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1 Clinical Pediatric Hematology-Oncology Volume 24 ㆍ Number 2 ㆍ October 2017 ORIGINAL ARTICLE 재발성 / 불응성소아급성림프모구백혈병환자의치료경향및성적에대한다기관후향적관찰연구 유건희 1 ㆍ정낙균 2 ㆍ조빈 2 ㆍ강형진 3 ㆍ신희영 3 ㆍ임호준 4 ㆍ서종진 4 임영탁 5 ㆍ유철주 6 ㆍ김순기 7 ㆍ전인상 8 ㆍ국훈 9 ㆍ구홍회 1 1 성균관대학교의과대학삼성서울병원소아과학교실, 2 가톨릭대학교의과대학서울성모병원소아과학교실, 3 서울대학교의과대학서울대학교어린이병원소아과학교실, 4 울산대학교의과대학서울아산병원어린이병원소아과학교실, 5 부산대학교의과대학양산부산대학교병원소아과학교실, 6 연세대학교의과대학세브란스어린이병원소아과학교실, 7 인하대학교의과대학인하대병원소아과학교실, 8 가천대학교의과대학가천대길병원소아과학교실, 9 전남대학교의과대학화순전남대학교병원소아과학교실 A Multicenter Retrospective Analysis on the Treatment Pattern and Outcome in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia Keon Hee Yoo, M.D. 1, Nak Gyun Chung, M.D. 2, Bin Cho, M.D. 2, Hyoung Jin Kang, M.D. 3, Hee Young Shin, M.D. 3, Ho Joon Im, M.D. 4, Jong Jin Seo, M.D. 4, Young Tak Lim, M.D. 5, Chuhl Joo Lyu, M.D. 6, Soon Ki Kim, M.D. 7, In-Sang Jeon, M.D. 8, Hoon Kook, M.D. 9 and Hong Hoe Koo, M.D. 1 1 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 2 Department of Pediatrics, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, 3 Department of Pediatrics, Seoul National University Children s Hospital, Cancer Research Institute, Seoul National University College of Medicine, 4 Department of Pediatrics, Asan Medical Center Children s Hospital, University of Ulsan College of Medicine, Seoul, 5 Department of Pediatrics, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, 6 Department of Pediatrics, Severance Children s Hospital, Yonsei University College of Medicine, Seoul, 7 Department of Pediatrics, Inha University Hospital, Inha University College of Medicine, 8 Department of Pediatrics, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, 9 Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea Background: Although the overall survival of childhood acute lymphoblastic leukemia (ALL) approaches 85-90%, the prognosis of relapsed or refractory (R/R) ALL is grave. This study aimed to identify the treatment pattern, treatment response, and overall survival of these patients. Methods: We reviewed data of 64 patients with R/R ALL whose initial diagnosis of ALL had been made between 1 and 21 years of age. Patients who received clofarabine as part of an induction regimen were excluded. Relapsed patients were limited to those who relapsed after 2 prior induction regimens. Treatment patterns, response rates, and overall survival were analyzed. Results: Patients median age was 15.0 years (range, ) at the diagnosis of R/R ALL. The most frequently used agents other than steroid were vincristine (54.0%), cytarabine (44.6%), and idarubicin (36.5%), while L-asparaginase was used in only one patient. The complete remission (CR) and overall response (OR) rates were 38.1 and 42.9%, respectively. Sixteen patients (25.4%) underwent allogeneic hematopoietic stem cell transplantation (HSCT). The 5-year overall survival was 6.7%. The survival of patients with HSCT was significantly higher compared with those without HSCT (35.2% vs 0%, P=0.0097). Among 14 patients who achieved CR or CR without platelet recovery (CRp) before HSCT, the 3-year survival was 46.9%. pissn / eissn Clin Pediatr Hematol Oncol 2017;24: Received on September 5, 2017 Revised on September 13, 2017 Accepted on September 25, 2017 Corresponding Author: Hong Hoe Koo Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: Fax: hhkoo@skku.edu ORCID ID: orcid.org/

2 Keon Hee Yoo, et al Conclusion: The survival of Korean patients with R/R childhood ALL was dismal despite a reasonable CR rate, whereas that of those who received HSCT after CR or CRp was excellent. More treatment options are needed to improve the overall outcome of R/R childhood ALL. Key Words: Childhood, Acute lymphoblastic leukemia, Relapsed, Refractory 서론급성림프모구백혈병 (acute lymphoblastic leukemia, ALL) 은소아에서는가장흔한악성질환으로, 국내에서는연간진단되는약 1,500명의소아암환자중약 300여명의 ALL 신환이발생한다 [1]. 소아 ALL은지난수십년간그치료성적이눈부시게향상되어최근서구선진국의보고에의하면전체환자의약 90% 가장기생존한다 [2]. 이러한치료성적의향상에는복합화학요법의발전, 예후인자및치료반응에기반한섬세한치료정책, 향상된지지요법등이기여하였다. 그럼에도불구하고재발성 / 불응성소아 ALL의치료성적은매우제한적이다. 재발성 / 불응성소아 ALL의주치료목적은완전관해를획득하여조혈모세포이식으로이행이가능하게하는데있다. 재발성 / 불응성소아 ALL의치료성적을향상시키기위해흔히동종조혈모세포이식이시행되는데, 성공적인결과를기대하기위해서는이식전완전관해에도달하는것이일차적으로중요하다. 이러한이유로재발성 / 불응성소아 ALL 환자의관해유도를위해서다양한조합의요법들이시도되어왔으나이들의완전관해율은아직약 8-40% 내외의수준에머물고있다 [3-7]. 이러한배경에서재발성 / 불응성소아 ALL의완전관해율을높이고조혈모세포이식으로잘이행될수있도록하는치료전략에대한연구가활발히진행중인가운데, 최근 Liu 등은 clofarabine, etoposide, cyclophosphamide의병합요법을통해 53% 완전관해율을얻었음을보고한바있다 [8]. 그럼에도불구하고현재국내의제반여건및의료보험제도체계하에서는신약또는새로운치료법의사용에상당한제한이있는것이현실이다. 다행히도최근에는재발성 / 불응성소아 ALL을대상으로 clofarabine 기반의항암화학요법에대해한시적으로보험급여가인정되고있는동시에이를통한다기관전향적임상연구가진행중이다. 이러한현실에서재발성 / 불응성소아 ALL에대한과거의치료경향과성적에대한국내자료의확보가필요하며, 이는전향적연구를통해 얻은치료성적과의비교자료로서유용하게활용될수있을것이다. 소아 ALL은성인에비해치료성적이우수하여재발성 / 불응성질환이상대적으로드물어이들의임상양상에대한분석을위해서는다기관연구가바람직하다. 본다기관, 서술적, 비중재적, 후향적관찰연구는기존의 2가지이상치료법에도재발하거나불응하는한국인소아 ALL 환자를대상으로치료경향과성적에대해분석해보고자하는목적으로계획되었다. 대상및방법 1) 대상 2007년 1월부터 2013년 11월사이에 2가지이상의항암화학요법에재발하거나불응하는한국인소아 ALL 환자로서, clofarabine을사용하지않은환자들을분석대상으로하였다. 본후향적연구에대해각참여기관의기관윤리사무국승인을획득하였다. 2) 선정및제외기준연구대상은 (1) French-American-British (FAB) 분류에따라골수에서림프모세포가 25% 이상, (2) 초기진단시연령이만 1-21세, (3) 이전에 2가지이상의항암화학요법에재발성 / 불응성을보이는경우등세가지조건을모두만족하는경우에한해선정하였다. 한편, clofarabine을국내혹은국외등지에서투여받은병력이있는환자는대상에서제외하였다. 3) 자료수집및검증자료는본연구에참여의사를전달한 11개기관으로부터서면자료수집표를사용하여수집하도록하였다. 주요수집자료는최초진단시특성, 선정기준에부합하는재발성 / 불응성 ALL 관련정보, 해당재발성 / 불응성 ALL 관련하여선택한치료, 치료반응, 생존여부등이다. 102 Vol. 24, No. 2, October 2017

3 A Retrospective Analysis of Relapsed/Refractory Childhood ALL 4) 통계분석 기록된자료에대해기술분석을수행하여요약하였고, 기초통계량은연속형변수의경우평균, 표준편차, 중앙값, 범위등을제시하였으며, 범주형변수의경우빈도와백분율을기술하였다. 치료반응은완전관해 (complete remission, CR: 골수의모세포<5%), 혈소판수를제외한완전관해 (CRp), 부분관해 (partial remission, PR: 골수의모세포 5-25%), 불응 (refractory: 골수의모세포>25%) 등으로구분하였다. 완전관해율은 CR에도달한환자수를전체대상환자수로나눈값의백분율로, 전체반응율은 CR, CRp, 또는 PR에도달한환자수를전체대상환자수로나눈값의백분율로기술하였다. 전체생존기간은재발성 / 불응성 ALL 진단일부터사망일 ( 원인에무관 ) 까지의기간으로정의하였고, 사망이확인되지않은환자는생존한것으로알려진마지막날짜에서중도절단되었다 Table 1. Patient characteristics Characteristics Number of patients (%), total N=64 Age (y) Mean±SD 14.3±4.5 Median (range) 15.0 ( ) Sex Male 39 (60.9) Female 25 (39.1) Height (N=63) Mean±SD 143.8±23.2 Median (range) ( ) Body weight (N=63) Mean±SD 41.1±18.5 Median (range) 39.0 ( ) Initial cytogenetics Diploid 5 (7.8) Hypodiploid 2 (3.1) Hyerdiploid 6 (9.4) t(1;19) 2 (3.1) t(9;22) 3 (4.7) Others 26 (40.6) NA 20 (31.3) Imunophenotype B 48 (75.0) T 11 (17.2) Mixed 4 (6.3) NA 1 (1.6) Disease status Refractory 13 (20.3) Relapsed 51 (79.7) NA, not available. (cencored). 생존율계산에는카플란-마이어추정값 (Kaplan- Meier estimates) 을이용하였고, 생존율의비교는로그순위법 (log-rank test) 으로검증하였다. 참여의사를보인 11개기관중 9개병원에서환자를등록하였고, 총 70명환자의의무기록을검토하여선정및제외기준에부합되는 64명의환자를분석하였다. 이중 1명은재발진단이후치료및추적자료가없어치료, 반응, 생존율분석에는 63명만이포함되었다. 1) 환자의특성 (Table 1) Table 2. Chemotherapeutic agents other than steroid used at the 1 st cycle for R/R ALL Agents 결 환자의중앙연령은 15.0세, 평균연령은 14.3±4.5세였으며남녀의비는 1.56:1이었다. 최초진단시다양한세포유전학적소견을보였으며, 면역표현형은 B세포계열이전체의 75% 를차지하였다. 재발성질환으로등록된경우가 51례로전체의 79.7% 를차지하여불응성질환 (13례, 20.3%) 에비해 4배가많았다. 2) 치료경향및치료반응 대상환자에대한치료방법은기관별로다양하였고, 재발성 / 불응성상태에서항암화학요법치료가시도된 63명에게첫주기에스테로이드를제외하고다빈도로사용된약제들은 vincristine (54.0%), cytarabine (44.6%), idarubicin (36.5%) 순이었다 (Table 2). L-asparaginase는단 1례에서만사용되었 Number of patients (%), total N=63 Vincristine 34 (54.0) Cytarabine 28 (44.6) Idarubicin 23 (36.5) Methotrexate 19 (30.2) Etoposide 5 (7.9) Cyclophosphamide 4 (6.4) Daunomycin 2 (3.2) Fludarabine 2 (3.2) Nelarabine 2 (3.2) Dasatinib 2 (3.2) Doxorubicin 1 (1.6) Ifosfamide 1 (1.6) L-asparaginae 1 (1.6) Mercaptopurine 1 (1.6) Rituximab 1 (1.6) R/R ALL, relapsed/refractory acute lymphoblastic leukemia. 과 Clin Pediatr Hematol Oncol 103

4 Keon Hee Yoo, et al 다. 치료를시행받은 63례중골수검사를통해반응을확인한경우는 45례로전체의 71.4% 이었고, CR, CRp, PR, 불응성이각각 14례 (22.2%), 10례 (15.9%), 3례 (4.8%), 16례 (25.4%) 였다. 골수검사미시행사유로는질병의지속 12례, 관해유도요법중사망 5례 (1례는질병의지속과중복보고됨 ), 기타 2례등이었다. 따라서, 전체반응율은 42.9%, 완전관해율은 38.1% 로확인되었다. 치료가이루어진 63명의환자중조혈모세포이식을시행받은환자는 16명 (25.4%) 이었다. 이들 16 명중 15명에서조혈모세포이식전골수검사가시행되었는데, 1명을제외한 14명에서 CR 또는 CRp에도달하였다. 조혈모세포이식을시행받지않은 47명에서미시행사유로는불응성또는질병의진행이 36명 (76.6%) 으로대부분을차지하였다. 기타사유로는완전관해의유지, 낮은수행평가점수, 공여자부재, 추적불가등이있었다. 3) 생존율치료를시행받은 63명의 1년, 2년, 3년, 5년생존율은각각 53.7%, 26.5%, 13.2%, 6.7% 이었다 (Fig. 1A). 조혈모세포이식을시행받은환자 16명의생존율은미시행환자 47명에비해유의하게높았다 (35.2% vs 0%, P=0.0097; Fig. 1B). CR 또는 CRp에도달한후조혈모세포이식을받은 14명의경우이식후 3년생존율은 46.9% 이었다 (Fig. 1C). 조혈모세포이식후생존중인 8명은모두이식전골수검사에서 CR 또는 CRp에도달했던경우들이었다. 고찰재발성 / 불응성 ALL은성인과소아를불문하고매우나쁜 예후를보이는것으로알려져있다. 특히소아의경우지난수십년간의노력에힘입어새로이진단받은 ALL의장기생존율이 85-90% 에육박하고있는점을감안할때재발성 / 불응성 ALL의효과적인치료법의마련은중요한이슈이다. 재발성 / 불응성 ALL에서재발은 2가지이상의항암화학요법에도불구하고질병이조절되지않은경우로국한되어정의되었으며, 본연구에서도같은기준을사용하였다. 국내에서는일찍이 1997년에단일기관의보고로서재발성 / 불응성소아 ALL 환자에서 ifosfamide와 etoposide를이용한재관해요법의효과에대해보고된바가있다 [3]. 20명의재발성 / 불응성환자중 6명 (30%) 이완전관해에도달하였고, 이중 2례에서주조직적합성항원 (human leukocyte antigen, HLA) 이일치하는혈연을통해동종골수이식을시행받을수있었다. 좀더최근에보고된국내연구중에는재발한소아 ALL 환자를대상으로 prednisolone, vincristine, L-asparaginase 등기본 3제요법에 idarubicin을추가하여완전관해율 57% 를얻을수있었다는보고가있다 [9]. 그러나, 이들환자군이얼마나자주재발하였는지에대한구체적언급이없고, 논문의문맥상 1차재발환자들이대부분을차지하는것으로보여, 2차이상의재발군을대상으로한본연구및다른연구결과들과의직접비교는어려울것으로보인다. 본연구는재발성 / 불응성소아 ALL을대상으로다기관후향적연구로서국내에서최초로이루어진연구라는점에서그의미가크다고하겠다. 본연구에서완전관해율은 38.1% 로기존에해외에서보고되어온결과들과유사하였다. 특히눈여겨볼점은대상환자들중조혈모세포이식을시행받지않은경우생존율이 0% 이었던것에비해시행군의경우 35.2% 의장기생존율을보여그차이가명확하였다 (Fig. 1B). Fig. 1. The Kaplan-Meier estimates of overall survival rate (OS). (A) The 5-y OS of all 63 patients with relapsed/refractory (R/R) childhood acute lymphoblastic leukemia (ALL) was 6.7%. (B) The OS was higher in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) compared with those who did not (35.2% vs 0%, P=0.0097). (C) The 3-y OS reached 46.9% among patients who achieved complete remission (CR) or CR without platelet recovery (CRp). 104 Vol. 24, No. 2, October 2017

5 A Retrospective Analysis of Relapsed/Refractory Childhood ALL 조혈모세포이식을시행하지못한이유로대부분 (76.6%) 에서항암화학요법에의한반응이불충분하였기때문이었던점, 반대로조혈모세포이식후생존한환자의경우모두항암화학요법을통해 CR 또는 CRp에도달했던점을감안할때, 재발성 / 불응성소아 ALL에서효과적인항암화학요법의적용및적극적동종조혈모세포이식시행이이들의생존율향상에가장중요한현실적전략임을알수있다. 본연구에서관찰한것처럼전체환자의 5년이상생존율은 6.7% 로극히저조하여향후재발성 / 불응성소아 ALL의치료성적을향상시키기위한치료전략의모색이필요하다. 본연구는국내현실을재고하고향후치료전략을수립하는데참고하기위한중요한자료로활용가능할것으로사료된다. 최근에는동종조혈모세포이식기법이눈부시게발전하여 HLA가일치하는혈연이없더라도 HLA 일치비혈연, 제대혈, HLA 불일치혈연등다양한공여자활용이가능하고, 이러한대체공여자를통한이식이 HLA 일치혈연이식과비교해도대등한수준의치료성적이보고되고있다 [10,11]. 국내에서도최근조혈모세포이식에대한의료보험급여범위가확대되고있는추세이기때문에과거에비해공여자확보의문제점이치료의방해요소가될가능성이그만큼낮아진셈이다. 이러한현실을감안할때, 재발성 / 불응성 ALL에대한항암화학요법이갖는의미는더욱크다고할수있겠다. Inagaki 등의연구에의하면재발한소아 ALL에서조혈모세포이식전 CR 획득의실패는이식후높은재발을예측하는유일한위험인자로작용하였다 [12]. 따라서, 이식전효율적인항암화학요법을통해질병의짐 (leukemic load) 을최소화하는것이동종조혈모세포이식후생존율향상에가장중요한요소로작용한다고볼수있다. 기존의세포독성치료제 (cytotoxic agents) 외에, 아주최근에는 CD19 양성 B세포를타겟으로 bispecific T세포 engager 항체인 blinatumomab을이용하여재발성 / 불응성소아 ALL을대상으로한최초의 1/2상임상시험결과가발표되었다 [13]. 주목할부분은완전관해율은 39% 로기존의보고와비슷하지만 CR을획득한환자중 52% 가미세잔존암 (minimal residual disease, MRD) 이음성이었다는점이다. 이렇게암세포의잔존수준을최소화한후조혈모세포이식을시행하는전략이향후환자들의생존율향상으로이어질지주목해야할필요가있다. 그러나, 국내의여건을감안할때국내소아환자를대상으로 blinatumomab 치료를적용하기까지는상당한시간이소요될수도있다. 이는현재국내에서재발성 / 불응성소아 ALL에대해한시적보험급여인정을받고있는 clofarabine을주목할필요가있는이유이기도하다. Clofarabine은 2세대 purine nucleoside analog로서이의 삼인산대사체 (triphosphate metabolite) 의세포내축적에의해세포독성을발휘한다 [14]. 림프구는 deoxycytidine kinase 는풍부하면서 5 -deoxynucleosidease는부족하므로 clofarabine에특히약한것으로알려져있다. 이미 2004년에미국 FDA에서는 2가지요법에실패한재발성 / 불응성소아 ALL에서 clofarabine의사용을승인한바있다. Clofarabine을근간으로하는요법은현재재발성 / 불응성소아 ALL에서가장많이사용되는방법이기도하며, 완전관해율은대체로 30-50% 내외로보고되고있다 [4,6,7,15-17]. 최근캐나다의한그룹에서는고위험재발성 / 불응성소아 ALL 치료에 nelarabine이나 clofarabine 근간의항암화학요법을도입한후조혈모세포이식을진행하는전략으로이들의 5년생존율을 56% 까지끌어올렸음을보고하였다 [18]. 본연구결과를통해주의깊게고찰하여야할점은완전관해율은 38.1% 로기존의보고와큰차이가없는반면, 5년생존율은 6.7% 로기존에재발성 / 불응성소아 ALL의생존율로평균적으로보고되고있는 20-40% 에비해현저하게낮다는점이다 [6,7,12,16,17,19]. 한편, CR 또는 CRp에도달후이식을받은환자의경우 46.9% 의생존율을보인점은매우고무적인결과라고하겠다. 재발성 / 불응성소아 ALL에서가능한모든방법을동원하여 CR을유도하여시의적절하게조혈모세포이식으로이어지도록하는전략이매우중요한이유이다. 이식전더욱낮은미세잔존암수준까지치료반응을유도할수있다면더욱치료성적이향상될수있을것이다. 치료후암의수준이예후와매우밀접한상관관계가있다는것은명확히알려진사실이다. 국내에서는아직미세잔존암측정방법의표준화가이루어지지못하고있으나, 최근여러전문가들을중심으로활발한논의가이루어지고있어머지않아국내소아 ALL을대상으로미세잔존암측정결과를바탕으로한세부치료전략구축이가능해질것으로기대한다. 또한, 국내에서재발성 / 불응성소아 ALL 환자를대상으로한 clofarabine 근간의항암화학요법의효과에대한다기관전향적연구의결과가발표될예정이어서, 국내환자들을대상으로최신요법을지속적으로활용할수있는기회가주어질지주목된다. 본연구를통해국내최초로재발성 / 불응성소아 ALL의치료경향과성적을분석해보았다. 수집표를이용한후향적연구라는한계로결론을내리기는어렵지만, 국내치료결과가선진국의수준에미치지못하고있음을확인할수있었다. 소아암중가장흔한소아 ALL의전반적치료성적을향상시키기위한다기관연구의활성화및이에대한국가적배려와지원이절실한현실이다. Clin Pediatr Hematol Oncol 105

6 Keon Hee Yoo, et al 감사의글 This study was funded by Sanofi. References 1. Kim H. Recent advances in the treatment of pediatric acute leukemia. J Korean Med Assoc 2016;59: Pui CH. Recent research advances in childhood acute lymphoblastic leukemia. J Formos Med Assoc 2010;109: Kim SS, Cho B, Jeong DC, Kim HK. Ifosfamide and etoposide in relapsed refractory childhood acute lymphoblastic leukemia. Korean J Pediatr Hematol Oncol 1997;4: Bernstein ML, Abshire TC, Pollock BH, et al. Idarubicin and cytosine arabinoside reinduction therapy for children with multiple recurrent or refractory acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 1997;19: Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006;24: Angiolillo AL, Yu AL, Reaman G, Ingle AM, Secola R, Adamson PC. A phase II study of Campath-1H in children with relapsed or refractory acute lymphoblastic leukemia: a Children's Oncology Group report. Pediatr Blood Cancer 2009;53: Ko RH, Ji L, Barnette P, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol 2010;28: Liu AP, Lee V, Li CK, Ha SY, Chiang AK. Refractory acute lymphoblastic leukemia in Chinese children: bridging to stem cell transplantation with clofarabine, cyclophosphamide and etoposide. Ann Hematol 2016;95: Yoon JH, Park JA, Kim EK, Kang HJ, Shin HY, Ahn HS. Improvement of induction remission rate by modifying the dose of idarubicin for relapsed childhood acute lymphoblastic leukemia. J Korean Med Sci 2009;24: Sakaguchi H, Watanabe N, Matsumoto K, et al. Comparison of donor sources in hematopoietic stem cell transplantation for childhood acute leukemia: A Nationwide Retrospective Study. Biol Blood Marrow Transplant 2016;22: Atta EH, de Oliveira DC, Bouzas LF, Nucci M, Abdelhay E. Less graft-versus-host disease after rabbit antithymocyte globulin conditioning in unrelated bone marrow transplantation for leukemia and myelodysplasia: comparison with matched related bone marrow transplantation. PLoS One 2014;9:e Inagaki J, Fukano R, Noguchi M, Kurauchi K, Tanioka S, Okamura J. Hematopoietic stem cell transplantation following unsuccessful salvage treatment for relapsed acute lymphoblastic leukemia in children. Pediatr Blood Cancer 2015;62: von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol 2016;34: Hijiya N, Barry E, Arceci RJ. Clofarabine in pediatric acute leukemia: current findings and issues. Pediatr Blood Cancer 2012;59: Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood 2011;118: Trioche P, Nelken B, Michel G, et al. French "real life" experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia. Exp Hematol Oncol 2012;1: Lu A, Fang Y, Du X, et al. Efficacy, safety and pharmacokinetics of clofarabine in Chinese pediatric patients with refractory or relapsed acute lymphoblastic leukemia: a phase II, multi-center study. Blood Cancer J 2016;6:e Ceppi F, Duval M, Leclerc JM, et al. Improvement of the outcome of relapsed or refractory acute lymphoblastic leukemia in children using a risk-based treatment strategy. PLoS One 2016;11:e Einsiedel HG, von Stackelberg A, Hartmann R, et al. Longterm outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87. J Clin Oncol 2005;23: Vol. 24, No. 2, October 2017

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy