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1 Clinical Pediatric Hematology-Oncology Volume 23 ㆍ Number 2 ㆍ October 2016 ORIGINAL ARTICLE 소아급성골수성백혈병에서공여자유형에따른조혈모세포이식결과 최하영ㆍ김건ㆍ이우진ㆍ최준식ㆍ백희조ㆍ국훈 전남대학교의과대학화순전남대학교병원소아과학교실 Outcomes of Hematopoietic Stem Cell Transplantation by Donor Types in Children with Acute Myeloid Leukemia Ha Yeong Choe, M.D., Gun Kim, M.D., Woo Jin Lee, M.D., Joon Sik Choi, M.D., Hee Jo Baek, M.D. and Hoon Kook, M.D. Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea Background: The aim of this study was to compare the outcomes of children with acute myeloid leukemia (AML) who received stem cell transplantation from different donor groups. Methods: This study included 37 pediatric AML patients who received allogeneic stem cell transplantation from March 1996 to December 2012 at Chonnam National University Hospital and Chonnam National University Hwasun Hospital. The overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of graft versus host disease (GvHD), relapse and transplant-related mortality (TRM) were compared between different donor groups. Results: Transplant donor groups included matched sibling donor (MSD, n=15), unrelated donor (URD=13), unrelated umbilical cord blood (UCB, n=7), or haploidentical donor (HD, n=2). Twenty-six patients survived with a median follow-up of 7.3 years. The 7-year EFS rates were 80.0±10.3% in MSD, 69.2±12.8% in URD and 57.1±18.7% in UCB, and 0% in HD, respectively (P=0.019). The CI of relapse at 5 years was 20.0%, 15.4%, 33.3%, 50%, respectively (P=0.721). The CI of TRM at 2 years was 0%, 15.4%, 16.7%, 50.0%, respectively in each donor group (P=0.017). The CI of grade II-IV acute and extensive chronic GvHD were higher in UCB (P=0.003, P=0.020, respectively). There were no significant differences in OS, EFS, and CI of TRM and relapse between allele-mismatched URD and UCB. Conclusion: Despite the limitation of small number of patients, the comparable outcome of pediatric AML patients transplanted from alternative donor with those transplanted from MSD are encouraging. Especially, if a matched donor is not available, allele-mismatched URD or UCB transplant may offer the advantage of prompt availability for patients who urgently require transplantation. Key Words: Acute myeloid leukemia, Stem cell transplantation, Children pissn / eissn Clin Pediatr Hematol Oncol 2016;23: Received on September 13, 2016 Revised on September 24, 2016 Accepted on October 10, 2016 Corresponding Author: Hee Jo Baek Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun 58128, Korea Tel: Fax: pe00069@jnu.ac.kr ORCID ID: orcid.org/

2 Ha Yeong Choe, et al 서론급성골수성백혈병은소아청소년에서급성림프구성백혈병다음으로흔한백혈병으로전체소아백혈병의 15-20% 를차지한다 [1,2]. 세포유전학및분자유전학적소견으로분류된위험군에따른개별화된치료, 항암화학요법의강화, 지지요법및조혈모세포이식술의발전으로최근소아급성골수성백혈병의장기생존율은 65-70% 에이른다 [3-6]. 소아급성골수성백혈병의위험군분류는여러연구그룹별로다양하다 [7-10]. 하지만, t(8;21), inv(16) 또는 t(15;17) 와같은양호한예후를보이는세포유전학적소견을갖는경우는저위험군에속하고, monosomy 5, monosomy 7, 5q-, 또는첫번째항암화학요법후골수의모세포비율이 15% 이상인경우는고위험군에해당한다는데에는대체로의견이일치하는것같다 [3,7-9]. 또한, 대부분의연구에서 t(8;21), inv(16) 또는 t(15;17) 와같은세포유전학적예후양호군이면서관해유도치료에반응이좋은경우와 Down 증후군에발생한급성골수성백혈병의경우에는조혈모세포이식의장기합병증을막기위해항암화학요법만으로치료를하고있다 [11]. 하지만, 중간위험군과고위험군의경우에는관해후치료방침에대해서는아직까지논란의여지가남아있다. 동종조혈모세포이식은소아급성골수성백혈병의공고요법으로가장좋은치료법이지만, 항암화학요법을단독으로시행했을때와비교하여비교적높은치료-관련사망률및후기합병증이보고되고있다 [11]. 조직적합성항원-일치형제간이식은고위험군백혈병에서효과적인것으로입증되었으나, 조직적합성항원이일치하는형제공여자를찾을수있는확률은약 30% 정도밖에되지않는다. 따라서, 최근에는조직적합성항원-일치또는 -불일치비혈연이식, 반일치이식및제대혈이식등대체공여자를이용한조혈모세포이식이점차증가하고있고, 치료성적역시향상되고있는추세이다 [12,13]. 비혈연이식은재발하였을때공여자로부터추가로조혈모세포를얻을수있는장점이있는반면, 조직적합성항원을검사하고이식을시행할때까지수개월의시간이필요하다는단점이있다. 반면, 제대혈이식은조직적합성항원검사가미리이루어져있으므로일치여부를신속하게판단하여조기에이식을시행할수있지만, 재발혹은이식실패가있는경우추가로세포를얻기힘든제한점이있다 [14,15]. 본연구에서는단일기관에서진단되어관해후치료로동종조혈모세포이식을시행받은소아급성골수성백혈병환자의생존율과이에영향을미치는인자를알아보고, 조혈모세 포공여자유형군에따른생존율, 이식편대숙주병의누적발생률, 누적재발률및이식-관련누적사망률의차이를비교해보고자한다. 대상및방법 1) 대상 1996년 3월부터 2012년 12월까지전남대학교병원및화순전남대학교병원소아청소년과에서급성골수성백혈병으로진단되고동종조혈모세포이식을시행한환자를조사하였다. 이중 Down 증후군, Fanconi 빈혈과같은유전질환이동반된경우, 골수형성이상증후군에서진행한경우, 이차급성골수성백혈병, 그리고 M3를제외한 37명의환자를대상으로의무기록을후향적으로분석하였다. 2) 진단및정의급성골수성백혈병의진단은골수도말검사에서비정상모세포가전체유핵세포의 20% 이상인경우로하였다. 면역표현형검사 (immunophenotype) 와핵형분석 (cytogenetics) 및형광제자리부합법 (fluorescent in situ hybridization, FISH) 을시행하였다. 또한, 2002년부터 2006년까지는 4종의유전자재배열검사를중합효소연쇄반응 (polymerase chain reaction, PCR) 으로, 2007년이후에는다중역전사중합효소연쇄반응 (multiplex reverse transcription-pcr) (HemaVision, DNA-Diagnostic, Risskov, Denmark) 을이용하여 28종의유전자재배열을검사하였다. 2010년 8월부터 fms-like tyrosine kinase receptor 3 internal tandem duplication (FLT3-ITD) 검사를시행하였다. 재발은골수내에 5% 이상의비정상모세포가발견되거나혹은골수외장소에서백혈병세포가발견되는것으로정의하였다. 생착실패는골수또는말초혈조혈모세포이식의경우에는이식후 28일, 제대혈이식의경우에는이식후 35일째까지말초혈액내백혈구가 /L 미만인것으로정의하였다 [16]. 중성구생착은절대중성구수가 3일연속 /L 이상인첫째날로정의하였고, 혈소판생착은수혈없이혈소판수가 7일연속 /L 이상인첫째날로정의하였다. 급성이식편대숙주병은 Glucksberg 등이정의한것에따라 [17], 만성이식편대숙주병은 Shulman 등에따라진단하고등급을나누었다 [18]. 세포유전학적소견에따라예후군을나누었다. 양호군은 inv(16), t(16;16), t(8;21) 을가지고있는경우로, 불량군은 7-/7q-, 5-/-5q 및복합핵형이상 ( 3개), t(8;16), t(6;9), t(16;21), FLT3-ITD가있는경우로, 중간군은정상핵형이거나 146 Vol. 23, No. 2, October 2016

3 Outcomes of HSCT by Donor Types in Children with AML 다른이상을가지고있는경우로하였다. 또한, 다른예후불량인자가없으면서 FLT3-ITD검사가시행되지않은경우는 NA군 (not applicable FLT3-ITD) 으로분류하였다 [7-9]. 3) 이식전치료와이식전처치관해유도요법으로 N 4 -behenoyl-1- -D-arabinofuranosylcytosine 300 mg/m 2 을 7일간, idarubicin 12 mg/m 2 을 3일간정주하였고, 관해후공고요법은이전발표에기술한방법 [19-21] 으로시행하였다. 관해가되면조직적합항원검사를시행하여일치하는형제가있으면형제간동종조혈모세포이식을시행하였고, 없으면타인, 제대혈, 또는반일치조혈모세포이식을시행하였다. 골수파괴형 (myeloablative) 전처치를시행한환자는총 28 명 (75.7%) 이었다. 20명은 busulfan을기본으로한전처치로 Bu-Cy (busulfan 1.0 mg po or 0.8 mg/kg/dose IV q 6 hr on D-7 D-4; cyclophosphamide 60 mg/kg/day on D-3, D-2) 를시행받았고, 이중반일치이식을시행한 2명은 Ara- C-BuCy-CCNU (cytarabine (Ara-C) 2.0 g/m 2 /dose q 12 hr on D-10 D-9; busulfan 0.8 mg/kg/dose IV q 6 hr on D-8 D-6; cyclophosphamide 1.8 g/m 2 /day on D-5, D-4; CCNU 250 mg/m 2 /day on D-3) 를시행받았다. 두명모두 rabbit anti-thymocyte globulin (ATG, 2.5 mg/kg/day on D-5 D-2) 가투여되었다. 진단시녹색종이있었던 4명의환자를포함한 8명에서전신방사선을포함한전처치를시행하였다. 2003년 5월이전에이식을시행한 3명은 Cy-Ara-C-TBI (cyclophosphamide 45 mg/kg/day on D-5, D-4; cytarabine 3.0 g/m 2 /dose q 12 hr on D-6 D-4; total body irradiation 200 cgy q 12 hr on D-3 D-1) 로, 이후에이식을시행한 5명은 Cy-TBI (cyclophosphamide 60 mg/kg/day on D-3, D-2; total body irradiation 200 cgy q 12 hr on D-7 D-5) 로전처치를하였다. 독성감소골수파괴형 (reduced-intensity myeloablative) 전처치는 2002년이후에시행되었으며, 9명에서 Flu-Bu (fludarabine 40 mg/m 2 /day on D-8 D-4; busulfan 0.8 mg/kg/dose IV q 6 hr on D-6 D-3) 를사용하였다. 이중 6명은 anti-lymphocyte globulin (ALG, 10 mg/kg/day on D-4 D-1) 또는 rabbit ATG (2.5 mg/kg/day on D-4 D-1) 가투여되었다. 4) 이식편대숙주병예방초창기조직적합성항원-일치형제간이식에 cyclosporine (CSA) 단독요법을사용한후 2004년까지는동종조혈모세포이식에서혈연과비혈연간에관계없이 CSA와단기간 methotrexate (MTX) 를병합하여사용하였고, 제대혈이식의경우 CSA 단독요법을사용하였다. 2005년부터는비혈연이식에서 tacrolimus와단기간 MTX병합요법을, 제대혈이식에서는 tacrolimus 단독또는 mycophenolate mofetil (MMF) 과병합하여사용하였다. 반일치이식은 CSA, tacrolimus 및 MMF를병합하여사용하였다. CSA은조혈모세포주입하루전에 5 mg/kg/day 로시작하여당일부터 1.5 mg/kg/dose를하루두번정맥주사하여혈중농도가 g/ml를유지하도록용량을조절하였다. Tacrolimus는조혈모세포주입하루전부터 0.03 mg/kg/day을연속주입하여혈중농도가 5-15 g/ml를유지하도록용량을조절하였다. 두약모두경구섭취가가능해지면경구용제제로바꾸어분복하도록하였다. MTX는이식 1일째에 15 mg/m 2 /day를, 3, 6, 11일째에 10 mg/m 2 /day를각각투여하였다. 5) 보존적치료환자들은조혈모세포이식 9일전에공기여과시설이갖춰진무균병실에입실하여엄격하게격리된상태에서치료를진행하였다. 모든환자는중심정맥도관을삽입하였고, 예방적 acyclovir와 trimethoprim-sulfamethoxazole 또는 pentamidine 흡입을시행하였다. 곰팡이감염의예방을위해 2011년이전에는경구 fluconazole을, 이후에는 micafungin을전처치시작일부터생착될때까지투여하였다. 발열 ( 38 o C) 이발생한경우에는광범위항생제로 ceftriaxone와 aminoglycoside 병합용법또는 cefepime를투여하였다. 간정맥폐쇄질환의예방을위해경구 ursodeoxycholic acid를복용하였고, 비혈연이식에서는 2005년부터 liposomal prostaglandin E1 (1 g/kg/day) 를, 2012년부터는간정맥폐쇄질환의고위험군에서 defibrotide (10 mg/kg/day) 를전처치시작부터이식후 21일까지투여하였다. 골수기능의회복을촉진시키기위하여 G-CSF를 5 g/kg/day로이식당일부터절대중성구수치가 3일연속 /L 이상될때까지투여하였고, 면역글로불린은이식후 100일째까지는격주로이후 6개월또는 9개월까지매달주입하였다. 영양섭취를위해이식다음날부터경구영양이가능할때까지총정맥영양을시행하였다. 6) 통계분석무병생존율 (event free survival, EFS) 은진단시부터재발혹은사망이없는시기까지로정의하였고, 전체생존율 (overall survival, OS) 의기간은진단시기부터마지막추적관찰까지혹은원인을불문한사망까지로정의하였다. 이식-관련사망률 (transplant-related mortality, TRM) 은재발또는질환의진 Clin Pediatr Hematol Oncol 147

4 Ha Yeong Choe, et al 행과관계없는사망으로정의하였다. 생착및이식편대숙주병의군간의차이에대해서는 Chi-square test, Kruskal-Wallis test 또는 ANOVA를이용하였다. 생존율및이식편대숙주병유무에따른재발률은 Kaplan- Meier 방법을이용하였고, 군간의차이는 log-rank 법을이용하여검정하였다. 재발, 이식편대숙주병, 이식-관련사망률과같은경쟁사건 (competing event) 의누적발생률은 Gray s test 로검정하였다. 통계분석은 SPSS 21.0 (SPSS Inc, Chicago, IL, USA) 와 EZR 1.31 [22] 을사용하였고, 검정의유의수준은 P<0.05로하였으며, 연구에등록된환자들을 2015년 8월까지추적관찰하여평가하였다. 본연구는화순전남대학교병원생명의학연구윤리심의위원회의승인 (CNUHH ) 을받았다. 결과 1) 환자의특징총 37명환자의특징은 Table 1에제시하였다. 남자가 17명 (45.9%), 여자는 20명 (54.0%) 이었고, 진단시중앙연령은 9.8 세 ( 범위, ), 이식시중앙연령은 10.5세 ( 범위, ) 이었다. French-American-British 분류로는 M2가 17명 (46.0%) 로가장많았다. 이식시첫번째관해상태 (1st complete remission, CR1) 인군이 30명 (81.0%) 으로가장많았고, CR2는 6명 (16.2%), CR3는 1명 (2.7%) 이었다. 세포유전학적예후양호군 7명 (19.0%), 중간군은 3명 (8.1%), 불량군은 3명 (8.1%), NA 군은 24명 (64.8%) 이었다. 양호군에서 CR1에이식을시행한경우는 5명이었다. 이중 1명은관해실패로, 2명은각각진단시안면마비를동반한중추신경계침범과녹색종으로, 나머지 2명은각각관해지연 (6주) 과 8/8 allele-일치비혈연공여자및혈연공여자존재로 CR1에이식을시행하였다. 불량군중 1명은 CR1에이식을거부하여 CR2에이식을시행하였다. 공여자는조직적합성항원-일치형제가 15명 (40.5%) 으로가장많았으며, 비혈연공여자 (allele-일치, 4명 ; 6/6 antigen-일치, 4명 ; allele-불일치 ; 5명 ) 는 13명 (35.1%), 제대혈 ( 이단위제대혈 4명포함 ) 은 7명 (18.9%), 반일치혈연공여자 ( 어머니, 아버지각각 1명 ) 는 2명 (5.4%) 이었다. 형제간공여자중 1명은쌍둥이형이었다. 조혈모세포공급원은골수가 22명 (59.5%), 말초혈액과제대혈이각각 8명 (21.6%), 7명 (18.9%) 이였으며, 진단시녹색종이있던군은 4명 (10.8%) 이었다. 대부분 (75.7%) 골수파괴형전처치를시행받았고, 9명 (24.3%) 가 Flu-Bu를사용한독성감 소골수파괴형전처치를시행받았다. 이식편대숙주병예방요법으로는 CSA와 MTX병합군이 15 명 (40.5%) 으로가장많았고, 다음은 tacrolimus와 MTX병합군 (8명, 21.7%) 으로모두비혈연이식에해당하였으며. 각각 2명에서 ATG를병합사용하였다. CSA 단독사용군은총 6명 (16.2%) 으로이중형제간이식 4명, 제대혈이식 2명이었고, 1 명이 ATG를병합사용하였다. Tacrolimus 단독사용군은 3명 (8.1%) 은모두제대혈이식에해당하였고, 2명에서 ATG를병합사용하였다. 나머지제대혈이식군중 2명은 tacrolimus와 MMF를병합투여하였고, 반일치이식군은네가지약제 (CSA, MTX, MMF and ATG) 를사용하였다. 2) 생착반일치이식후 3일째 Pseudomonas 패혈증으로사망한 1 명을제외한 36명에서생착이확인되었다. 중성구생착까지시간의중앙값은형제간이식군, 비혈연이식군, 제대혈이식군에서각각 15일, 15일, 19일이었고 (P=0.267), 혈소판생착까지시간의중앙값은각각 21일, 17일, 42일이었다 (P=0.002). 중성구가 1,000/mm 3 까지회복되기까지시간은제대혈이식군에서형제간이식군과비혈연이식군보다통계적으로의미있게길었다 (P=0.025). 또한, 혈소판생착까지의시간도제대혈이식군에서형제간이식군과비혈연이식군보다통계적으로의미있게길었다 (P=0.001). 하지만, 비혈연이식군은형제간이식군과중성구와혈소판생착까지시간에는차이를보이지않았다 (Table 2). 3) 전체생존율과무병생존율전체 38명환자의이식후 7년-전체생존율은 70.3±7.5% 이었고, 7년-무병생존율은 67.6±7.7% 이었다 (Fig. 1A, B). 공여자군에따른 7년-전체생존율은형제간이식군은 86.7±8.8%, 비혈연이식군은 69.2±12.8%, 제대혈이식군은 57.1±18.7%, 반일치이식군 0% 로통계적으로유의한차이를보였다 (P= 0.007). 공여자군별 7년-무병생존율도형제간이식군은 80.0± 10.3%, 비혈연이식군은 69.2±12.8%, 제대혈이식군은 57.1± 18.7%, 반일치이식군 0% 로통계적으로유의한차이를보였다 (P=0.019) (Fig. 1C). 하지만, 비혈연이식군과제대혈이식군간의 7년-전체생존율 (P=0.424) 및무병생존율 (P=0.454) 의차이는통계적으로의미있지않았다. 또한, 비혈연이식군중 8/8 allele-일치군 (4명) 의 7년-무병생존율은 75.0±21.7% 로비일치군 (5명) 을 60.0±21.9% 과유의한차이를보이지는않았다 (P=0.549). 진단시녹색종이있는군의무병생존율은없는군에비해 148 Vol. 23, No. 2, October 2016

5 Outcomes of HSCT by Donor Types in Children with AML Table 1. Clinical characteristics of patients Characteristics MSD URD UCB HD Total Number of patients Year of transplant Prior to (46.7) 3 (23.0) 0 (0) 0 (0) 10 (27.0) After (53.3) 10 (77.0) 7 (100.0) 2 (100.0) 27 (73.0) Sex (male : female) 6:9 8:5 1:6 2:0 17:20 Median age at diagnosis (years) ( ) Median age at transplant (years) ( ) French-American-British classification M0 0 (0) 1 (7.7) 0 (0) 0 (0) 1 (2.7) M1 1 (6.7) 0 (0) 0 (0) 0 (0) 1 (2.7) M2 3 (20.0) 7 (53.8) 6 (85.7) 1 (50.0) 17 (46.0) M4 6 (40.0) 2 (15.4) 0 (0) 0 (0) 8 (21.6) M5 2 (13.3) 1 (7.7) 1 (14.3) 0 (0) 4 (10.8) M6 0 (0) 1 (7.7) 0 (0) 1 (50.0) 2 (5.4) M7 2 (13.3) 1 (7.7) 0 (0) 0 (0) 3 (8.1) Missing data 1 (6.7) 0 (0) 0 (0) 0 (0) 1 (2.7) Disease status at the time of transplant CR1 15 (100.0) 10 (76.9) 4 (57.1) 1 (50.0) 30 (81.1) CR2 0 (0) 2 (15.4) 3 (42.9) 1 (50.0) 6 (16.2) CR3 0 (0) 1 (7.7) 0 (0) 0 (0) 1 (2.7) Cytogenetics a) Favorable 1 (6.7) 4 (30.8) 2 (28.6) 0 (0) 7 (18.9) Intermediate 2 (86.7) 0 (0) 0 (0) 1 (33.3) 3 (8.1) Unfavorable 1 (6.7) 0 (0) 2 (28.6) 0 (0) 3 (8.1) NA 11 (45.8) 9 (37.5) 3 (12.5) 1 (4.1) 24 (64.8) Chloroma Yes 2 (13.3) 2 (15.4) 0 (0) 0 (0) 4 (10.8) No 13 (86.7) 11 (84.6) 7 (100.0) 2 (100.0) 33 (89.2) Graft BM 14 (93.3) 8 (61.5) 0 (0) 0 (0) 22 (59.5) PB 1 (6.7) 5 (38.5) 0 (0) 2 (100.0) 8 (21.6) CB 0 (0) 0 (0) 7 (100.0) 0 (0) 7 (18.9) Conditioning regimen Myeloablative 13 (86.7) 9 (69.2) 4 (57.1) 2 (100.0) 28 (75.7) Busulfan-based 10 (76.9) 5 (55.6) 3 (75.0) 2 (100.0) 20 (71.4) ATG containing TBI-based 3 (23.1) 4 (44.4) 1 (25.0) 0 (0) 8 (28.6) Non-myeloablative 2 (13.3) 4 (30.8) 3 (42.9) 0 (0) 9 (24.3) ATG/ALG containing GvHD prophylaxis CSA/shout course MTX [+ATG] 10 (66.7) 5 [2] (38.5) 0 (0) 0 (0) 15 [2] (40.5) Tacrolimus/MTX [+ATG] 0 (0) 8 [2] (61.5) 0 (0) 0 (0) 8 [2] (21.7) CSA [+ATG] 4 (26.7) 0 (0) 2 [1] (28.6) 0 (0) 6 [1] (16.2) Tacrolimus [+ATG] 0 (0) 0 (0) 3 [2] (42.8) 0 (0) 3 [2] (8.1) Tacrolimus/MMF 0 (0) 0 (0) 2 (28.6) 0 (0) 2 (5.4) CSA/MTX/MMF [+ATG] 0 (0) 0 (0) 0 (0) 2 [2] (100.0) 2 [2] (5.4) No prophylaxis 1 (6.6) 0 (0) 0 (0) 0 (0) 1 (2.7) Clin Pediatr Hematol Oncol 149

6 Ha Yeong Choe, et al Table 1. Continued Characteristics MSD URD UCB HD Total HLA match High resolution 8/ (29.7) 7/ (2.7) 6/ (10.8) 5/ (0) 4/ (5.4) Low/intermediate resolution 6/ (32.4) 5/ (1) b) 0 4 (10.8) 4/ (1) b) 0 1 (2.7) 3/ (2) b) 0 2 (5.4) MSD, matched sibling donor; URD, unrelated donor; UCB, unrelated cord blood; HD, haploidenticalfamily donor; CR, complete remission; BM, bone marrow; PB, peripheral blood; CB, cord blood; ATG, anti-thymocyte globulin; ALG, anti-lymphocyte globulin; TBI, total body irradiation; GvHD, graft versus host disease; CSA, cyclosporine A; MTX, methotrexate; MMF, mycophenolate mofetil. a) Cytogenetics were classified as favorable if t(8:21), inv(16), or t(16;16) was detected, unfavorable if 7-/7q-, 5-/-5q, complex karyotype (at least 3 unrelated abnormalities), t(8;16), t(6;9), t(16;21) or fms-like tyrosin kinase receptor 3 internal tandem duplication (FLT3-ITD) was detected, NA if no unfavorable cytogenetics was not detected and FLT3-ITD was not applicable, and intermediate for all other abnormalities or a normal karyotype. b) Double cord blood transplantation. Table 2. Hematologic recovery after stem cell transplantation MSD (n=15) URD (n=13) UCB (n=7) HD a) (n=2) P b) P c) Days to ANC>500/ L, median (range) 15 (10-25) 15 (10-23) 19 (13-38) Days to ANC>1000/ L, median (range) 18 (10-32) 16 (11-24) 26 (17-40) Days to platelet of / L, median (range) 21 (10-34) 17 (9-33) 42 (27-99) Days to platelet of / L, median (range) 23 (12-45) 23 (13-42) 45 (42-103) Primary graft failure MSD, matched sibling donor; URD, unrelated donor; UCB, unrelated cord blood; HD, haploidentical family donor; ANC, absolute neutrophil count. a) Analysis was performed only one patient because the other died from sepsis at post-transplant 3 days. b) MSD vs. URD vs. UCB. c) MSD vs. URD. 통계적으로의미있게낮았다 (25.0±21.7% vs. 72.7±7.8%, P=0.044) (Fig. 1D). 2003년전후로나눈이식시기별전체생존율및무병생존율에는유의한차이가없었다 (70.4±14.5% vs. 70.4±8.8%, P=0.945; 70.0±14.5% vs. 66.7±9.1%, P= 0.859). 세포유전학적예후군에따른무병생존율은불량군 (33.3±27.2%) 에서양호군 (71.4±17.1%) 에비해낮았지만통계적의미는없었다 (P=0.258). 또한, 단변량분석에서성별, 진단시나이, 진단에서이식까지기간, 조혈모세포종류, 전처치종류 ( 골수파괴성대독성감소골수파괴성 ), 전처치에 TBI 포함여부, grade II-IV 급성이식편대숙주병, 광범위만성이식편대숙주병발생여부가전체생존율과무병생존율에의미 있는영향을주지는않았다 (Table 3). 4) 재발및사망중앙추적관찰기간 7.3년 ( 범위, 0-9.6) 동안총 8명이재발하였다. 각각형제간이식군 3명, 비혈연이식군 2명, 제대혈이식 2명, 반일치이식군에서 1명이재발하였다. 이중형제간이식군 1명을제외하고모두사망하였고, 생존한환자는재발후 CR2에이차이식으로비혈연이식을시행하였고, 이차이식후 2년간무질병상태이다. 제대혈이식군에서재발한 2명은 CR2에, 나머지는모두 CR1에이식을시행하였다. 각군간의 5년-누적재발률은유의한차이가보이지않았다 (20.0% vs. 150 Vol. 23, No. 2, October 2016

7 Outcomes of HSCT by Donor Types in Children with AML Fig. 1. (A) The 7-year overall survival (OS) rate after transplant of total 36 patients was 70.3±7.5% and (B) event-free survival (EFS) rate was 67.6±7.7%. (C) The 7-year EFS rates according to the donor types. The EFS at 7 year was 80.0±10.3% in MSD group (n=15), 69.2±12.8% in URD group (n=13), 57.1±18.7% in UCB group (n=7) and 0% in HD group (n=2) (P=0.019). (D) The 7-year EFS rate according to the presence of chloroma at diagnosis. The EFS at 7 year in no chloroma group and in chloroma group was 72.7±7.8% and 25.0±21.7%, respectively (P=0.044). 15.4% vs. 33.3%, vs. 50%, P=0.721). 급성이식편대숙주병이있었던환자군 (13명) 은없었던환자 (23명) 군보다재발률이낮았고 (16.7±10.8% vs. 27.3±9.6%, P=0.478), 만성이식편대숙주병이있었던환자군 (9명) 이없었던환자군 (27명) 에비해재발률이낮았으나 (12.5±11.7% vs. 26.1±8.5%, P=0.463) 통계적으로유의하지는않았다. 본연구에서사망한환자는총 11명이었다 (Table 4). 형제간이식군 2명, 비혈연이식군 4명, 제대혈이식군 3명에서사망하였고반일치이식군은 2명모두에서사망하였다. 7명 (63.6%) 이불응성백혈병으로사망하였고, 4명은이식-관련합병증으로사망하였다. 이식-관련합병증으로사망한환자는형제간이식군에는없었고, 비혈연이식군에서폐를침범한만성이식편대숙주병으로 2명, 제대혈이식군에서위장관급성이식편 대숙주병으로 1명, 반일치이식군에서 Pseudomonas 패혈증으로 1명이었다. 각군간 2년이식-관련누적사망률은통계적으로유의한차이를보였다 (0% vs. 15.4% vs. 16.7% vs. 50.0%, P=0.017) (Fig. 2D). 5) 이식편대숙주병생착된 36명의환자중 6명 (16.7%) 에서 grade II-IV 급성이식편대숙주병이발생하였다. Grade IV 급성이식편대숙주병은 2명에서발생하였고, 이중 1명은위장관급성이식편대숙주병으로사망하였다. Grade II-IV 급성이식편대숙주병의누적발생율은제대혈이식군에서다른공여자군과비교하여통계적으로유의하게높았다 [ 형제간이식군 vs. 비혈연이식군 vs. 제대혈이식군 vs. 반일치이식군 =0% vs. 15.4% (95% CI, Clin Pediatr Hematol Oncol 151

8 Ha Yeong Choe, et al Table 3. Survivals by prognostic variables (univariate analysis) Variable No. of patients Death 7-yr OS (%) P Event 7-yr EFS (%) P Sex Male ± ±11.6 Female ± ±10.2 Age at diagnosis <10 years ± ± years ± ±10.6 Age at transplant <10 years ± ± years ± ±9.5 Interval between diagnosis and transplant <12 months ± ± months ± ±18.7 Chloroma at diagnosis No ± ±7.8 Yes ± ±21.7 Cytogenetics a) Favorable ± ±17.1 Intemediate ± ±27.2 Unfavorable ± ±27.2 NA ± ±8.8 Graft Bone marrow ± ±9.5 Peripheral blood ± ±17.1 Cord blood ± ±18.7 Donor type Matched sibling ± ±10.3 Unrelated donor ± ±12.8 Unrelated cord blood ± ±18.7 Haploidentical family Conditioning regimen Myeloablative ± ±9.1 Non-myeloablative ± ±13.9 TBI-based conditioning No ± ±8.3 Yes ± ±17.7 ATG-containing regimen No ± ±8.5 Yes ± ±16.6 Year of transplant Prior to ± ±14.5 After ± ±9.1 Acute GvHD grade II b) No ± ±8.1 Yes ± ±20.4 Chronic GvHD, extensive b) No ± ±8.2 Yes ± ±17.7 EFS, event free survival; HSCT, hematopoietic stem cell transplantation; TBI, total body irradiation; GvHD, graft-versus-host disease. a) Cytogenetics were classified as favorable if t(8:21), inv(16), or t(16;16) was detected, unfavorable if 7-/7q-, 5-/-5q, complex karyotype (at least 3 unrelated abnormalities), t(8;16), t(6;9), t(16;21) or fms-like tyrosin kinase receptor 3 internal tandem duplication (FLT3-ITD) was detected, NA if no unfavorable cytogenetics was not detected and FLT3-ITD was not applicable, and intermediate for all other abnormalities or a normal karyotype. b) Acute and chronic GvHD analysis were performed for the 36 patients surviving after engraftment and more than 100 days after transplant, respectively. 152 Vol. 23, No. 2, October 2016

9 Outcomes of HSCT by Donor Types in Children with AML Table 4. Outcomes after transplantation MSD (n=15) URD (n=13) UCB (n=7) HD (n=2) P Death Total number of death, 2 (13.3) 4 (30.7) 3 (42.8) 2 (100) Relapse, 2 (13.3) 2 (15.4) 2 (28.6) 1 (50) Transplant-related, 0 2 (15.4) 1 (14.3) 1 (50) Acute GvHD (gut) 0 Chronic GvHD 0 2 (lung) 0 0 Infection Cumulative incidence, % (95% CI) Acute GvHD a) (day 100) Grades I-IV 13.3 ( ) 46.2 ( ) 83.3 ( ) Grades II-IV ( ) 66.7 ( ) Chronic GvHD a) (2 year) All 6.7 ( ) 38.5 ( ) 50 ( ) Extensive type ( ) 50 ( ) day-trm (0-87.5) TRM ( ) 16.7 (4-56.7) 50 (0-96.0) Relapse 20.0 ( ) 15.4 ( ) 33.3 ( ) 50 (0-98.7) MSD, matched sibling donor; URD, unrelated donor; UCB, unrelated cord blood; HD, haploidentical family donor; GvHD, graft versus host disease; TRM, transplant-related mortality; CI, confidence interval. a) Acute and chronic GvHD were evaluated in 36 patients who survived after engraftment, and more than 100 days after transplantation, restrospectively. 2.2%-39.9%), 66.7% (95% CI, 12.3%-92.4%), 0%, P=0.003] (Fig. 2A). 이식후 100일이후평가가능한 36명의환자에서만성이식편대숙주병은총 9명 (24.3%; 국소적, 1명 ; 광범위, 8명 ) 에서발생하였다. 2년-광범위만성이식편대숙주병의누적발생율도제대혈이식군에서다른공여자군과비교하여통계적으로유의하게높았다 [ 형제간이식군 vs. 비혈연이식군 vs. 제대혈이식군 vs. 반일치이식군 =0% vs. 38.5% (95% CI, 12.9%-64.0%), 50.0% (95% CI, 7.1%-83.4%), 0%, P=0.020] (Fig. 2B). 6) 제대혈이식군의특징과 allele-불일치비혈연이식군과의이식성적비교제대혈이식군에서 Flu-Bu 전처치에이식편대숙주병예방으로 ATG를병합한환자는 3명이었다. 이중제대혈이식후 63일째재발로사망하여평가가불가능한 1명을제외하고, 1 명에서 grade II-IV 급성및만성광범위이식편대숙주병이발생하였고, ATG 사용없이골수파괴형전처치를시행한 4 명중 3명에서 grade II-IV 급성이식편대숙주병이발생하였다. Allele 수준에서조직적합성항원검사가시행된 9명의비혈연이식군중불일치-비혈연이식군은 5명이었다. Allele-불일치비혈연이식군과제대혈이식군의전체생존율과무병생존율, grade II-IV 급성및만성이식편대숙주병의누적발생율, 이식-관련누적사망률및누적재발률에는두군간에차이를보이지않았다 (Table 5). 고찰소아급성골수성백혈병은지난 30년간생물학적인연구와이해가진행되면서강력한항암화학요법및지지요법의발달로약 65-70% 에서완치율을보고하고있다 [5,6]. 하지만여전히약 30-35% 의환자들은재발및치료관련독성으로인해사망하고있다 [23]. 소아급성골수성백혈병은임상양상이매우다양한질환군으로, 최근치료경향은어른의경우와마찬가지로위험인자에따라위험군을분류하여치료강도에차이를두는것이다. 아형에따라항암화학요법만을시행하는경우도있으나반드시조혈모세포이식을시행해야하는경우도있다. 또한, 조혈모세포이식을시행하는경우에이식시기, 공여자의종류, 이식방법, 이식전처치등에대하여도여전히많은논의가이루어지고있는상태이다. 여러연구에서양호한예후를보이는세포유전학적특성을가진경우에는동종조혈모세포이식이필요하지않으나, 그렇지않은경우에는 CR1에서조직적합성항원-일치형제공여자를통한동종조혈모세포이식을시행할것을권고하고있다 [23]. Clin Pediatr Hematol Oncol 153

10 Ha Yeong Choe, et al Fig. 2. (A) The 100-day cumulative incidence (CI) of grade II to IV acute graft versus host disease (GvHD) according to donor type was 66.7% in UCB group, 15.4% in URD group, 0% in MSD and HD group (P=0.003). (B) The 2-year CI of extensive chronic GvHD according to donor type was 50.0% in UCB group, 38.5% in URD group, 0% in MSD and HD group (P=0.020). (C) The CI of relapse according to donor type. The CI of relapse was 20.0% in MSD group, 15.4% in URD group, 33.3% in UCB group and 50% in HD group (P=0.721). (D) The CI of transplant-related mortality (TRM) according to donor type. The CI of TRM was 0% in MSD group, 15.4% in URD group, 16.7% in UCB group and 50.0% in HD group (P=0.017). Table 5. Comparison of outcomes between allele-mismatch unrelated donor and unrelated cord blood transplantations Allele-mismatch URD (n=5) UCB (n=7) P OS, % (95% CI) 60 ( ) 50.0 ( ) EFS, % (95% CI) 60 ( ) 50.0 ( ) Cumulative incidence, % (95% CI) Acute GvHD (day 100) Grade I-IV 40 ( ) 83.3 ( ) Grade II-IV 20 (4-63.2) 66.7 ( ) Chronic GvHD (2 year) All 40 ( ) 50.0 ( ) Extensive 40 ( ) 50.0 ( ) TRM 20 (4-62.1) 28.6 ( ) Relapse 20 (4-63.2) 33.3 ( ) URD, unrelated donor; UCB, unrelated cord blood; OS, overall survival; EFS, event free survival; GvHD, graft versus host disease; TRM, transplant-related mortality; CI, confidence interval. 154 Vol. 23, No. 2, October 2016

11 Outcomes of HSCT by Donor Types in Children with AML Children s Oncology Group (COG) 연구에서는소아급성골수성백혈병의 CR1에서조직적합성항원-일치가족공여자로부터이식을시행하였을때 (181명), 항암치료만을단독으로시행하였을때 (179명) 보다좋은결과를얻었다고보고하였다 (60±9% vs. 53±8%, P=0.05) [24]. 다른COG 연구에서는소아급성골수성백혈병중간위험군에서조혈모세포세포이식을받은 480명의 8년-전체생존율은 62±7%, 무병생존율은 58±7% 로보고하였다 [25]. St. Jude 소아병원에서는 2002년부터 2008 년까지 AML02 프로토콜로치료한소아급성골수성백혈병환자들 (128명) 의 4년-무병생존률을 62.4% 로보고하였다 [26]. Associazione Italiana di Ematologia e Oncologia Pediatica (AIEOP) 의전향적연구에따르면 [27], 소아급성골수성백혈병고위험군에서동종조혈모세포이식을받은환아 (141명) 의 8년- 무병생존율은 73% 였다. 본연구에서는 7년-전체생존율 70.3± 7.5%, 무병생존율 67.6±7.7% 로타연구 [24-27] 와비교하여나쁘지않은성적을보였다. 동종조혈모세포이식을시행받은소아급성백혈병및골수이형성증후군환자 93명을대상으로한연구에서나쁜예후인자로아프리카계미국인, 진단시높은백혈구수, 진단시중추신경계침범, 짧은 CR1 기간이해당되지만, 공여자의종류는유의한영향을미치지않는다는보고도있다 [28]. 하지만, 본연구에서예후인자에따른무병생존율을비교하였을때, 진단시녹색종의존재여부및공여자의종류가생존율에유의한영향을미치는것으로나타났으며, 진단시녹색종이없는군의무병생존율이있는군에비해통계적으로유의하게높았다 (72.7±7.8% vs. 25.0±21.7%, P=0.044). 1989년부터 2006년까지진단된 21세미만의급성골수성백혈병세포유전학적예후불량군을대상으로한대단위 COG연구 [29] 에서는 CR1에항암화학요법만시행한군, 조직적합항원- 일치혈연간이식군및비혈연이식군의 5년-전체생존율은각각 43%, 46%, 50% 로차이가없다는보고를하였다. 하지만, 본연구에서는특정세포유전학적예후군만으로한정하진않았지만, 공여자군에따른 7년-전체생존율은형제간이식군에서가장높았고, 비혈연이식군, 제대혈이식군, 반일치이식군순이었다 (86.7±8.8%, 69.2±12.8%, 57.1±18.7%, 0%, P= 0.007). 이는이식-관련누적사망률이형제간이식군에서다른군에비해의미있게낮았기때문으로생각된다. 조혈모세포이식을시행받은 73명의소아급성골수성백혈병예후불량군을대상으로공여자별이식성적을후향적으로분석한중국의다기관연구 [12] 에서형제간이식군, 비혈연이식군, 제대혈이식군의중성구생착일수는비슷하였지만, 혈소판생착일수는각각 15.9일, 16.5일, 38.5일로제대혈이식 군에서유의하게길었다 (P=0.01). 또한, 공여자군별급성이식편대숙주병의누적발생률은각군간차이가없었지만, 만성이식편대숙주병은제대혈이식군에서가장낮았으며, 제대혈이식군이형제간이식군에비해높은조기이식-관련누적사망률을보였다고보고하였다. Hwang 등 [30] 의소아급성골수성백혈병에서비혈연이식과제대혈이식을비교한메타분석결과를보면, 만성이식편대숙주병의빈도는제대혈이식에서의미있게낮았고, grade III-IV 급성이식편대숙주병과 2년-전체생존율은두군간에차이가없었다. 본연구에서도제대혈이식의생착기간이형제간, 비혈연이식군보다길었지만, 형제간이식과비혈연이식간의중성구및혈소판생착일수에차이가없었다. 하지만, 다른연구들 [12,30] 과달리제대혈이식군에서 grade II-IV 급성이식편대숙주병과만성광범위이식편대숙주병의누적발생율은다른군들보다통계적으로의미있게높았다. 이는 ATG 사용없이골수파괴형전처치를시행한제대혈이식군 (4명) 에서 grade II-IV 급성이식편대숙주병의발생률 (3명) 이높았기때문으로보인다. 재발은백혈병치료실패의가장주요한원인으로알려져있다. 본연구에서도총사망환자 11명중 7명 (63.6%) 이불응성 / 재발한백혈병이원인이었다. 5년-누적재발율은형제간, 비혈연, 제대혈, 반일치이식군에서유의한차이를보이지않았으나 (20.0% vs. 15.4% vs. 33.3%, vs. 50%, P=0.721), 제대혈이식군에서높은경향을보였다. 이는제대혈이식군에서형제간및비혈연이식군보다 CR2이상에서이식을시행한경우 ( 형제간이식 vs. 비혈연이식 vs. 제대혈이식 =0% vs. 23.1% vs. 42.9%) 와진단시세포유전학적불량군인경우 (6.7% vs. 0% vs. 28.6%) 가많았기때문으로생각된다. 아울러, 제대혈이식군에서재발한 2명은모두 CR2에이식을시행받은경우였다. 본연구에서이식-관련누적사망률은반일치이식군에서가장높았고형제간이식에서는없었다. 하지만비혈연이식군과제대혈이식군간에차이는보이지않았다 (15.4% vs. 16.7%, P=0.812). 또한, allele-불일치비혈연이식군과제대혈이식군간의전체생존율과무병생존율, grade II-IV 급성및만성이식편대숙주병의누적발생율, 이식-관련누적사망률및누적재발률에차이를보이지않았다. 본연구는조직형일치가족공여자를찾기힘들어지는추세에대체공여자의필요성이많이대두되는현재에동종조혈모세포이식이필요한소아급성골수성백혈병환자에서공여자유형에따른생존율의차이를비교함으로써, 공여자선택에유용한정보를제공하기위한목적으로시행되었다. 비록대상환자수가적고, 단일기관연구이며, 후향적분석이라는 Clin Pediatr Hematol Oncol 155

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