurea. Theoretically, JAK inhibitors may also delay the progression of leukemia transformation and myelofibrosis but there is still no evidence of this. The cost of JAK inhibitors for the treatment of patients with PV/ET is a difficult hurdle for its use as a first-line treatment. (Korean J Med 2016;90: ) Keywords: Polycythemia vera; Thrombocythemia, Essential; Therapeutics; Janus kinases 서론진성적혈구증가증과진성혈소판증가증은일차골수섬유증과더불어골수증식종양의범위에들어가는혈액종양이다. 두질환모두가만성적인경과를가지고, 질환으로인한직접적인사망의빈도가높지않기때문에일반인과거의비슷하거나약간낮은기대수명을가진다. 환자들의합병증및사 망은주로는혈전증및출혈때문에생기고, 드물게이차적으로생길수있는백혈병이나이차골수섬유증으로진화로인해일어난다. 이차적인백혈병이나골수섬유증은빈도가낮기때문에환자치료의목적이질환자체를호전시키는것보다는주로혈전증을예방하는방향으로발전되어왔고출혈예방, 백혈병이나이차골수섬유증으로의변화에대한예방적치료는거의발전되지않은상태이다. Correspondence to Sung-Yong Kim, M.D., Ph.D. Division of Hemato-Oncology, Department of Internal Medicine, KonKuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea Tel: , Fax: , sykim@kuh.ac.kr Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Sung-Yong Kim. Treatment advances of PV and ET - 하지만질환의 Janus kinase (JAK)-2 유전자돌연변이와같은분자생물학적특성들이밝혀짐에따라이를표적으로하는약제개발과더불어임상시험들이진행되고있으며, 특히최근국내에도도입되어골수섬유증에현재보험급여가되고있는룩소니티닙을이용한임상시험들이상당부분진행되어하이드록시유레아에반응이없거나투여가어려운진성적혈구증가증환자에서기존 2차약제에비하여우월한효과가입증되었다. 이글을통해두질환의기존치료법을정리하고새로운기대를갖게하는약제의위치를살펴보고자한다. 본론치료의목표진성적혈구증가증과진성혈소판증가증은구분되어진단되고있지만두질환의구분이모호한중간단계의환자도존재하고유전학적특성도공유하는부분이많다. 또한두질환의질환의경과및합병증이빈도의차이가있을뿐거의비슷하기때문에두질환의치료의목적및방법이거의동일하게발전해왔다. 크게혈전 / 출혈합병증과백혈병 / 골수섬유증으로의진화가환자의삶의질및생존율을악화시킨다. 혈전합병증은진성적혈구증가증에서 34-39%, 진성혈소판증가증에서 10-29% 의환자에서발생하며, 출혈합병증은각각 2.9% 와 0.3% 의환자에서생긴다 [1]. 백혈병의진화로는각각 15년동안 5.5% 와 2% 의환자에서발생한다 [1]. 이두질환을가진환자에대하여혈전 / 출혈합병증및백혈병 / 골수섬유증진화위험을최소화하는것을치료의목표로두어야할것으로생각할수있지만, 가장발생빈도가높은혈전증을최소화하는치료만으로도성별및연령이같은인구군에비해환자의생존율은통계학적으로는차이가없거나 [2,3] 약간낮은생존율을보인다고보고하였다 [4]. 이처럼환자들의생존율이거의일반인에가깝고백혈병이나골수섬유증으로진화의빈도가매우낮고백혈병 / 골수섬유증진화를억제한다고증명된약제가아직은없는현재상황에서질환의자연경과를바꾸는치료를목표로하는것은적절치않다고판단이된다. 따라서발생빈도가높고삶의질을현저히저하시키는혈전증위험도를낮추는것을치료의목표로두는것이현재시점에서는옳은판단이다. 혈전증위험도에따른치료선택혈전위험도를낮추는치료를선택하기위해서는먼저혈전증위험도를계층화하여그계층에따른전략을세우는것이추천되고있다 [5]. 위험도에따른계층은나이가 60세미만이면서혈전증과거력이없는저위험군과둘중하나라도있는고위험군으로나뉜다 (Table 1). 사혈을이용하여헤마토크리트를 45% 미만으로낮추는것이 45-50% 로유지하는것보다혈전증의위험도를낮추어환자의생존율을증가시킨다고입증되었기때문에 [6,7] 모든환자에서사혈 (phlebotomy) 을이용하여헤마토크리트를 45% 미 Table 1. 진성적혈구증가증과진성혈소판증가증의혈전증위험군구분과위험군에따른치료 위험군 진성적혈구증가증 진성혈소판증가증 사혈 ( 목표헤마토크리트 <45%) a 및심혈관위험인자조절 저위험군 (60세미만이고혈전증과거력없는환자 ) 혈소판 1,000,000/mm 3 저용량아스피린 1) 저용량아스피린, 또는 2) JAK2 돌연변이와심혈관위험인자모두없는경우관찰 혈소판 > 1,000,000/mm 3 1) ristocetin cofactor activity > 30% 이면저용량아스피린 2) ristocetin cofactor activity 30% 이면관찰 1) ristocetin cofactor activity > 30% 이면저용량아스피린 2) ristocetin cofactor activity 30% 이면관찰 3) ristocetin cofactor activity 상관없이 JAK2 돌연변이와심혈관위험인자모두없는경우관찰 고위험군 (60세이상이거나혈전증과거력있는환자 ) 하이드록시유레아투여가능한경우 저용량아스피린 + 하이드록시유레아 저용량아스피린 + 하이드록시유레아 하이드록시유레아불응또는불내성 저용량아스피린 + 인터페론알파 (<65 세 ) 또는부설판 ( 65 세 ) 저용량아스피린 + 인터페론알파 (<65 세 ) 또는부설판 ( 65 세 ) a 진단에상관없이심혈관위험인자, 즉흡연, 고혈압, 당뇨, 고지혈증은조절하여야하며, 적혈구증가가있다면사혈하여헤마토크리트를 45% 미만으로유지한다.

3 - 대한내과학회지 : 제 90 권제 4 호통권제 668 호 만으로내려야한다. 그리고기본적인심혈관위험인자, 즉흡연, 당뇨, 고혈압, 고지혈증을조절하여야한다. 다음단계로, 위험군에따라아스피린및혈구수치를낮추는약제를선택한다. 저위험군은아스피린단독, 고위험군은아스피린과하이드록시유레아를같이투여한다. 진성적혈구연구회 (Polycythemia Vera Study Group) 에서시행되었던연구에의하면고위험군에서사혈만으로치료한환자보다하이드록시유레아를투여한환자에서혈전증빈도가낮다고증명되었다 [8]. 적혈구와는달리백혈구치료목표치는명확한기준을제시하는데이터는부족하지만백혈구수치의증가가일부의연구에서혈전증의독립적인위험인자로제시되고있어서 [9,10] 정상화를목표로하는것이바람직하다. 혈소판의치료목표치역시인위적이지만고위험군에서의임상연구들에서는혈소판수치가 600,000/mm 3 미만이나정상화를목표로임상연구들이진행되었다 [11]. 단순하게보이지만자세히살펴보면몇가지고려할것이있는데, 첫째, JAK-2 유전자돌연변이가없으면서심혈관위험인자가없는저위험군인경우아스피린투여없이관찰만할수도있다. 둘째, 혈소판이너무높은경우후천성폰빌레브란트병이동반되는경우가있어오히려출혈의위험도가높기때문에혈소판이 1000,000/mm 3 이넘는경우는 ristocetin cofactor activity (von Willebrand factor activity) 를측정하여활성도가 30% 이하라면아스피린을투여하지말아야한다 [12,13]. 셋째, 고위험군에서하이드록시유레아사용이어렵다면인터페론알파 (interferon-α) 나부설판 (busulfan) 을사용한다. 넷째, 정맥혈전증의과거력이있는경우아스피린보다는항응고제를사용할수있다 [5]. 하이드록시유레아는 500 mg bid, 부설판은 4 mg/day로시작하고혈구수치에따라용량을조절하는것이보편적이다. 부설판은다른골수억제제와병용투여시백혈병진화위험이있어단독투여해야한다 [2]. 인터페론알파의권장용량은주 3회 3백만단위씩이며, 페길화인터페론알파 (pegylated interferon alpha) 는주 1회 45 μg에서시작하여반응과부작용에따라용량을올린다. 혈소판수치만을조절하기위해사용되는 anagrelide 는하이드록시유레아에비하여혈전증예방측면에서약간열등하거나동등한효과를보여주었다 [14,15]. 따라서혈소판이증가된진성혈소판증가증환자에서단독으로사용하거나진성적혈구증가증환자에서하이드록시유레아와보조적으로사용할수있으며, 대개 1 mg bid로시작하며용량을조절한다. 출혈예방을위한치료아이러니하게도혈전증을잘일으키는이두질환은출혈위험도역시일반인에비하여높은데, 특히혈소판이매우높은환자에서출혈위험이더크며, 이는혈소판이지나치게높게되면폰빌레브란트인자다합체 (von Willebrand factor multimer) 가감소되어후천성폰빌레브란트병이생기기때문이라고설명한다 [16]. 아스피린은혈소판이높은환자의출혈위험도를높이기때문에 [12,13], 앞서언급한대로혈소판이매우높은경우 ristocetin cofactor activity (von Willebrand factor activity) 를측정하며활성도가 30% 이하인경우사혈과골수억제제또는 anagrelide를통해헤마토크리트및혈소판수치를조절하되아스피린을투여하지말아야한다. 하지만임상적출혈은혈소판의수치및폰빌레브란트인자활성도와반드시일치하지는않기때문에임상적으로출혈경향이있다면검사결과에상관없이아스피린사용을주의하는것이바람직하다 [17,18]. 백혈병 / 골수섬유증으로진화예방현재사용되는약제는혈전증위험도를낮추지만백혈병 / 골수섬유증으로진화를예방내지는지연시키는역할을하여질환의자연경과를바꿀수있다는증거는없다. 따라서환자에게이사실을주지시키는것이중요하다. 혈구수치를낮추기위해사용되는골수억제제중일부는오히려백혈병진화를촉진할수도있으니주의해야한다. 클로람부실 (chlorambucil), radiophosphorus, popobroman 과같은골수억제제는하이드록시유레아와비교하여백혈병의발병률을높일수있어서현재는사용되지않고있다 [2,8,19]. 따라서하이드록시유레아에적절한반응이없거나투여가어려운경우부설판 (busulfan) 이나인터페론알파를사용하는것이추천되며, 최근의임상연구에서부설판에대해서는그효능성과함께다른골수억제제병용없이부설판단독투여시백혈병에관한안정성은검증되었다 [2,20]. 인터페론알파역시백혈병위험도를높이지않고대부분의환자에서적혈구나혈소판수치를잘조절하며비장비대와소양증을완화시킬수있다 [21]. 투여편의와부작용을줄이기위해개발된페길화인터페론알파 (pegylated interferon alpha) 는주 1회 90 μg 이하로투여하였을때 70% 의환자에서 3개월내혈액학적관해를얻을수있었고, JAK-2 돌연변이및 CALR 돌연변이대립유전자 (allele burden) 도줄이면서 5-10% 환자에서는분자생물학적완전관해도얻을수가있다고하였다 [22,23]

4 - 김성용. 진성적혈구증가증과진성혈소판증가증의치료 - 소양증 (pruritus) 과홍색사지통증 (erythromelagia) 일부환자가소양감, 특히목욕후소양감을호소한다. 하이드록시유레아나인터페론같은혈구수치를조절하는약제로해결되는경우도있지만, 해결되지않는경우항히스타민, H2 차단제, 광선치료를보조적으로사용한다 [24-26]. 홍색사지통증이란손발에작열감과함께발적, 창백또는청색증이생기는증상을말하며주로혈소판이높을때나타나고저용량의아스피린 ( mg) 으로잘조절된다. JAK 억제제의역할진성적혈구증가증 / 진성혈소판증가증은유전자이상을보이는클론질환이다. 진성적혈구증가증환자중 95% 와진성혈소판증가증환자중 60% 정도가 JAK-2 유전자돌연변이가관찰되고있고이유전자이상이병태생리에서중요한역할을하는것으로알려져있다 [27,28]. 만성골수백혈병에서의이마티닙 (imatinib) 처럼, 변형된유전자내지는이변형된유전자가만들어낸형질을조절할수있는약제가있다면질환의자연경과를바꿀수도있을것이다. JAK 억제제인룩소니티닙은제2상임상시험에서하이드록시유레아에반응이없거나부작용으로인해투여가힘든진성적혈구증가증환자에투여하여 97% 의환자에서투여 6개월이내에사혈없이도헤마토크리트를 45% 미만으로유지할수있었고, 소양증, 야간식은땀, 뼈통증도호전시킴을보였다. 부작용으로는 3등급이상의빈혈및혈소판감소가있었으나용량을감량하면쉽게혈액학적부작용을조절할수있음을보고하였다 [29]. 최근발표된제3상임상시험에서는룩소니티닙과기존보편적으로사용중에있던 2차표준치료를비교하였고, 혈구수치조절, 비장종대감소, 혈액학적완전관해율, 모든측면에서룩소니티닙의효과가 2차표준치료에비해월등한것으로나타났다 [30]. 약제투여는 10 mg bid에서시작하여사혈없이헤마토크리트를 45% 미만으로유지하는것을목표로증량하였다. 이임상시험의아쉬운점은, 룩소니티닙이환자들의 JAK-2 돌연변이대립유전자의양을줄이는것을증명하기는하였지만혈전증및백혈병 / 골수섬유증발생을포함한장기생존율이연구목적에포함되지않아질환의자연경과를관찰할만큼오랜기간동안추적이이루어지지않았기때문에이약제가과연질환의경과를바꿀수있는지는알수가없다는것이다. 일차치료로서의효능은현재표준사용중인약제에비해우월할것으로추정되지만, 비교임상연구가없고현재의 JAK 억제제의가격이비싸고기존표준사용중인약제의치료목적에부합하는효능이우수하기때문에 JAK 억제제가일차선택으로되기는장기간어려울것으로보인다. 결 진성적혈구증가증 / 진성혈소판증가증의치료는혈전증 / 출혈합병증예방하는것을목표로혈전증위험도에따라선택해는것이추천된다. JAK 억제제가골수섬유증에상용화되고있고진성적혈구증가증에 2차적으로사용시효과는기존약제에비해좋고 JAK-2 돌연변이대립유전자의양을줄인다고하였지만질병의경과를바꾼다는증거는아직없기때문에 JAK 억제제를이용한질병경과를제어하고자하는노력은아직은현실적이지않다. 향후질환에대한질환특이적병태생리가더밝혀지고이를표적으로하는약제를이용한충분한임상시험결과로혈전 / 출혈합병증뿐아니라백혈병 / 골수섬유증진화억제에도효과가입증되어진다면이러한표적치료제들의사용이제한된환자에서현실화되는것을기대할수있을것이다. 중심단어 : 진성적혈구증가증 ; 진성혈소판증가증 ; 치료 ; 야누스키나아제 론 REFERENCES 1. Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 2014;124: Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 2013;27: Barbui T, Thiele J, Passamonti F, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol 2011;29: Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014;124: Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015;90: Silverstein A, Gilbert H, Wasserman LR. Neurologic complications of polycythemia. Ann Intern Med 1962;57:

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract