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1 대한내과학회지 : 제 76 권제 2 호 2009 특집 (Special Review) - 골수이형성증의병태생리, 진단과치료 골수이형성증의분자표적치료제 성균관대학교의과대학내과학교실 장준호 New agents for the treatment of myelodysplastic syndromes Jun Ho Jang, M.D., PhD. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell disorders commonly characterized by a hypercellular and dysplastic bone marrow, cytopenias resulting from impaired peripheral blood cell production, and an increased risk of leukemic transformation. Currently, azacitidine, decitabine, and lenalidomide are approved by the US Food and Drug Administration for the treatment of MDS. The DNA methyltransferase (DNMT) inhibitors such as azacitidine and decitabine have demonstrated the ability to alter the natural history of disease and thus prolong time to leukemic transformation. In addition, azacitidine has shown the capacity to extend survival compared with the previous gold standard of conventional care regimens. Recently, decitabine has been shown to be well tolerated with a toxicity profile expected for this class of agent. Recent studies also suggest that decitabine may result in additional improvements in response. As more is learned about the mechanism of hypomethylating agents, new roles are emerging for decitabine in combination therapy for MDS. The third agent, lenalidomide, is a thalidomide analogue with significant activity in a subset of patients with low-risk MDS, anemia and chromosome 5 alterations. Several other agents are being evaluated in MDS. This review summarizes the existing clinical experience on DNMT inhibitors and other drugs for the treatment of MDS. (Korean J Med 76: , 2009) Key Words: Myelodysplastic syndrome; DNA methyltransferase inhibitors; Lenalidomide 서론골수형성이상증후군은진행되는범혈구감소와급성백혈병으로전환될수있는특징을가지는클론성악성혈액질환이다. 이러한골수형성이상증후군에서는다양한분자이상이나타나는데세포주기와아프토시스의변화 1), DNA 메틸화 2), 암유전자의변화및골수미세환경변화등의다양한형태로나타난다 3-5). 서양에서이질환발생연령의중앙값은 70세로보고되고있고연령이증가함에따라발생빈도도증가한다 6). 2003년한연구보고에의하면미국에서일년에약 10,000명의신환이발생하는것으로조사되었다 7). 골수형성이상증후군의분류는초창기에 French-American- British (FAB) 에의해이루어졌으며 8) 최근에는 World organization classification (WHO) 의분류에따른다 9). 예후인자측정에는 International Prognostic Scoring System (IPSS) 가널리사용되고있으며 10), 최근 WHO classification-based Prognostic Scoring System (WPSS) 11, 12) 및 M.D Anderson Scoring System 등이소개되었으나아직 IPSS 를치료의결정및예후측정에실제적으로사용하고있다. 이 IPSS를통해환자의생존률및급성백혈병으로의이환을예측할수있다 10). 골수형성이상증후군의치료에는전통적으로최적의보존적치료및고위험군에서항암화학요법및동종조혈모세포

2 - The Korean Journal of Medicine: Vol. 76, No. 2, (gene silencing) 현상이일어나서, 종양억제유전자 (tumor suppressor gene) 의비활성화를유발한다. 이과정에서 histone deacetylase가같이작용한다. 치료에있어이러한 DNA 메틸화가중요한점은화학적으로가역적이며 DNA methytransferase (DMT) 에결합하여작용을억제하는 5-azacitidine (AZA) 이나 5-aza-2 -deoxycitidine (DAC) 이메틸화에의해동면상태인종양억제유전자를다시활성상태로만들어종양세포의분화, 세포고사, 노화등의과정을유도하여소멸시킨다 13) ( 그림 1). 5-azacitidine ( 비다자 ) Figure 1. Effects of methylation and histone deacetylation on gene expression and silencing. De novo methylation, by itself, has a minimal effect on gene expression (left). However, methylated DNA (m) attracts methyl-binding proteins (MBP). These methyl-binding proteins in turn attract a protein complex that contains histone deacetylases (HDAC). At this point, synthesis of messenger RNA synthesis is inhibited and no functional protein can be made from the gene. Through the action of methyl-binding proteins and histone deacetylases, the DNA structure changes to a compact, "condensed chromatin" configuration (right), which results in permanent inhibition of messenger RNA and protein production (silencing). Hypomethylating agents can reverse this silenced state and restore messenger RNA and protein expression (top). Histone deacetylase inhibitors act synergistically with hypomethylating agents to restore functional gene expression. 이식술이시행되어왔으나, 최근 5년사이새로운개념의표적치료제에의해질환의생태변화및생존률의향상을가져와이때까지의치료원칙인최적의보존적치료 (best supportive care) 를대체하는새로운치료법으로대두되었고, 다양한약제와의 combination therapy가활발하게진행되고있다. 이러한새로운개념의약제중 DNA methyltransferase inhibitor인 5-aza-cytidine (azacitidine, 비다자주 ) 과 5-aza-2 - deoxycitidine (decitabine, 다코젠주 ), thalidomide의유도체인 lenalidomide 등의세가지약제가현재미국식품의약안정청 (FDA) 의공인을받아사용되고있다. 본논고에서는골수형성이상증후군치료에서최근활발히임상적용이되고있는새로운개념의표적치료제에대해서소개하고자한다. DNA 저메틸화제제 (DNA hypomethylating agents) 세포에서 DNA 메틸화은골수형성이상증후군의중요한분자학적이상소견이다. 유전자가메틸화되면유전자동면 5-azacitidine은최초로 FDA 공인을받은약물로현재추천되는표준요법은 75 mg/m 2 를 7일간피하주사하고, 4주마다반복하는것이다. 비다자치료군과보존적치료군으로나누어진행된 CALGB 9221 임상연구에의하면, AZA 치료군의전체반응률은 60% 였고, 완전관해, 부분관해, 혈액학적개선은각각 7%, 16%, 37% 를보였으나, 보존적치료군에서는완전관해와부분관해는없었고, 5% 의환자에서만혈액학적개선이관찰되었다. 백혈병으로의진행혹은사망까지의기간의중앙값은 AZA 치료군에서 21개월로보존적치료군의 12개월보다통계학적으로유의한차이를나타냈다 (p=0.007) 14) ( 그림 2). 또다른 3상임상연구에의하면, AZA 치료군에서전체반응률은 47% 로완전관해, 부분관해, 혈액학적개선은각각 10%, 1%, 36% 로나타나보존적치료군의혈액학적개선 17% 에비해우수한성적을보였다. 치료에반응시까지의치료중앙값은 9회였고, 반응기간의중앙값은 15개월이었다. 65명의수혈의존환자들중 29명에서치료후수혈에의존하지않게되었고, 중앙값은 9개월이었다 15). 5-azacitidine의주된이상반응은골수억제에따른혈액학적독성이다. 치료에따른 3~4 도의호중구혹은혈소판감소증은약 40% 에서발생하였다. 비혈액학적독성은오심, 구토, 주사부위의발적등이보고되었다. 5-azacitidine의 7일요법은주말투여가문제가되어 5-2-2요법, 5-2-5요법그리고 5일요법등세가지다른투여형태가연구되었다. 모두주말투여를피하는요법으로 3군모두전체반응률에는차이가없었다 16). 최근한연구에의하면비다자와 hydroxyurea 의병용투여는두약제사이에길항작용을나타냄을보여투여에주의가필요하다 17). 5-aza-2 -deoxycytidine ( 데시타빈, 다코젠주 ) 데시타빈 (5-aza-2 -deoxycytidine) 은비다자의유사체로써

3 - Jun Ho Jang. New agents for the treatment of myelodysplastic syndromes - Figure 2. Time to AML transformation or death. Measured from entry on study to the time of first event, either transformation to AML or death, and estimated according to the Kaplan-Meier method. 초기에는 15 mg/m 2 를하루 3회 3일간투여하고 6주간격으로반복하는요법을사용하였으나, 최근에는 20 mg/m 2 로 1 일 1회 1시간투여하고 4주간격으로반복하는표준요법으로권장되고있다. 95명의환자를대상으로한 MD Anderson 암센터의연구에서는 20 mg/m 2 5일주사요법, 10 mg/m 2 10 일주사요법, 20 mg/m 2 피하요법등의세가지용법이연구되었는데 20 mg/m 2 5일주사요법에서가장높은완전관해율을보고하였다. 전체반응율은 73% 였고 32명의환자에서완전관해를관찰하였다 18). 저자가경험한데시타빈치료성적도비교적짧은중앙치료주기인 2주기에서고위험군환자군에서의전체반응율이 50% 로높은치료효과를보였다. 특히반응군의 75% 가 2주기이내에반응을보였다 (unpublished data). 데시타빈을이용한다른 3상연구에서는데시타빈치료군에서의반응율이 17% ( 완전관해 9%) 였고, 혈액학적개선은 13% 의환자에서관찰되었다. 보존적치료군에서의반응은관찰되지않았다. 데시타빈치료의중앙값은 3회였고, 반응기간의중앙값은 10.3개월이였다. 데시타빈치료군과보존적치료군에서급성백혈병으로의진행혹은사망까지의기간은 12.1개월과 7.8개월로통계학적유의성은없었으나, 고위험군환자에서는 12.0개월과 6.8개월로통계학적으로유의성을보였다 19) ( 그림 3). Lenalidomide ( 레날리도마이드 ) Lenalidomide는 thalidomide의유도체로염색체 5q 소실골수형성이상증후군환자의치료에 FDA 공인을받은약물로 Figure 3. Higher risk MDS patients treated with decitabine experienced a longer median time to AML or death than those who received supportive care. 권장되는투여용량은하루 10 mg을경구투여하는것이다. 하지만현재국내에서는보험적용이되지않는한계점이있다. Lenalidomide는다발성골수종의치료에서 thalidomide에서보이던신경학적독성은보이지않은대신골수억제및혈전생성등의이상반응이보고되고있다 20). Erythropoietin (Epo) 불응성환자나 Epo 수치가 500 U/L 이상인환자를대상으로시행한 1상임상시험에서 56% 의전체반응률을나타내었고, 32명의수혈의존성환자에서 20명이치료후수혈이필요없게되었다. 특히염색체 5q 소실환자에서 75% 의완전세포유전학적반응과 83% 의높은적혈구반응을보였다. 치료에환자들은순응적이었으며, 중성구감소와혈소판감소는각각 65% 와 74% 를보였다 18). 148명을대상으로시행된 2상연구에따르면 76% 환자에서적혈구반응을나타내었고, 67% 환자가수혈비의존성이되었다. 적혈구반응까지의중앙값은 4.6주였고, 수혈비의존성기간의중앙값은 2년이었다 21). 약제의주요이상반응은골수억제이다. 3~ 4도의중성구감소와혈소판감소는각각 54.7% 와 43.9% 로보고되었고, 다른비혈액학적독성은발적, 피로, 설사등이드물게나타났다. 치료중사망은 8% 의환자에서발생하였고, 사망환자의 40% 인 3명의환자에서약제와관련된치료에따른중성구감소로인한패혈증으로사망하였다 22). 임상연구중인다른표적치료제 다른임상연구중인약물들로는 histone deacetylase (HDAC) inhibitor, farnesyl transferase inhibitors (FTI), arsenic trioxide (ATO) 와 all-transretinoic acid (ATRA) 등이있다. 현재 phenylbutarate 23), valproic acid 24), vorinostat 25), MGCD ),

4 - 대한내과학회지 : 제 76 권제 2 호통권제 582 호 그리고 MS275 27) 등의다양한 HDAC inhibitor 가단독, 혹은제메틸화제제와의병용요법으로 1상및 2상임상시험이진행되고있다. 비소 (ATO) 는재발한급성전골수성백혈병의치료에널리쓰이는제제로현재미국과유럽에서골수형성이상증후군환자를대상으로 2개의임상시험이진행되고있는데반응율은 20% 정도로보고되고있다 28, 29). Ras 유전자이상은골수형성이상증후군환자에서다양하게보고되고있는바 30) 현재 tipifarnib 과 lonafarnib 등의 FTI 가임상연구에사용되고있다 31, 32). 요 최근몇년사이에골수형성이상증후군환자의치료에서보존적요법에서적극적인치료로의변화가일어났다. 그것은 FDA 공인을받은저메틸제제와 thalidomide 유도체인 lenalidomide의출현으로가능하게되었다. 하지만아직어떤제제를 1차에서표준치료로해야할지, 이식의전처치로서의역할은어떤지, 언제까지치료를하여야하는지등의문제는더많은임상연구가뒷받침되어야하겠다. 하지만현재까지의임상시험및실제임상에서사용되는저메틸화제제는골수형성이상증후군환자에서매우높은반응률및생존률향상을보여앞으로이러한표적치료제및다양하게개발되고있는다른표적치료제등의병합요법및단독요법등으로골수형성이상증후군환자의치료성적향상에많은도움이될것으로기대된다. 약 중심단어 : 저메틸화제제 ; 데시타빈 ; 비다자 REFERENCES 1) Parker JE, Mufti GJ. The myelodysplastic syndromes: a matter of life or death. Acta Haematol 111:78-99, ) Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Kohler G, Wijermans P, Jones PA, Lubbert M. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 100: , ) Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O'Brien S, Keating M, Freireich E, Albitar M. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96: , ) Gersuk GM, Beckham C, Loken MR, Kiener P, Anderson JE, Farrand A, Troutt AB, Ledbetter JA, Deeg HJ. A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 103: , ) Stifter G, Heiss S, Gastl G, Tzankov A, Stauder R. Overexpression of tumor necrosis factor-alpha in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis. Eur J Haematol 75: , ) Rollison DE, Hayat, M. and Smith, M.. First Report of National Estimates of the Incidence of Myelodysplastic Syndromes and Chronic Myeloproliferative Disorders from the U.S. SEER Program. ASH Annual Meeting Abstracts 108:247, ) Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109: , ) Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: , ) Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100: , ) Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: , ) Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25: , ) Park MJ, Kim HJ, Kim SH, Kim DH, Kim SJ, Jang JH, Kim K, Kim WS, Jung CW. Is International Prognostic Scoring System (IPSS) still standard in predicting prognosis in patients with myelodysplastic syndrome? External validation of the WHO Classification-Based Prognostic Scoring System (WPSS) and comparison with IPSS. Eur J Haematol 81: , ) Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med 134: , ) Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20: , ) Silverman LR, McKenzie, D. R. and Peterson, B. L.. Azacitidine Prolongs Survival and Time to AML Transformation in High-Risk Myelodysplastic Syndrome (MDS) Patients leq

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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