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1 대한내과학회지 : 제 88 권제 4 호 만성골수성백혈병한국치료가이드라인 - 대한혈액학회 1 울산대학교의과대학서울아산병원혈액내과, 2 서울대학교의과대학분당서울대학교병원혈액종양내과, 3 순천향대학교의과대학순천향대학교서울병원종양혈액내과, 4 고려대학교의과대학고려대학교안암병원종양혈액내과, 5 동아대학교의과대학동아대학교병원혈액종양내과, 6 전남대학교의과대학화순전남대학교병원혈액내과, 7 서울대학교의과대학서울대학교병원내과, 8 아주대학교의과대학아주대학교의료원종양혈액내과, 9 부산대학교의학전문대학원부산대학교병원혈액종양내과, 10 연세대학교의과대학혈액내과학교실, 11 성균관대학교의과대학삼성서울병원혈액종양내과, 12 충남대학교의과대학내과학교실, 13 경북대학교의과대학경북대학교병원혈액종양내과 김대영 1 이정옥 2 김경하 3 김병수 4 김성현 5 김여경 6 김형준 6 김인호 7 박선양 7 박준성 8 정주섭 9 정준원 10 정철원 11 조덕연 12 손상균 13 ; 대한혈액학회만성골수성백혈병연구회 Korean Guidelines for Treating Chronic Myelogenous Leukemia - The Korean Society of Hematology Chronic Myelogenous Leukemia Working Party Dae-Young Kim 1, Jeong-Ok Lee 2, Kyung-Ha Kim 3, Byung Soo Kim 4, Sung Hyun Kim 5, Yeo-Kyeoung Kim 6, Hyeoung-Joon Kim 6, Inho Kim 7, Seonyang Park 7, Joon Seong Park 8, Joo-Seop Chung 9, June-Won Cheong 10, Chul Won Jung 11, Deog-Yeon Jo 12, Sang Kyun Sohn 13 ; and Chronic Myelogenous Leukemia Working Party, the Korean Society of Hematology 1 Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul; 2 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; 3 Department of Oncology and Hematology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine; 4 Division of Oncology and Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul; 5 Division of Hematology and Oncology, Department of Internal Medicine, Dong-A University Hospital, Dong-A University College of Medicine, Busan; 6 Department of Hematology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju; 7 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; 8 Department of Hematology-Oncology, Ajou University Medical Center, Ajou University School of Medicine, Suwon; 9 Department of Hemato-oncology, Pusan National University Hospital, Pusan National University School of Medicine, Busan; 10 Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine; 11 Division of Hematology and Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; 12 Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon; 13 Department of Hemato-Oncology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea Received: Revised: Accepted: Correspondence to Sang Kyun Sohn, M.D., Ph.D. Department of Hemato-Oncology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu , Korea Tel: , Fax: , sksohn@knu.ac.kr *Dae-Young Kim and Jeong-Ok Lee contributed equally to this work as co-first authors. Copyright c 2015 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 - Dae-Young Kim, et al. CML Korean guidelines - Background/Aims: The first edition of the Korean treatment guidelines for chronic myelogenous leukemia (CML) was published in We intend to update those guidelines to include the use of next-generation tyrosine kinase inhibitors (TKIs). Methods: New guidelines were developed in 2012 based on the results of a survey and a consensus meeting of various Korean experts, the reports of recent clinical studies, and updated guidelines from external study groups. Results: An assessment of risk factors is strongly recommended before treating newly diagnosed chronic phase CML. Imatinib, dasatinib, and nilotinib are reimbursable in Korea as first-line treatments, and the patient s age, comorbidities, and possible adverse events should be considered in the choice of treatment. Molecular studies are recommended for assessing treatment efficacy instead of invasive cytogenetic response evaluations, and an early response is believed to correlate with a good prognosis. Second-line TKIs can be considered for patients who fail or are intolerant of first-line therapy, pending analysis of ABL tyrosine kinase mutation status. For treating advanced stages, a combination of TKIs with cytotoxic agents and hematopoietic cell transplantation is recommended. The adverse effects of TKI therapy can be managed via dose reduction and supportive care, or switching to an alternate TKI. Conclusions: The use of TKIs has improved the outcome of CML treatment. Treatment-free remission after discontinuing TKIs might be possible in select patients who achieve sufficient response, indicating that curative treatment for CML can be expected in the future. (Korean J Med 2015;88: ) Keywords: Leukemia, chronic myelogenous; Protein-tyrosine kinases; Guideline 서론만성골수성백혈병 (chronic myelogenous leukemia, CML) 은 2000년대이후티로신키나아제억제제 (tyrosine kinase inhibitor, TKI) 인이매티닙 (imatinib) 의도입으로그치료성적의획기적인향상을가져왔다. 더나아가서 2012년 2세대 TKI인다사티닙 (dasatinib) 과닐로티닙 (nilotinib) 이만성기 CML (chronic phase CML) 의초치료로국내에서도보험급여가인정됨으로써 CML 초치료를위해다약제의시대가본격적으로도래되었다. 2006년대한혈액학회산하만성골수성백혈병연구회에서작성한한국치료가이드라인 [1] 이배포된이후에여러새로운약제의도입과함께치료반응평가와적절한반응의시기별기준등에많은변화가있어새로운치료가이드라인의도입필요성이제기되었다. 만성골수성백혈병한국치료가이드라인 [2] 정립의취지는첫째, 서구에서발표된 CML에대한치료가이드라인이제시되고있지만한국실정에맞게재정립하고자하며둘째, 어느병원에서진료를받든가장표준적추적검사일정, 치료방침을적용하는데도움이되고자함이며마지막으로국내 CML 환자의치료경과에대한자료를수집할필요가있을경우를대비하여각병원에서표준치료및경과검사를시행하도록유도하여향후의임상연구에많은도움이되고자함이다. 이에국내 에서발표된현황 [3] 들을참고하고대한혈액학회산하만성골수성백혈병연구회에서국내전문가를대상으로시행한설문결과및자문과컨센서스미팅을통해얻은자료 [4] 와함께최근개정된유럽및미국의가이드라인및유수국제학술지에발표된관련자료를참고하여만성골수성백혈병한국치료가이드라인을작성하여보고하는바이다. 대상및방법본가이드라인은국내 CML 전문가들을대상으로진단및치료와관련된여러논의점들에대한의견을종합하여작성된것으로, 본가이드라인작성에앞서 2012년 10월 6일가이드라인에관한첫번째컨센서스미팅이개최되었고, 2013 년 1월 25일부터 2월 12일까지 29개기관의 32명의전문가가참여한 CML 치료의전반적인치료현황에관한설문조사가이루어졌으며, 2013년 5월 30일최종자문미팅을가졌다. 이를통해얻은국내전문가들의의견을참고했고 2013 년 8월까지발표된유수국제학술지논문들을참고하여본가이드라인을작성하였다

3 - 대한내과학회지 : 제 88 권제 4 호통권제 656 호 결과진단및초기검사병력의청취, 비장크기측정을포함한신체검진을시행한후전체혈구및백혈구감별계산, 간기능검사, 신기능검사, 전해질검사를시행한다. 진단은골수흡인세포에서 20개이상의분열중기 (metaphase) 세포를확보하여 G-분염법 (Giemsa banding technique) 을통해필라델피아염색체 (Philadelphia chromosome, Ph) 를발견하는것이표준방법이며골수검사를통해세포의형태학적평가뿐아니라 Ph 외동반된다른염색체이상유무를확인할수있다. 골수채취를할수없는경우나골수에서충분한수의중기세포를관찰할수없는경우에한해골수혹은말초혈액에서형광표지염색체검사법 (fluorescent in situ hybridization, FISH) 으로분열중기 (metaphase) 세포에서 t (9; 22) 재배열을확인하거나중합효소연쇄반응검사 (polymerase chain reaction, PCR) 를통해 BCR-ABL1 전위 (translocation) 를발견함으로써진단할수있다. 치료시작전에말초혈액혹은골수흡인검체에서 BCR-ABL1 전사체 (transcript) 의정량검사를시행해야하며, 진단시가속기혹은급성기인경우에는 BCR-ABL 키나아제결합부위 (kinase domain) 돌연변이검사 (mutation test) 도시행하는것을추천한다. 예후인자들 CML의예후와관련된인자들에는나이, 비장크기, 혈소판수, 말초혈액의골수모구, 호산구및호염기구의비율등이포함되며흔히사용되는대표적인세가지예후인자모델은 Sokal 점수 [5], Hasford 점수 [6], European Treatment and Outcome Study (EUTOS) 점수 [7] 이다 (Table 1). 진단시 Ph 양성세포에서관찰되는부가적인염색체이상 (additional cytogenetic abnormalities, ACA) 이약 5% 에서존재하며이는일반적으로 TKI 치료에나쁜예후인자로알려져있고 major route ACA ( 예를들어 second Philadelphia chromosome, trisomy 8, isochromosome 17 q, 또는 trisomy 19) 가존재하는경우에특히예후가불량하다 [8]. 2013년개정된유럽의치료지침 (European Leukemia Net, ELN) 에서는앞서의세가지예후모델에서의고위험군에해당하는환자들과더불어 major route ACA 가있는경우 CCA/Ph+ (clonal chromosome abnormalities in Ph+ cells) 로명명하고주의 (warning) 환자로분류하고있다 [9]. 만성기만성골수성백혈병 (CP-CML) 의초치료이매티닙 400 mg 1일 1회요법새로진단된 CP-CML에서이매티닙 (400 mg 1일 1회복용 ) 으로초치료시 12개월째완전세포유전학적반응률 (complete cytogenetic response, CCyR) 은 International Randomized Study of Interferon and STI571 (IRIS) 연구에서는 68%, 이후의 3상연구들에서는 49-72% 였다 [10,11]. 이매티닙치료 12개월째주요분자학적반응률 (major molecular response, MMR) 은 IRIS 연구에서는 38%, 최근의 2세대 TKI와비교 3상연구에서의이매티닙군은 22-28% 였다 [12-14]. IRIS 연구의 8년추적결과에따르면, 이매티닙군의 8년째전체생존율 85% (CML 과관련된사망만을고려했을때는 93%), 가속기나급성기로진행하지않는비율이 92% 로이매티닙치료의장기생존율은우수했다. 하지만 45% 의환자들에서는약제부작용 (6%), Table 1. Risk stratification Risk Calculation a Risk definition by calculation Sokal Exp (age in years ) (spleen ) [(platelet count 700) ] (blast cells -2.10) Low < 0.8 Intermediate High > 1.2 Hasford when age 50 years + (0.042 spleen) when platelet count > 1, L + ( blast cells) when basophils > 3% + ( eosinophils) Low 780 Intermediate 781-1,480 High > 1,480 EUTOS Spleen 4 + basophils 7 Low 87 High > 87 EUTOS, European Treatment and Outcome Study. a Web calculator ( utos_score/).

4 - 김대영외 14 인. 만성골수성백혈병가이드라인 - 불충분한치료효과 (16%), 동종조혈모세포이식시행 (3%), 사망 (3%), 기타다른이유 (17%) 로이매티닙치료가중단되었다. 이매티닙과관련된기타치료현재까지일차약제로고용량이매티닙을투여한여러연구들의결과는독일그룹의연구를제외하고는분자학적반응의속도는빨라지지만 12개월째 CCyR에서유의한차이를보이지못했으며부작용이증가했기에 [15] 일반적으로이매티닙의용량증가는추천하지않는다. 그러나일부고위험군에대해선택적인효과를얻을수있을지여부에대해서는향후추가적인연구가필요하겠다. 이외에이매티닙과인터페론의병합요법또한반응률또는생존율의향상없이부작용의발생률이상대적으로높아현재로서는추천하지않는다 [16]. 2세대 TKI ( 다사티닙, 닐로티닙 ) CP-CML의일차약제로서 2세대 TKI가이매티닙에비해빠르고깊은치료반응과함께가속기및급성기로의진행을줄인다는두가지 3상임상연구결과가발표되었다. 다사티닙에대한 Dasatinib versus Imatinib Study in Treatment- Naïve CML Patients (DASISION) 연구 [17] 에서는다사티닙 100 mg 1일 1회복용과이매티닙 400 mg 1일 1회복용을비교했고연구의 1차목표인치료 12개월째 CCyR이이매티닙군에서는 73% 였던것에반해다사티닙군에서는 85% 로유의하게높았다. 분자학적반응에서는다사티닙대이매티닙의 MMR 은 1년째 46% 대 28%, 3년째 68% 대 55% 였고 BCR/ABL IS 0.01% (molecular response 4 [MR 4 ]) 획득률은 2년째 28% 대 18%, 3년째 35% 대 22% 였으며 BCR-ABL IS (MR 4.5 ) 획득률은 2년째 17% 대 9%, 3년째 22% 대 12% 로다사티닙군에서유의하게높았다. 3년추적결과치료약복용중가속기및급성기로의진행률은이매티닙군의 5% 에비해다사티닙군은 3% 로낮았다. 다만 3년무진행생존율 ( 다사티닙 91.0%, 이매티닙 90.9%) 과전체생존율 ( 다사티닙 93.7%, 이매티닙 93.2%) 은차이가없었다 [17]. 닐로티닙에대한 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) 연구에서는닐로티닙 300 mg 1일 2회복용, 닐로티닙 400 mg 1일 2회복용과이매티닙 400 mg 1일 1회복용의세군을비교했고연구의 1차목표인치료 12개월째 MMR 획득률은닐로티닙 300 mg군 55%, 닐로 티닙 400 mg군 51%, 이매티닙군은 27% 로닐로티닙군에서유의하게높았다. 닐로티닙군 (300 mg 1일 2회복용 ) 대이매티닙군의 MMR 획득률은 3년째 73% 대 53%, 4년째 76% 대 56% 였고 BCR/ABL IS 0.01% (MR 4 ) 획득률은 3년째 50% 대 26%, 4년째 56% 대 32% 였으며, BCR-ABL (MR 4.5 ) 획득률은 3년째 32% 대 15%, 4년째 40% 대 23% 로닐로티닙군에서유의하게높은분자학적반응률을보였다 [18,19]. 4 년추적관찰결과가속기및급성기로의진행비율은이매티닙군의 4.2% 에비해닐로티닙군은 % 로낮았으나 4 년무진행생존율 ( 닐로티닙 300 mg 1일 2회 96.1%, 이매티닙 94.7%) 과, 전체생존율 ( 닐로티닙 94.3%, 이매티닙 93.3%) 은차이가없었다 [18]. 초치료 TKI 선택지침 위연구결과에근거하여현재 CP-CML의초치료제로승인된약제는이매티닙 (400 mg 1일 1회 ), 닐로티닙 (300 mg 1 일 2회 ), 다사티닙 (100 mg 1일 1회 ) 이며국내에서도 2011년 10월부터다사티닙이, 2012년 7월부터닐로티닙이건강보험급여하에처방이가능하다. 2세대 TKI는이매티닙과비교시빠르고깊은효과를보이고가속기및급성기로의진행위험을낮추는효과가있음이증명되었으나, 관련연구의추적관찰기간이 5년미만으로짧으며현재까지의결과에서는무진행생존율및전체생존율에있어서이매티닙에비해유의한차이를보이지않으므로여전히이매티닙을치료약제로고려할수있다. 따라서 CP-CML의일차약제는이세가지약제중에서환자의나이, 기저질환및각각의 TKI 가가지는부작용을고려하여선택하는것을추천한다. Table 2. Check list before treatment Blood tests: complete blood cell count, liver/renal function, electrolytes (Na/K/Ca/P/Mg), HBsAg/Ab, amylase, lipase, fasting blood glucose level, serum β-hcg Chest X-ray Electrocardiography: for QTc prolongation Echocardiography Smoking history Medical history: coronary vascular disease, cardiopulmonary disease, diabetes mellitus, pancreatitis, peripheral arterial obstructive disease, etc. Drugs: CYP3A4 inhibitor/enhancer, QTc prolongation inducer, etc. Plan for pregnancy and childbearing hcg, human chorionic gonadotropin; QTc, corrected QT interval

5 - The Korean Journal of Medicine: Vol. 88, No. 4, TKI 치료전확인해야할사항들일차약제로 TKI를선정하는단계에서복용시작전에확인해야할사항들은표 2와같다. 특히개별 TKI의흔한부작용을숙지하고처음약제를투약하게될환자가각각의부작용발생위험도가높은지에대한평가를해야한다. CP-CML 치료반응평가치료반응의분류및정의 CML의반응평가는혈액학적 (hematologic response), 세포유전학적 (cytogenetic response) 및분자학적반응 (molecular response) 으로분류한다 (Table 3). 혈액학적반응은말초혈액의미성숙세포, 백혈구및혈소판수, 비장종대의유무를확인하여평가한다. 세포유전학적반응은진단시와같이 G- 분염법염색체검사를통해골수천자세포에서 20개이상의분열중기세포를확인하여 Ph 염색체의감소정도를확인하는것이표준방법이다. FISH는골수검사가불가능한경우나 G-분염법으로 20개이상의중기세포를확인하지못하는경우, 또는 CCyR에도달한경우세포유전학적반응을추적검사하기위해사용할수있으며적어도 200개이상의 핵을확인해야한다. 분자학적반응은 BCR-ABL 실시간정량 PCR 검사 (real time quantitative polymerase chain reaction, RQ- PCR) 를이용하여 BCR-ABL mrna 와대조유전자 (BCR, ABL, beta glucuronidase 등 ) 전사체들의비율이감소하는정도를확인하여판정한다. BCR-ABL 정량검사는 100,000개의정상세포중하나의 CML 세포를발견할수있을정도의민감도를보이지만 RQ-PCR 방법의차이, 대조유전자의종류등여러변수에따라검사실간결과값의차이가발생하므로이를표준화하기위하여 International Scale (IS) 이도입되어사용되고있다 [20]. 초치료시추적검사지침본지침에서는일차약제시작후반응평가를위한추적검사로전혈구검사및분획검사 (complete blood cell and differential count) 를첫 1개월동안은매 1-2주, 그다음 2개월 ( 첫투여일로부터 3개월 ) 까지는매 1-2개월, 3개월이후에는매 3개월마다시행하도록권장한다 (Table 4). 세포유전학적반응평가를위한골수검사는 CCyR 획득시까지 3개월과 6개월째에시행한다. 이후 CCyR에도달할때까지는 6개월마다시행하며 CCyR 도달후분자학적검사가불가한경우 Table 3. Criteria for response in CML Hematologic response (HR) Complete hematologic Peripheral blood (PB) WBC < /L response (CHR) Platelets < /L No immature cells, such as myelocytes, promyelocytes, or blasts in PB No signs or symptoms of disease with disappearance of palpable splenomegaly Cytogenetic response (CyR) Complete (CCyR a ) No Ph+ metaphases Partial (PCyR a ) 1-35% Ph+ metaphases Minimal (mcyr) 36-65% Ph+ metaphases Minor (mincyr) 66-95% Ph+ metaphases No CyR > 95% Ph+ metaphases Molecular response (MR) MR log reduction in International scale of BCR-ABL mrna (BCR-ABL IS %) MR 4 4-log reduction in International scale of BCR-ABL mrna (BCR-ABL IS 0.01%) Major (MMR) 3-log reduction in International scale of BCR-ABL mrna (BCR-ABL IS 0.1%) CML, chronic myelogenous leukemia; WBC, white blood cell; CCyR, complete cytogenetic response; PCyR, partial cytogenetic response; mcyr, minimal cytogenetic response; mincyr, minor cytogenetic response, IS, international units; MMR, major molecular response. a A minimum of 20 metaphases should be examined. Fluorescence in situ hybridization (FISH) can replace chromosome study after achieving a CCyR, and more than 200 metaphase nuclei should be evaluated

6 - Dae-Young Kim, et al. CML Korean guidelines - Table 4. Monitoring recommendations during TKI treatment for CML in CP Monitoring CBC BM examinations with metaphase cytogenetics a Quantitative real-time PCR (RQ-PCR) BCR-ABL kinase domain mutation analysis Adherence Timeline At diagnosis, then every 1-2 weeks for 1 month, and then every month until CCyR has been achieved. Following CCyR, at least every 3 months or as required. At diagnosis, at 3 and 6 months, and then every 6 months until CCyR has been achieved. Following CCyR, every 12 months if molecular monitoring is not available. Upon treatment failure or unexplained cytopenia. Every 3 months until MMR has been achieved and then every 3-6 months. If 1-log increase in BCR-ABL transcript level without loss of MMR occurs, follow-up test within 1-3 months is required. In cases of failure or warning during 1st line TKI treatment. In cases of secondary failure at any time during TKI treatment. Pill counts at every visit. TKI, tyrosine kinase inhibitor; CML, chronic myelogenous leukemia; CP, chronic phase; CBC, complete blood count; CCyR, complete cytogenetic response; BM, bone marrow; MMR, major molecular response; PCR, polymerase chain reaction; RQ, real-time quantitative. a Cytogenetic response should be defined based on an evaluation of a minimum of 20 bone marrow metaphases. If bone marrow metaphases are not feasible, interphase fluorescence in situ hybridization (FISH) can substitute for chromosome banding analysis to monitor the completeness of a CCyR, provided that BCR-ABL1 extrasignal, dual color, dual fusion, or in situ hybridization probes are used and that at least 200 nuclei are scored. 는매 12개월마다시행하도록권장한다. BCR-ABL RQ-PCR 검사는 MMR까지매 3개월마다, 이후에는매 3-6개월마다시행하며추적검사상 BCR-ABL 전사체가 1 log (10배) 이상증가하는경우 1-3개월내에재검사를시행한다. BCR-ABL kinase domain 돌연변이검사는초치료에적절한반응 (optimal response) 을보이지않는경우, 그리고치료반응을보이다가이차실패 (complete hematologic response [CHR] 소실, CCyR 소실, MMR 소실 [2회연속으로 > 0.1% 이고, 1회는 > 1%], CCA/Ph+ 발생, 가속기및급성기로의진행 ) 를보이는경우에반드시시행해야한다. 최근개정된 ELN 진료지침에따르면 IS에근거한적절한분자학적반응평가가가능한경우에한해분자학적반응평가가골수검사에의한세포유전학적평가를대신할수있다고권고하고있다 [8]. 따라서 RQ-PCR (IS) 이가능하지않은경우에는 CCyR 확인까지골수검사와말초혈액 RQ-PCR 검사를함께시행해야한다. 초치료 TKI 치료시기별반응의정의최근많은대규모연구들에서 TKI의종류와관계없이일차치료후 3개월째 BCR-ABL/ABL 전사체비가 10% IS (1 log 감소 ) 이하로감소하는것이무진행생존율및전체생존율에중요한예후예측인자로밝혀졌다 [21,22]. 한편치료 6개월째반응지표에있어서는 6개월째 CCyR을획득하지못하거나 BCR-ABL/ABL 전사체의비가 1% 를초과하는경우가 Figure 1. Response evaluation 3 months after the initial treatment for chronic myelogenous leukemia (chronic phase). CHR, complete hematologic response; TKI, tyrosine kinase inhibitor; HSCT, hematopoietic stem cell transplantation. 전체생존기간이짧은것으로보고되었다 [23]. 또한 IRIS 연구 5년추적관찰결과에서는 12개월째 CCyR을획득한환자에서 MMR을획득한경우가그렇지못한환자에비하여 2 년무진행생존율이높은것으로나타났다 [12]. 2009년 ELN 지침에서는 18개월째 MMR을적합한반응으로평가하였으나최근국외연구에서는 12개월째그리고 18개월째 CCyR 을획득한환자에서분자학적반응의획득여부는무진행

7 - 대한내과학회지 : 제 88 권제 4 호통권제 656 호 Figure 2. Response evaluation 6 months after the initial treatment for chronic myelogenous leukemia (chronic phase). TKI, tyrosine kinase inhibitor; HSCT, hematopoietic stem cell transplantation. 생존율혹은전체생존율에유의한영향을미치지않는것으로보고되었고 [24], 국내환자를대상으로한연구에서도 18개월째 MMR 획득여부는이매티닙초치료환자의무진행생존기간및전체생존기간에유의한영향을미치지못하는것으로나타났다 [25]. 앞서의연구결과들을바탕으로하여일차치료후 3개월째 BCR-ABL/ABL 전사체비가 10% 이하 (Fig. 1), 6개월째 1% 미만 (Fig. 2) 및 12개월째 0.1% 이하로감소하는경우 (Fig. 3) 적합한반응으로정의하고초치료 TKI를유지하도록한다. 초치료중 치료실패 ( 일차치료실패 ) 는 3개월째 CHR 획득실패혹은 Ph+ > 95%, 6개월째 Ph+ > 35% 혹은 BCR-ABL > 10%, 12개월째 Ph+ > 0% 혹은 BCR-ABL > 1% 인경우로정의한다. 이러한일차치료실패에대해서는환자의약물순응도및약물상호작용을조사하고 BCR-ABL kinase domain 의돌연변이검사를시행하여적합한이차약제로변경해야하며이차약제로변경이불가능한경우에는동종조혈모세포이식혹은 TKI 증량을고려해볼수있다. 일차치료에적합한반응과치료실패사이의구간을과거 suboptimal response 로판정했는데 2013년 ELN 지침에서는이를 주의 (warning) 로판정하고분자학적반응검사를좀더자주시행함으로써조기에치료실패를발견, 적절하게약제를변경하기를권장하고있다. 따라서치료 3개월째 BCR-ABL/ABL 전사체비가 10% 이상인경우 바로약제를변경하기보다는주의깊게추적관찰을하면서 Figure 3. Response evaluation 12 months after the initial treatment for chronic myelogenous leukemia (chronic phase). TKI, tyrosine kinase inhibitor; HSCT, hematopoietic stem cell transplantation. 6개월째반응평가에의해치료실패를판정하는것을추천하고있다. 본지침에서도 주의 환자의경우약물순응도및약물상호작용을확인하고 BCR-ABL kinase domain 의돌연변이를확인하며세포유전학적및분자학적반응평가를좀더자주시행하여치료실패여부를평가할것을권장한다. 또한치료전골수로부터의세포유전학검사상 Ph+ 세포에서클론성염색체이상이발견되거나치료도중 Ph- 세포에서클론성염색체이상으로 monosomy 7 혹은 del (7 q) 가발견되는경우예후가좋지않은것으로보고된바있어역시주의환자로판정한다 [26]. 앞서언급한바와같이 3개월째 BCR-ABL/ABL 전사체비가 10% 이상인경우장기적인생존율이불리함이알려지고있으며이와같은불량한예후를보이는환자군의비율이이매티닙을투여했을경우보다 2세대 TKI를투여했을경우가보다낮다고보고되고있어이러한점을초치료약제결정시고려해야한다. 이차치료실패는초치료후적합한반응을보였다가이러한반응이소실되는경우로 CHR 소실, CCyR 소실, 2회연속 RQ-PCR 검사시 MMR 소실, BCR-ABL kinase domain 돌연변이의발생, Ph+ 세포에서클론성염색체이상의발현및가속기혹은급성기로진행하는경우들로이차치료실패시반드시 BCR-ABL kinase domain 의돌연변이를확인하여이에따라추후약제를선택하도록한다

8 - 김대영외 14 인. 만성골수성백혈병가이드라인 - 만성기중동종조혈모세포이식 TKI의등장이후동종조혈모세포이식의역할은축소되어현재는만성기로진단된환자에서는다음과같이제한된경우에한해서만시행을권고한다. 첫째, TKI 투여중치료실패또는불내약성등으로약제를전환해야하는상황에서약제의전환이불가능할경우, 둘째, BCR-ABL 유전자의 T315I 돌연변이가확인될때, 셋째, 특수한고려 ( 비용문제, 평생투약을희망하지않는경우 ) 에의해 TKI보다동종조혈모세포이식을환자가선호하는경우등이있겠다. 이차약제변경및이후의치료반응평가현재국내 CP-CML에서일차약제로사용가능한것은이매티닙, 다사티닙, 닐로티닙이있다. 일부환자들의경우약제에대한부작용으로인해불내약성 (intolerance) 을보이거나, 내성 (resistance) 이발생하여일차약제에대해시기별만족할만한반응을획득하지못하거나, 만족할만한반응을획득한이후반응을소실한경우에이차약제로변경하여투약하는것을고려해야한다. 현재국내국민건강보험을기준으로일차약제로이매티닙을사용한경우불내약성혹은내성이발생시다사티닙, 닐로티닙, 라도티닙으로의변경이가능하며이들이차약제에불내약성혹은내성이있는경우에도서로다른약제로의변경또한가능하다. 일차약제로 2세대 TKI로치료한경우불내약성혹은내성이있어이매티닙으로변경하는임상연구는없으나불내약성의경우에는이차약제로이매티닙투여를고려할수있다. 불내약성의정의불내약성의정의에대해일관된정의는없으며대표적인임상연구들에따르면 [15] 적절한용량감소와최적의증상적치료에도불구하고 3도이상의비혈액학적부작용이반복해서나타나거나 4도의혈액학적독성이 7일이상지속되는경우로정의하고있다. 내성의정의약제에대한내성은일차내성 (primary resistance) 과이차내성 (secondary resistance) 두가지로분류된다. 일차내성은 TKI 사용후적절한반응에도달하지못한경우이다. 일차내성은시기별치료반응정도에따라 [8] 일차혈액학적내성 (primary hematologic resistance) 과일차세포유전학적내성 (primary cytogenetic resistance) 으로구별할수있는데이매티 닙을일차약제로사용한경우일차혈액학적내성은드물게발생하며일차세포유전학적내성은 15-25% 까지나타난다 [27]. 이차내성은처음에는적절한반응을보이다가반응이소실되는경우로이매티닙을일차약제로 CP-CML에투여한경우 2년째약 8% 에서나타난다 [28]. 내성이확인된다면가속기혹은급성기여부등병의상태에대한재평가가필요하며 BCR-ABL kinase domain 의돌연변이에대한검사가필요하다. 또한환자의약제순응도에대한평가가필요하며다른투약되는약물상호작용등을확인해야한다. 결과적으로이차약제로의변경혹은동종조혈모세포이식이가능한지를고려, 치료방침을결정해야한다. 이차약제의선택이차약제를선택하는데있어어떤것이더좋은지에대한무작위연구는아직없으며환자가가지고있는다른질환을감안하고이차약제의부작용을고려하여선택한다. 2 세대 TKI 제제들은이매티닙과부작용이서로다르며이매티닙에불내약성을보여이차약제로서투약했을때교차불내약성은적은것으로보고되었다 [29]. 이러한경우, 일반적으로는내성으로인해약제를변경한경우보다는불내약성으로인해변경한경우가반응률이더높다. 또한내성의경우에는돌연변이의결과에따라약제감수성이있는약제를고려하여선택해야한다. 이매티닙에내성혹은불내약성을보인 CP-CML 환자들을대상으로하여다사티닙 70 mg 하루두번을투약한연구에서는내성환자들의 39%, 불내약성환자들의 80% 가주요세포유전학적반응 (minimal cytogenetic response, MCyR) 에도달하였고내약성이좋았다 [30]. 또다른연구에서는다사티닙 70 mg 하루 2회군과이매티닙 400 mg 하루 2회군을비교했을때다사티닙군에서 MCyR (52% 대 33%) 과 MMR (16% 대 4%) 이다사티닙군에서의미있게높았다 [31]. 한편이매티닙에내성혹은불내약성을보인 CP-CML 환자들을대상으로하여닐로티닙 400 mg을하루 2회투약한연구에서 6개월째 MCyR 은 48% 였고 [32] 24개월이상추적관찰시 MCyR 은 59% 로 CCyR 중 59% 는 MMR에도달하였다 [33]. 마지막으로이매티닙에내성혹은불내약성을보인 CP-CML 환자들에게라도티닙 400 mg을하루 2회투약한연구에서 MCyR 은 64% 에도달하였다 [34]

9 - The Korean Journal of Medicine: Vol. 88, No. 4, 이상의연구들을종합했을때이매티닙에불내약성혹은내성을보인경우 2세대 TKI 제제들은일관되게좋은반응을나타내며, 세포유전학적반응과분자생물학적반응이무진행생존율및전체생존율을향상시키는것을고려한다면환자의기저질환및약제들의부작용을고려하여 2세대 TKI 제제로치료하는것을권고한다. 국내에서는허가되지않았지만이러한경우보수티닙 (bosutinib) 도높은반응률을보여향후이차약제로고려할수있겠다 [35]. 이매티닙을일차치료로사용하여치료에실패한경우다사티닙혹은닐로티닙을이차약제로사용했을때의반응평가의기준이 ELN 2013 guideline에서최근발표되었으며, 다른이차약제들을같은적응증에사용한경우에도반응평가에대해서는잠정적으로같이적용될수도있음이제시된바있다 [8]. 이차약제투여후 3개월마다 BCR-ABL/ABL 전사체비및세포유전학적반응의정도에따라적합 / 주의 / 실패등의기준을정의했으며 TKI로치료하던환자가동종조혈모세포이식을고려해야하는상황에대한기준이될수있으나현재로서는닐로티닙과다사티닙의치료에만적용이가능하다. 가속기및급성기의치료가속기및급성기의정의가속기및급성기에대해서는여러가지정의가있으며국내에서널리사용되는기준으로는 World Health Organization (WHO) 기준 [36] 과 ELN 기준이있다 [8]. 이중 ELN의기준은다국적다기관임상연구에서많이사용되지만한국치료가이드라인에서는국내임상의및진단검사의학전문의들의의견을반영하여 WHO 기준을제시하는바이다 (Table 5). 가속기및급성기로진행시의치료진단시가속기또는급성기일경우 BCR-ABL kinase domain에대한돌연변이검사를시행해야하며, 가속기일경우이매티닙 600 mg을하루 1회, 닐로티닙 400 mg을하루 2회, 또는다사티닙 140 mg을하루 1회투여한다. 급성기에대해닐로티닙은임상연구가진행된바가없으며허가를받지못하여현재로서는투여를고려할수없다. 또한급성기의경우 TKI 단독투여또는세포독성항암제와의병용투여를고려할수있는데국내현실에서는병용투여시건강보험급여가가능한지여부를확인할필요가있다. 만성기에서 1차 TKI 투여중가속기또는급성기로진행 (progression) 할경우이는치료실패 (failure) 에해당한다. 미국지침 (National Comprehensive Cancer Network [NCCN] guideline) 및유럽지침 (ELN guideline) 모두 BCR- ABL kinase domain에대한돌연변이검사를시행할것을권고하고있으며, 본가이드라인에서도이를적극권고한다. 물론투여하던일차약제를중단하고다른약제로변경해야한다. 가속기로진행한경우에는일차약제가이매티닙이었다면이차약제로닐로티닙 400 mg을하루 2회, 또는다사티닙 140 mg을하루 1회투여하며만약일차약제가닐로티닙이었다면이차약제를다사티닙으로, 일차약제가다사티닙이었다면이차약제는닐로티닙으로변경한다. 가속기및급성기치료의반응평가진단시이미가속기 / 급성기로진단이되었거나, 진단시에는만성기였다가치료도중가속기 / 급성기로진행하여이차약제로변경한경우얼마나자주반응평가를할것인가 Table 5. Definition of accelerated phase/blast crisis (WHO criteria) Accelerated phase Blasts 10-19% of WBCs in peripheral blood or nucleated bone marrow cells Peripheral blood basophils 20% Persistent thrombocytopenia (< /L) unrelated to therapy, or persistent thrombocytosis (> 1, /L) unresponsive to therapy Increasing spleen size and increasing WBC count unresponsive to therapy Cytogenetic evidence of clonal evolution WHO, World Health organization; WBC, white blood cell Blast crisis Blasts 20% of peripheral blood white cells or of nucleated bone marrow cells Extramedullary blast proliferation Large foci or clusters of blasts in the bone marrow biopsy

10 - Dae-Young Kim, et al. CML Korean guidelines - 에대해서는구체적인근거가명확하지않다. 그러나일반적인치료일정에준해 complete blood count (CBC) 는첫 1개월까지는매주, BCR-ABL RQ-PCR은 CCyR을획득할때까지 1-2개월의간격으로, 골수검사는 CCyR 획득시까지매 3개월마다실시할것을권고하는데이는일차약제에실패한경우이차약제로변경하였을때 1차치료시보다좋지않은치료반응이예상되기때문이다. 한편반응이적절한지여부에대한기준또한현재로서는명확한기준이없으나가속기및급성기에서치료시작후성공적으로만성기로전환된이후에는만성기의치료방침에따르는것을추천한다. 진단시가속기, 또는가속기로진행해이차약제로변경한경우투여중인 TKI의반응에따라향후치료방침이달라질수있다. 반응이만족스럽다면신중하게반응평가를실시하면서투여중인 TKI를계속유지할수있다. 그러나 TKI 의반응이만족스럽지못하다면다른종류의 TKI로변경함은물론동종조혈모세포이식을적극적으로고려해야한다. 급성기중동종조혈모세포이식진단시급성기, 또는급성기로진행해이차약제로변경한경우에는가급적동종조혈모세포이식을시행하는것을권고한다. 이식당시만성기상태에서이식할경우가보다진행된상태에서이식할경우보다성적이양호하므로가급적만성기상태를유도하는것이필요하지만지속적인 TKI 단독또는세포독성항암제와의병용투여에도불구하고만성기로회복되지않을경우구제요법으로서의동종조혈모세포이식을고려해볼수있다. 동종조혈모세포이식에대한최선의전처치요법에대한근거는부족하며환자의전신상태와공여자의종류에따라적절한전처치요법을선택하길권고한다. 동종조혈모세포이식을통해완전세포유전학적관해를획득한경우 BCR-ABL RQ-PCR은이식후첫 2년동안은매 3개월마다, 이후 3년간은 6개월마다시행할것을권고한다. 이식후 6개월이지난후 RQ-PCR 이 3 log 이상또는정성 PCR 검사에서양성으로변환된경우 ( 분자학적재발 ) 골수검사및골수흡인액으로부터염색체검사를실시하여양성으로확인되면세포유전학적재발에준하여다음치료를진행한다. 그러나염색체검사에서음성으로확인되면반복해서 RQ-PCR을확인하여 2회이상양성일경우새로운 TKI의단독투여또는공여자림프구주입술을병용하여 RQ-PCR이음전되는것을확인한다. 이식후완전세포학적관해를얻는데실패하거나또는세포유전학적재발이확인될경우 BCR-ABL kinase domain 의돌연변이검사를실시하고새로운 TKI의투여및면역억제제의중단및공여자림프구주입술등을통해완전세포유전학적반응을다시얻도록노력한다. 독성평가및관리혈액학적독성 ( 만성기 ) TKI 치료후호중구 < 1,000/µL 혹은혈소판 < 50,000/µL 의혈액학적독성이발생할경우투여를일시중단한다. 이후 2주이내에호중구 1,000/µL 및혈소판 50,000/µL 로회복되면초기용량으로투여를다시시작하지만회복되는기간이 2주를초과하면 1단계로용량을줄여서투여한다. 감량투여한이후에도호중구 < 1,000/µL 혹은혈소판 < 50,000/µL 의혈액학적독성이발생하거나이와같은혈액학적부작용이 4주이상지속될경우투여중단을고려한다. TKI 의용량감량단계는표 6을참고한다. Table 6. Dose of tyrosine kinase inhibitors (mg) CP Imatinib Nilotinib Dasatinib Radotinib AP/BC CP (1st line) CP (2nd line) and AP CP AP/BC CP (2nd line) qd 800 qd 400 bid 140 qd qd 600 qd 300 bid 400 bid 100 qd 140 qd 400 bid qd 400 qd 400 qd 400 qd 70 qd 100 qd 400 qd -2 a 200 qd 300 qd 300 qd 300 qd 50 qd 70 qd 300 qd CP, chronic phase; AP, accelerated phase; BC, blast crisis. a Level -2 is usually not recommended, except for intolerant patients who are elderly or have a low body-surface area while maintain the optimal response.

11 - 대한내과학회지 : 제 88 권제 4 호통권제 656 호 혈액학적독성 ( 가속기, 급성기 ) TKI 치료 14일후호중구 < 500/µL 혹은혈소판 < 20,000/µL 의독성발생시에는골수검사를다시시행하여혈구감소증과백혈병의관련성을확인해야한다. 골수검사결과고세포성 (hypercellular) 골수상태를보이는경우투여를지속하지만, 모세포 (blast) < 5% 이면서저세포성 (hypocellular) 골수상태를보이는경우우선투여를중단한다. 투여중단이후 2주이내에호중구 1,000/µL 및혈소판 20,000/µL로회복되면초기용량으로투여를다시시작한다. 2주이상경과후에도호중구 < 1,000/µL 혹은혈소판 < 20,000/µL 이지속될경우용량을 1단계줄여서투여하고, 이후호중구 < 1,000/µL 혹은혈소판 < 20,000/µL 의혈액학적독성이 2주이상지속될경우경우 1단계더줄여서투여하도록한다. 2회이상용량감량이필요한경우는사례별로적용하기를권고한다. 비혈액학적독성 TKI 투여와관련된비혈액학적독성으로잘알려진것들은오심, 설사, 두통, 발진, 부종, 흉막삼출, 혈당 / 리파아제상승, 간효소치상승, corrected QT interval (QTc) 연장등이있다. 일반적인비혈액학적독성발생시등급 (grade) 2인경우는대중적치료를, 등급 3-4인경우등급 1 이하로호전시까지중단후용량을줄여서재투여하도록한다. 간기능검사이상, 아밀라제 / 리파아제의상승의경우에도동일한방법으로투여한다. 등급 2 이상의 QTc 연장발생시등급 1 이하로호전시까지중단하고칼륨, 마그네슘등의전해질을교정한다. 2주이내에 450 msec 로회복될경우기존용량으로재투여하지만 2주이후에도 msec 일경우용량을줄여서재투여하고, 등급 2 이상의 QTc 연장이재발생될경우투여를영구중단한다. 등급 1의흉막삼출이발생할경우는이뇨제및스테로이드투여등의대중적치료를하면서투여를지속하고, 등급 2 이상일경우는우선약제투여를중단하고이뇨제와스테로이드치료로 7일이내에등급 1 이하로호전시용량을줄여서재투여한다. 만일등급 4의흉막삼출이발생하면투여를영구중단한다. 닐로티닙은혈당 / 리파아제상승, 간효소치상승, 두통, 발진의발생빈도가높은편이며다사티닙은흉막삼출, 감염, 출혈등의빈도가좀더높다. 따라서약제마다복용초기및용량증량초기에특정독성에대한주기적주의관찰을권장하고있다. 닐로티닙은혈당상승에대해공복혈당검사를, 간효소 / 췌장 효소상승에대해 amylase/lipase, 간기능검사를, QTc 연장에대해심전도 (electrocardiography, ECG) 시행을주기적으로할것을권장한다. 그리고말초동맥폐쇄질환 (peripheral arterial obstructive disease, PAOD) 을의심할증상이발생할경우진단적검사로 ankle-brachial index (ABI), doppler ultrasonography, angiography 등의시행을고려해볼수있다. 다사티닙은흉막삼출에대해흉부 X-선촬영, QTc 연장에대해 ECG 시행, 폐동맥고혈압 / 울혈성심부전에대해 ECG, 심초음파등의검사시행을권장한다. 고찰 CML의치료는근간에큰발전이있었으며 2세대 TKI 약제의우월성이여러임상연구에서입증되었다. CML 의 TKI 치료에있어 TKI들의항백혈병효과외에도이들약제의부작용과환자들의삶의질등다른중요한변수들을고려해야한다. 치료반응평가는원칙적으로치료에따른생존율의향상이있는지에중점을두어야하나, 이를위해서는상당히긴관찰기간이필요하므로 CML에서의평가는분자학적반응및세포유전학적반응으로대치하게되었는데 [37] 이들치료반응에대한정의는치료를지속할지여부를결정하는기준으로서중요한가치가있다. 처음진단된 CML 에서일차약제의선택에대해두개의임상시험에서이매티닙과비교하여닐로티닙, 다사티닙의우월성을확인하였으며 [11,38] 최근연구들에서는 3개월째조기분자학적반응정도가예후와유의한연관이있다고보고하였으나 [22] 1회의분자검사만을토대로치료를변경하기보다는추가적인반응평가를통해결정하는것을여러지침에서는권고하고있다. CML 환자의 TKI 제제의선택시치료효과뿐만아니라부작용도중요한사항으로고려되어야한다. 이매티닙의부작용은대부분경미하였고, 생명을위협하는경우는드물었으며비교적안전하게잘견딜수있음에비해 [39] 2세대 TKI 제제들은이매티닙의부작용의빈도는낮으나일부환자에서심각한부작용을초래할수있다. 따라서 CML에서 TKI는장기간사용해야하는약제라는특성과중증이아닌부작용조차도환자들의삶의질및치료순응도에영향을미칠수있다는점을감안해야하며중증의부작용을피하기위해각각의환자들의특성에맞춰약제를선택하려는노력을기울여야한다. 향후 CML의치료적인측면에있어

12 - 김대영외 14 인. 만성골수성백혈병가이드라인 - 서급성기의치료및여러종류의 TKI에대해모두저항성을가지는경우의치료에대해서는새로운치료약제의개발과적절한동종조혈모세포이식의적용등의많은노력을기울여야하며, 한편 TKI 투여후장기간분자학적관해를유지할경우과연 TKI 제제를영구적으로중단할수있는지에대한의문도해결해야할숙제이다 [40]. 이러한문제에도불구하고 TKI의등장에의한 CML 치료의발전은혈액암치료의발전에있어큰이정표라할수있으며궁극적으로완치를기대할수있는획기적인시대를보내고있다고할수있겠다. 요 목적 : 만성골수성백혈병의진단및치료를위한한국치료가이드라인은한국실정에맞춘내용을통해국내치료방침및연구기준을표준화하기위하여제정되었다. 방법 : 국내만성골수성백혈병전문가들을대상으로한설문조사와자문미팅을거쳐본가이드라인을작성하였다. 결과 : 본가이드라인에는만성골수성백혈병의진단및초기검사, 예후인자, 만성기에서의초치료및치료중확인사항과반응평가, 이차약제변경및이후의치료반응평가, 가속기및급성기에서의치료와반응평가, 동종조혈모세포이식, 독성평가및관리등만성골수성백혈병의전반에대한국내전문가들의의견을종합한권고안을제시하고있다. 결론 : 만성골수성백혈병의치료는최근많은발전이있었으며향후예후평가에대한연구및약제의중단가능성평가연구등다양한연구들을통해더욱더많은향상이있을것으로기대된다. 중심단어 : 만성골수성백혈병, 티로신키나제억제제, 진단및치료지침 약 REFERENCES 1. Sohn SK, Jung JS, Jung CW, et al. Korean Guidelines for Treating Chronic Myelogenous Leukemia. 1st ed. Seoul: The Korean Society of Hematology, Kim KH, Kim DY, Kim BS, et al. Korean Guidelines for Treating Chronic Myelogenous Leukemia. 2nd ed. Seoul: Elsevier Korea L.L.C., Kim DW. Recent advances of management for chronic myeloid leukemia. Korean J Med 2012;83: Lee JO, Kim KH, Kim DY, et al. Survey results on current controversial issues and clinical practice in CML through website from Korean CML experts: Korean CML working party. Proceedings of 15th International Conference CML- Biology and Therapy. Estoril: Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984;63: Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90: Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;118: Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Blood 2013;122: Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011;118: Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011;29: Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362: Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355: Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011;12: Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012;119: O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348: Simonsson B, Gedde-Dahl T, Markevärn B, et al. Combina

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