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1 제대혈이식술후발생한간정맥폐쇄질환의 Defibrotide 를이용한치료경험 전남대학교의과대학 1 소아과학교실, 충북대학교의과대학 2 소아과학교실 이준선 1 국훈 1 노하영 1 백희조 1 김소연 1 손경란 1 최익선 1 박현진 2 황태주 1 Defibrotide Treatment for Hepatic Veno-occlusive Disease after Umbilical Cord Blood Transplantation Jun Sun Yi, M.D. 1, Hoon Kook, M.D. 1, Ha Young Noh, M.D. 1, Hee Jo Baek, M.D. 1 So Youn Kim, M.D. 1, Kyoung Ran Sohn, M.D. 1, Ik Sun Choi, M.D. 1, Hyun Jin Park, M.D. 2 and Tai Ju Hwang, M.D. 1 Department of 1 Pediatrics, Chonnam National University Medical School, Gwangju, Department of 2 Pediatrics, Choongbook National University Medical School, Cheong-ju, Korea Veno-occlusive disease (VOD) of the liver is a life-threatening complication occurring early after blood or bone marrow transplantation (BMT). Effective treatment has not been established in case of severe forms of VOD. Defibrotide, a single-stranded polydeoxyribonucleotide, has been used on a compassionate basis in recent clinical trials with promising results. We report here with the first Korean experience of using defibrotide for the treatment of hepatic VOD occurring after unrelated umbilical cord blood transplant in a 2-year-old child with acute lymphoblastic leukemia. Defibrotide was administered for 23 days without any significant side effects with resolution of signs and symptoms of VOD. (Korean J Pediatr Hematol Oncol 2004;11:92~96) Key Words: Venoocclussive disease, Umblical cord blood transplantation, Defibrotide 서 소아백혈병의치료로동종골수및제대혈조혈모세포이식이많이시행되고있는데 1), 이식과관련된중한합병증중의하나로간정맥폐쇄질환이발생할수있다. 이는주로이식후 30일이내에발생하는것으로급격한체중증가, 상복부통 론 책임저자 : 국훈, 광주광역시동구학동 8 번지전남대학교병원소아과, Tel: , Fax: hoonkook@chonnam.ac.kr 증, 간비대, 황달을특징으로하며심할경우여러장기의기능부전을동반할수있다 2-4). 이러한간정맥폐쇄질환은이식시이용된전처치및간의상태, 골수이식의형태, 유전적요인과관계가있다고알려져있다 5,6). 중증이아닌경우는비교적예후가양호하지만특히여러장기의기능부전을동반한경우에는최근까지도효과적인치료나예방법이없는실정이다. 그동안 heparin 7,8), tissue plasminogen activator (tpa) 9) 등의약물로일부환자들에서성공적인치료가보고되었으나, 중한출혈이나타날수 대한소아혈액종양학회지제 11 권제 1 호

2 Defibrotide in Hepatic Veno-occlusive Disease 93 있어이중 20~50% 는사망할수있다 9). Defibrotide (DF) 는 single-stranded polydeoxyribonucleotide 로최근에간정맥폐쇄질환의치료에비교적안전하며효과적이라고알려진약제이나 10-12), 아직시판되지않아국내에서는사용경험이없다. 저자들은재발한급성림프구성백혈병 (ALL) 으로제대혈이식을받은환아에서발생한간정맥폐쇄질환을무상으로공급받은 DF를이용하여성공적으로치험하였기에이를보고하는바이다. 증례환아 : 조OO, 2세, 여아주소 : 재발된 ALL에서비혈연간제대혈이식위해현병력 : 8개월전쉽게멍이들어내원하였으며말초혈액검사상백혈구수 68,600/mm 3, 골수검사및면역표현형검사에서 precursor B ALL (L1), 로진단되었다. 세포유전학검사상세포가배양되지않았으나, BCR-ABL, E2A-PBX1, MLL-AF4에대한 FISH 및 multiplex RT-PCR은음성이었고, 뇌척수액검사상중추신경계침범은없었다. 환아는고위험군으로관해유도요법을시행하여 14일만에관해를성취하였고, 공고요법및중추신경예방요법과중간유지요법을시행하였다. 그러나, 항암치료도중 4개월만에 ALL이재발하였고, 고용량 ara-c가포함된 2차례재관해요법으로관해가되었다. 환아는 2차관해상태에서 1개항원불일치제대혈이식을위하여입원하였다. 과거력및가족력 : 특이사항없음. 진찰소견 : 입원당시몸무게는 12.0 kg이었고, 활력징후는특이소견없었다. 진찰소견상간비종대는없었다. 치료및경과 : 이식을위한전처치로 ara-c (3.0 g/m 2 /dose, 정주, 12시간간격 3일간 ), cyclophosphamide (45 mg/kg/day, 정주, 2일간 ), 전신방사선 ( 총 1,200 cgy, 6회분할 ) 조사를시행하였다. 이식된제대혈의총유핵구수는 /kg, CD34 양성세포수는 /kg이였다. 급성이식편대숙주반 응의예방으로 cyclosporine을사용하였으며, 간정맥폐쇄질환의예방목적으로 PGE1 (Eglandin ) 을 1μg/kg/day로지속주입하였다. 환아는이식후 18일째갑자기체중이급증 (13.7 kg, 14%) 하며, 상복부통증과압통을호소하였으며, 간비대를보여시행한검사상총빌리루빈이 2.2 mg/dl로증가되었다. 단순흉부방사선및복부방사선사진상간비대소견외특이소견보이지않았으며, 간기능검사, 신기능검사또한특이소견없었다. 제대혈이식후발생한간정맥폐쇄질환을의심하고 PGE1을증량하며 ursodeoxycholic acid (UDCA) 를추가복용하였으나총빌리루빈은계속상승하였다. 이식 25일째총빌리루빈이 7.9 mg/dl까지증가하여 DF (Prociclide, Gentium, Como, Italy) 를사용하기시작하였다. DF 50 mg을생리식염수 50 ml에섞어 2시간에걸쳐하루 4회주입하였다 (15 mg/kg/day). 이때 PGE1의사용은중단하였다. 이식 27일째총빌리루빈이 11.6 mg/dl까지증가하여 DF 용량을하루 300 mg (23 mg/kg/day) 으로증량하였으며, N-acetylcysteine Fig. 1. Bilirubin changes as a manifestation of hepatic veno-occulsive disease after umbilical cord transplantation. Treatment modalities are also illustrated. UDCA, ursodeoxycholic acid. (NAC, 100 mg/kg/day) 을추가로사용하였다. 이식

3 94 이준선 국훈 노하영등 28일째부터점차체중과총빌리루빈이감소하였으며간비대, 상복부통증및압통은호전을보였다. 이식 34일째총빌리루빈은 4.4 mg/dl까지감소하였다가, 다시 6.3 mg/dl까지증가하여 DF를 400 mg/day (31 mg/kg/day) 까지증량하였다. 하지만당시에체중증가및간비대소견은보이지않고피부발진과설사가증가하여서급성이식편대숙주반응의치료로 methylprednisolone 1 mg/kg/ day를병용투여하였다. 3일이후총빌리루빈, 피부발진, 설사의호전을보였다. 이식 47일째총빌리루빈이 2 mg/dl 이하로감소하여 DF, NAC, UDCA 투여를중단하였다. DF는총 23일간투여되었으며이와연관된부작용은관찰되지않았다 (Fig. 1). 이식후 28일째중성구 500/mm 3 이상, 32 일째중성구 1,000/mm 3 이상소견을보였고, 혈소판은이식후 74일째에 20,000/mm 3 이상으로 3일연속증가하였다. 환아는이식후 4개월경부터거대세포바이러스에의한장염, 폐렴과포도막염이발생하여 ganciclovir, 정주용감마글로불린을사용하였고, 만성이식편대숙주반응이발생하여 methylprednisolone, cyclosporine, tacrolimus, thalidomide 등을사용하였으나호전을보이지않아이식후 276일째사망하였다. 사망당시골수에서는재발소견없이공여자키메리즘을유지하고있었다. 고찰이식후발생하는간정맥폐쇄질환은 busulphan, cyclophosphamide, 전신방사선등을이용한전처치와관계가많은것으로알려져있으며 5,6), 동종골수이식후진단기준의차이와보고자에따라 5~40% 정도에서발생한다 8,12). 간정맥폐쇄질환의진단기준으로 McDonald 등 2,4) 은이식후 20일이내다음 3개기준중 2개를만족하는경우로하였다 : 1) 고빌리루빈혈증 (>2 mg/dl); 2) 간종대혹은간성우상복부통증 ; 3) 체액저류에의한급속체중증가 (>2%). 또한 Jones 등 13) 은이식후 21일이내에간기능이상으로고빌리루빈혈증 (> 2 mg/dl) 과함께다음소견중 2 가지이상 ( 복수, 간종대-주로압통동반, 5% 이상의체중증가 ) 이있으면진단하였다. 간정맥폐쇄질환의중증도는대부분후향적으로평가되며, 임상적으로명백한간정맥폐쇄질환을보이지만특별한치료없이호전을보이는경우를경증, 치료를요하였으나완전히치료되는경우를중등도, 간부전과관련된증상을보이며치료를하였으나 100일이상간정맥폐쇄가지속되는경우, 혹은다장기부전이동반되는경우를중증으로분류하며, 다장기부전이동반된중증간정맥폐쇄질환의경우 90% 이상의높은사망률을보인다 4,6,12). 따라서간정맥폐쇄질환의발생을예방하기위하여 heparin 7,8), PGE1 14) 등이시도되었으나유의한효과를보지못하였고, 진단당시중증질환을예견해보려는시도가있었으나미흡하며 15), 또한혈전용해제등의적극적인치료를언제시작할것인지에대한지침도부족한실정이다 8). 간정맥폐쇄질환이심하게발생한경우의치료는매우어려운데, tpa와 heparin을사용한 Seattle 연구에서 42명의성인환자중 29% 에서만반응하였고, 생명을위협하는출혈경향이있었다 9). 또한 Mayo Clinic의보고에서도 10% 의생존율을보고하여 tpa의치료가효과적이질못하였으며 16) 더욱이소아에서효과적이라는보고는전무한실정이다. 그외의약물로 ursodeoxycolic acid을사용하여대조군에비해간정맥폐쇄질환의빈도가줄었다는보고 17) 와 NAC가도움이될수있음을시사하였으나 18) 더연구가필요하다. DF는최근에간정맥폐쇄질환의치료로서관심을받고있는제제로돼지의조직에서얻어진 single-stranded polydeoxyribonucleotide이다 10). 이는 prostacyclin의혈관이완과혈소판응집억제작용을증가시키며, tpa의기능증가, plasminogen activator inhibitor 1 (PAI-1) 의감소, tissue factor pathway inhibitor의억제작용을통한혈전용해작용과항염증성, 항허혈성작용을갖는다. 또한시험관내에서 adenosine 수용체 A1과 A2에친화성이있어 thrombin 길항작용을나타내고, 전임상연구에서

4 Defibrotide in Hepatic Veno-occlusive Disease 95 손상된미세혈관계에를보호하는역할을하는것으로알려져있다 10,19). 그러나, heparin이나 tpa제재와는달리전신성출혈성부작용은거의없는것으로알려져있다. 유럽의최근무상연구에서는 40례의간정맥폐쇄질환에서 DF 10~40 mg/kg/day를평균 18일간사용하여 43% 에서완전회복을보였으며, 중증질환에서도 36% 에서완전회복을보고하였다 20). Richardson 등 11) 은다장기부전을동반한중증간정맥폐쇄질환을가진 88명의환자에서 DF을 5~ 60 mg/kg/day를평균 15일사용하여 36% 의완전회복을보였으며, 이식후 100일째 35% 의생존율을보고하였다. 최근에다기관연구에서는 DF로치료한 45명의소아간정맥폐쇄질환환자에서 76% 의완전회복과 64% 의이식후 100일생존율을보고하였으며, 중증질환의경우에도 50% 의완전회복과 36% 의장기생존율을보고하였다 12). 이는기존의치료방법에비해매우고무적인성적이고, 완전회복을이루기위해서는 DF를빨리사용하는것이가장중요한인자라고하였다 12). 이환아는 cyclophosphamide와전신방사선요법이포함된전처치를받았으나, 특별한간정맥폐쇄질환의위험인자는없었다. 이환아에서사용되었던 PGE1 예방요법은별도움이되지않았었으며, 이식 18일째 McDonald 등의진단기준에 4) 따라간정맥폐쇄질환으로진단하였다. 진단당시간기능은정상이였으며, 다른장기들의기능부전을의심할만한소견은없는경증간정맥폐쇄질환으로생각되어보존적처치만을시행하였으나, 호전을보이지않고중둥도질환으로진행하였다. 환아는골수기능회복되지않은상태로매일혈소판을수혈받았으며, 경한장출혈증상을동반하여 tpa 와 heparin을사용할수없어 NAC와 DF를사용하였다. DF는총 23일간투여하였으나이와연관된부작용은보이지않았다. 저자들은제대혈이식후발생한간정맥폐쇄질환을가진환아에서무상으로공급받은 DF를사용하여특별한부작용없이간정맥폐쇄질환을치험하였기에이를보고하는바이다. 참고문헌 1. Cho B. Pediatric allogeneic hematopoietic stem cell transplantation in Korea-April 2000-The Korean Society of Pediatric Hmeatology-Oncology. J Pediatr Hematol Oncol 2001;8: McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984;4: Shulman H, Hinterberger W. Hepatic veno-occlusive disease-liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant 1992;10: McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993;118: Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev 2003;17: Vogelsang GB, Dalal J. Hepatic venoocclusive disease in blood and bone marrow transplantation in children: incidence, risk factors, and outcome. J Pediatr Hematol Oncol 2002;24: Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the european group for blood and marrow transplantation. european group for blood and marrow transplantation chronic leukemia working party. Blood 1998;92: Reiss U, Cowan M, McMillan A, Horn B. Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol 2002;24: Bearman SI, Lee JL, Baron AE, McDonald GB. Treatment of hepatic venoocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood 1997;89: Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, et al. Defibrotide, a single-

5 96 이준선 국훈 노하영등 stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol 1993;238: Richardson PG, Mrakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002;100: Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant 2004;33: Jones RJ, Lee KSK, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987;44: Bearman SI, Shen DD, Hinds MS, Hill HA, McDonald GB. A phase I/II study of prostaglandin E1 for the prevention of hepatic venocclusive disease after bone marrow transplantation. Br J Haematol 1993;84: Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman HM, McDonald GB. Veno-occlusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol 1993;11: Litzow MR, Repoussis PD, Schroeder G, Schembri- Wismayer D, Batts KP, Anderson PM, et al. Venoocclusive disease of the liver after blood and marrow transplantation: analysis of pre- and post-transplant risk factors associated with severity and results of therapy with tissue plasminogen activator. Leuk Lymphoma 2002;43: Essell JH, Schroeder MT, Harman GS, Halvorson R, Lew V, Callander N, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebocontrolled trial. Ann Intern Med 1998;128: Ringden O, Remberger M, Lehmann S, Hentschke P, Mattsson J, Klaesson S. N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2000;25: Palmer KJ, Goa KL. Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993; 45: Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000;111:1122-9

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R