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1 대한내과학회지 : 제 90 권제 4 호 특집 (Special Review) - 골수증식종양 : 진단과치료의발전 골수섬유증치료의발전 가톨릭대학교의과대학서울성모병원혈액내과 엄기성 Evolution of Myelofibrosis Treatment Ki-Seong Eom Division of Hematology, Department of Internal Medicine, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Myelofibrosis (MF) is a classical Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal proliferation of pluripotent stem cells, dysfunctional kinase signaling, and abnormal cytokine release. MF is a heterogeneous disease, ranging from asymptomatic to being associated with one or more of the following problems: profound anemia, splenomegaly, constitutional issues, and even rapid progression to overt leukemia. Recently, important progress has been made. A Janus kinase (JAK) 2 mutation affects both pathogenesis and prognosis. Conventional treatment is primarily palliative and has only limited effects on the natural course of the disease. Allogeneic stem cell transplantation is the only curative treatment, but is presently limited to eligible intermediate-2 and high-risk patients. Ruxolitinib, the first drug approved by the Food and Drug Administration for treatment of intermediate-2 and high-risk patients, is currently the best available therapy for symptomatic MF patients. Additional JAK inhibitors are under investigation. Emerging therapies include immunomodulators and inhibitors of histone deacetylase (HDAC), mammalian target of rapamycin (mtor), and telomerase. A better understanding of disease pathogenesis will lead to the development of better treatments modifying the disease course and, ultimately, curing the condition. (Korean J Med 2016;90: ) Keywords: Myelofibrosis; Treatment; JAK 서론골수섬유증 (myelofibrosis) 는이전에는특발성골수섬유증 (idiopathic myelofibrosis) 또는특발성골수화생증 (agnogenic myeloid metaplasia) 이라불렸던질환으로전형적필라델피아염색체음성골수증식성종양 (classic Philadelphia chromosome negative myeloproliferative neoplasm) 중의하나이다 [1]. 골수섬유증은다시일차성 (primary myelofibrosis) 과이전에진성적혈구증가증 (polycythemia vera, PV) 이나특발성혈소판증가증 (essential thrombocythemia, ET) 으로진단된후속발하는골수섬유증 (post-pv or post-et MF) 으로나뉘어지나 [2], 그임상적양상및예후에는차이가없다. 골수섬유증은다능성조혈 Correspondence to Ki-Seong Eom, M.D., Ph.D. Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: , Fax: , dreom@catholic.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 - The Korean Journal of Medicine: Vol. 90, No. 4, 모세포 (pluripotent hematopoietic stem cell) 의클론성증식이원인이되어비정상적세포집단이다양한사이토카인과성장인자를생산하고이러한물질에인해골수의섬유화가발생하고비장비대를동반하는골수외조혈 (extramedullary hematopoiesis) 과말초혈액의백적혈구모구반응 (leukoerythroblastic reaction) 을특징으로하는질환이다. 2010년미국통계에의하면연간인구십만명당유병률은 4-6명정도이며 [3] 국내에서는최근 10년사이에 3.8배가증가하여 [4] 유병률이 1.24명정도인것으로알려져있다 [5]. 골수섬유증환자들의임상경과는매우다양하여국제예후인자 (international prognostic scoring system, IPSS) 로저위험군의경우중앙생존기간이 10년이상인장기생존을기대할수있는반면고위험군의환자는중앙생존기간이 27개월에불과하다 [6]. 최근 Janus kinase 2 (JAK2) 유전자돌연변이 (V617F) 의발견은골수섬유증의병태생리학적발생기전을이해하는데있어매우중요한진전이며 JAK2 돌연변이에뒤이어서 Calreticulin (CALR), Myeloproliferative leukemia protein (MPL) 등의돌연변이도발견되었다. 골수섬유증의치료골수섬유증의치료에있어다음의두가지사항을먼저고려해야한다. 첫번째로환자의예후이며두번째는환자의증상의유형과경중이다. 고위험군은생존기간의중앙값이 27개월에불과하므로 [6] 동종조혈모세포이식의시행이우선적으로고려되어야한다. 그러나여러가지이유로고위험군의환자중상당수가동종조혈모세포이식을받을수없으며이런환자들에게서는임상연구또는증상경감치료가적합한치료방법이다. 반면, 저위험군의환자는생존기간의중앙값이 11년이넘고대부분의환자가무증상이므로보존적치료가합리적인것으로판단된다. 대부분의환자에서증상의유형과경중이치료를선택하는데있어주된결정요인이된다. 주된증상은빈혈, 비장비대, 전신증상 (constitutional symptom) 으로동종조혈모세포이식이외에환자의모든증상을조절하기는어려우므로각환자의주된증상을조절하는데초점을맞추는것이현재의치료이다. 이러한증상을복합적으로가지고있는경우한가지증상을호전시키기위해시도하는치료가다른증상을악화시킬수있기때문에 ( 예를들면, 비장비대를경감시키기위해투여하는 hydroxyurea가빈혈이나혈소판감소를악화시킴 ) 이러한경우세포감소치료 (cytoreductive therapy) 와빈혈을치료하기위한치료를병용하는것이통상적이다. 과거및현재의치료지금까지의치료는환자의증상, 혈구감소증및비장비대를경감시키고감염을예방하고증상을조절하며삶의질을향상시키는데집중되어왔다. 과거및현재의치료는대개증상을호전시키거나골수섬유증의부작용을예방하거나줄이기위한비특이적 대증적지지요법이었다면향후의치료는좀더병태생리학적발생기전을표적으로하는치료로옮아갈것으로보인다. 편두통, 시야장애, 피부홍통증 (erythromelagia) 및비전형적일과성허혈성발작 (atypical transient ischemic attack) 과같은미세혈관증상은아스피린으로조절되는경우가많다. 피로감은빈혈이주된원인이지만질환자체에의한증상일수도있다. 빈혈에의한피로감은빈혈의교정에의해호전을보일수있으나질환자체에의한피로감의조절은만족할만한결과를기대하기는어렵다. 전신증상은세포감소치료 [7] 또는스테로이드로일부의환자에서일시적인효과는보이나 JAK2 억제제이외에만족할만한결과를기대하기는어렵다. 빈혈빈혈은골수섬유증의가장흔한증후로골수에서의생산감소, 비효율적적혈구생성 (ineffective erythropoiesis), 비장기능항진증또는출혈에의해유발된다. 치료가가능한다른원인 ( 철결핍, 비타민 B12 결핍, 용혈성빈혈 ) 이있는지확인해서교정해야한다. 골수섬유증에의한빈혈의치료의선택사항으로는안드로젠제제, 조혈자극인자 (erythropoietin-stimulating agents, ESA), 면역조절제제 (immunomodulator), 비장절제술및스테로이드가있다. 헤모글로빈수치가 10 g/dl 이하인경우치료를시작하는것이일반적이다. 안드로젠제제인다나졸은 40% 정도의환자에서빈혈의호전을보이며그중절반정도는지속적인반응을유지한다 [8]. 충분한용량 ( 하루 600 mg) 을최소 6개월이상투여한후반응을유지하는최소용량 ( 대개하루 200 mg) 으로점차용량을줄여야한다. 간암발생에대한정기적인간기능검사, 간초음파검사및전립선암에대한스크리닝검사가필요하다. 재조합인간 erythropoietin (recombinant human erythropoietin) 이나 α-darbepoetin으로 23-60% 의환자에서빈혈에대한반응

3 - Ki-Seong Eom. Evolution in myelofibrosis treatment - ( 정상헤모글로빈수치와수혈비의존적이됨, 수혈이 50% 이상감소함, 수혈비의존적인환자에서헤모글로빈이지속적으로 2 g/dl 이상상승함 ) 을기대할수있으며반응지속기간의중앙값은 12개월정도인것으로보고되었다 [9-11]. 이들환자의절반에서는반응이장기간유지되었으며, 이들은대부분은 erythropoietin 이낮은 (< 125 mu/ml) 환자들이었다. 빈혈에대한반응은대개수주이내에시작되며 3개월이내에반응이오지않는다면치료는중단되어야한다. Thalidomide 투여시 29% 에서빈혈의호전을보이는것으로알려져있으나 [12] 이상감각, 진정, 혈액학적독성및골수증식의가속 (myeloproliferative acceleration) 등의부작용이흔한것이문제이다 [12]. 이러한부작용을줄이기위해저용량 ( 하루 50 mg) 의 thalidomide를스테로이드와병용하는것이추천된다 [13]. 이외에 lenalidomide는 5 q 결실이있는경우사용할수있다 [14]. 약물치료에반응하지않는수혈의존성빈혈의경우비장절제술을고려해볼수있으나수술전후상당한이환율과약 10% 내의사망률을보이고있으므로신중히결정해야한다 [15]. 약물치료에반응하지않는골수섬유증관련자가용혈성빈혈이있는경우비장절제술이추천된다. 비장비대 Hydroxyurea는비장과간의크기를줄여주고전신증상, 소양증및뼈의통증을호전시키며백혈구및혈소판증가증을조절할수있게하며 40% 에서이러한효과를볼수있고 13.2 개월의반응지속의중앙값을보인다 [16]. 그러나이러한반응이완전히비장비대를없애주거나지속적으로유지되는경우는매우드물다. 비장반응을유도하기위해서하루 2-3 g 의고용량이필요한경우가흔하며이경우골수억제에의한혈구감소증의악화가동반될수있다. 다른약물로 busulfan 이나 melphalan 을고려해볼수있지만독성이나백혈병으로의전환의위험때문에일반적으로권장되지는않는다. 면역조절약물, 특히 thalidomide +/- prednisolone이간비장비대및빈혈에효능이있음이보고된바있다 [13]. 비장절제술은비장비대가매우심하고기존의치료에불응성인혈구감소증이있을때고려해볼수있다. 방사선치료는간이나비장이외의부위에발생한골수외조혈부위나증상을동반한간비장비대에고려해볼수있다. 동종조혈모세포이식동종조혈모세포이식은골수섬유증의완치를위한유일한 치료방법이지만고령, 전신상태가불량한환자나병발한질환을가지고있는환자에서시행하기는어려우며상당한치료관련이환율과사망률을가지고있는문제가있다. 최근동종조혈모세포이식을받은 intermediate-2나 high risk의환자가이식을받지않은같은위험군의환자에비해생존율이향상되었으나사망의위험은 dynamic IPSS (DIPSS) 위험군이높을수록높았다는보고가있었다 [17]. 따라서 intermediate-2 나 high risk의환자중이식에적합한상태를가진환자에게만고려되어야한다. 국제골수이식등록기관 (International bone marrow transplantation registry, IBMTR) 자료에의하면골수파괴성전처치로이식을시행하는경우 5년전체생존율이 30-40% 이며무병생존율은 22-33% 로상당한이환율및사망률이있고이식에의한혜택을예측하기가어렵다 [18]. 저용량전처치이식의도입으로특히고령의환자에서이식이다소용이해졌으며한전향적연구결과에의하면 51% 의 5년무사고생존율과 16% 의 1년치료관련사망률을보여주어 [19] 골수파괴성전처치에의한이식에비해향상된성적을보였으며, 고위험군환자의예후와비교하여좋은치료결과를보여주었다. 동종이식에적합한 intermediate-2 및 high risk 환자에서이식을시행에대해서는넒은공감대가형성되어있지만나머지환자에대해서는불량한예후인자가나타나거나기존의치료에불응성을보일때까지이식을보류하는것이합리적인대안으로보인다. 새로운치료제및향후의치료방향 JAK 억제제 JAK2 V617F 돌연변이의골수증식성종양발생에서의역할에대한발견은다수의 JAK2 억제제의개발을가능하게하였다. Ruxolitinib은 2011년에미식약청으로부터 intermediate-2 및 high risk 골수섬유증환자의치료제로최초로허가를받은 JAK 억제제로제3상임상시험 (COMFORT-1/2) 결과비장부피의감소및골수섬유증과관련된증상의호전과생존율의향상을가져올수있으나빈혈과혈소판감소증이상당수에서발생하기때문에이러한문제를가진환자에서의사용은제한적이다 [20,21]. 이러한결과를바탕으로 ruxolitinib은동종조혈모세포이식에적합하지않은증상을가진 intermediate-2 또는 high risk 환자에서가장효과적일것으로보인다. Ruxolitinib이골수의섬유화를역전시킬수있는지 JAK2 대립유전자양을경감할수있는지또는백혈병으로진행을차단할수있는지는불확실하다

4 - 대한내과학회지 : 제 90 권제 4 호통권제 668 호 Momelotinib은 JAK1/2 억제제로비장비대및골수섬유증관련증상의감소뿐만아니라적혈구수혈량도줄여줄수있는것으로보고되었다 [22]. 빈혈및비장반응은각각 59%, 48% 에서관찰되었고 70% 의환자가수혈비의존적이되었다. Grade 3/4의혈소판감소증이 25% 에서관찰되었다. Pacritinib는 JAK2를선택적으로억제하는약물로 57% 의환자에서비장크기를경감시키는동시에골수억제의부작용이거의없는장점을가지고있다 [23]. 최근개발중인치료제텔로미어억제제인 imetelstat는인간텔로미어역전사효소 (human telomere reverse transcriptase inhibitor) 의 RNA 주형을표적으로하는올리고핵산염으로 12% 의환자에서골수섬유조직소실을보이는완전관해를포함한 21% 의반응률을보여주었으며이러한반응지속기간의중앙값은 18개월이었다. Grade 4의혈소판감소 (18%), 호중구감소 (12%) 및빈혈 (30%) 이발생하였다. 현재제2상임상시험이진행중이다. mtor 억제제인 everolimus 는제1/2상임상시험에서각각 69% 와 80% 의환자에서전신증상과소양감의완전한소실을보인약물로대부분의환자에서 grade 1과 2의구내염이가장흔한부작용이었다 [24]. HDAC 억제제는 janus kinase/signal transducers and activators of transpcription (JAK/STAT) 경로에대한억제효과를가지고있으며현재 givinostat, panobistat, pracinostat에대한연구가진행중이다. 병용요법 Ruxolitinib은비장크기나증상을상당히줄여주지만모든증상을다조절할수는없으며치료에따른빈혈이나혈소판감소등의골수억제부작용이문제가된다. 따라서이를보완하기위한다른약물과의병용치료가합리적인치료의대안이될수있을것으로기대된다. Lenalidomide, 단클론항체 GS-6624, ESA, lenalidomide와 ruxolitinib과의병용요법에대한연구가진행중이며최근개발된 panobistat 또는 hedgehog 억제제와병용요법이질환의경과를변화시키기위해시도되고있다. 결론골수섬유증은질환의경과및예후가매우다양한이질적인질환이므로치료또한개개환자의예후인자및증상의 경중이나유형에따라결정되어야한다. 이러한환자의예후인자및증상은매우유동적으로변화한다는것을항상염두에두고이러한변화에따라치료에대한결정도변화하여야한다. 기존의치료는기본적으로증상완화및경감치료법이며질환과관련된이환율과사망률을변화시킬수없다. 동종조혈모세포이식은골수섬유증의완치를위한유일한방법이며 intermediate-2 또는 high risk 환자가적합한대상이지만시행에는상당한제약이따른다. Ruxolitinib은상당한정도의증상및증후의완화와일정부분의생존율의향상을가져올수있는것으로보이지만질환의경과를변화시킬수있을지는아직미지수이다. 골수섬유증의발생기전에대한보다나은이해가질환의자연경과를변화시키고궁극적으로완치에이를수있는새로운치료방법으로나아갈수있게할것으로기대된다. 중심단어 : 골수섬유증 ; 치료 ; JAK REFERENCES 1. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-pv MF), post essential thrombocythemia myelofibrosis (post-et MF), blast phase PMF (PMF-BP): consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res 2007;31: Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110: Stein BL, Gotlib J, Arcasoy M, et al. Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms. J Natl Compr Canc Netw 2015;13: Choi CW, Bang SM, Jang S, et al. Guidelines for the management of myeloproliferative neoplasms. Korean J Intern Med 2015;30: Bang SM, Kim HY, Kim HJ, et al. Diagnostic and therapeutic guideline for myeloproliferative neoplasm. J Korean Med Assoc 2011;54: Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113: Martínez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyper

5 - 엄기성. 골수섬유증치료의발전 - proliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol 2010;89: Cervantes F, Alvarez-Larrán A, Domingo A, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol 2005;129: Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3:e Guglielmelli P, Biamonte F, Score J, et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood 2011; 118: Brecqueville M, Rey J, Bertucci F, et al. Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes Chromosomes Cancer 2012;51: Barosi G, Elliott M, Canepa L, et al. Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma 2002;43: Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003;101: Tefferi A, Lasho TL, Mesa RA, et al. Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia 2007;21: Tefferi A, Mesa RA, Nagorney DM, et al. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000;95: Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29: Scott BL, Gooley TA, Sorror ML, et al. The dynamic international prognostic scoring system for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood 2012;119: Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010;16: Kröger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114: Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366: Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366: Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 2013;27: Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 2010;115: Guglielmelli P, Barosi G, Rambaldi A, et al. Safety and efficacy of everolimus, a mtor inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood 2011; 118:

7.Æ¯Áýb71ÎÀ¯È« š

7.Æ¯Áýb71ÎÀ¯È« š J KMA Special Issue Myelodysplastic Syndrome June Won Cheong, MD Yoo Hong Min, MD Department of Internal Medicine, Yonsei University College of Medicine E mail : jwcheong70@yumc.yonsei.ac.kr minbrmmd@yumc.yonsei.ac.kr