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ISSN 0377-9556 (PRINT) ISSN 2383-9457 (ONLINE) 약학회지제 60 권제 3 호 118~127 (2016) Yakhak Hoeji Vol. 60, No. 3 DOI 10.17480/psk.2016.60.3.118 종설 Short Report ABCB1 유전적다형성이만성골수성백혈병환자의 Imatinib 치료반응에미치는영향 : 체계적문헌고찰및메타분석 하혜민 천부순 # 인제대학교약학대학 (Received April 4, 2016; Revised April 19, 2016; Accepted April 25, 2016) ABCB1 Polymorphisms and Imatinib Response in Chronic Myeloid Leukemia Patients: A Systematic Review and Meta-analysis Hye Min Ha and Pusoon Chun # College of Pharmacy, Inje University, Gimhae 50834, Korea Abstract A growing number of studies have demonstrated that ABCB1 gene polymorphisms are associated with the variability of responses to imatinib. However, the effects of ABCB1 polymorphisms on imatinib response in chronic myeloid leukemia (CML) are inconsistent. The aim of the present study was to clarify the associations between ABCB1 polymorphisms and imatinib response in CML. A systematic literature review was performed. The databases of PubMed, Embase, and Cochrane Library were searched for all published studies from inception to December 2015. The following terms were used with functions of AND and OR : chronic myeloid leukemia, CML, ABCB1, MDR1, polymorphism, SNP, and imatinib. Using the Review Manager 5, odds ratios (ORs) were pooled to estimate the effect of ABCB1 polymorphisms on imatinib response in CML. The pooled analysis showed that ABCB1 2677 G allele was significantly associated with poor response to imatinib in African and Asian patients (GG vs TT, OR: 0.32, p<0.0001; GG+GT vs TT, OR: 0.44, p=0.0005). In subgroup analyses, African patients carrying ABCB1 1236 C allele exhibited higher risk for worse response, whereas Asian patients with 1236 C allele showed better response (CC+CT vs TT, OR: 0.41, p=0.008 for African; OR: 1.65, p=0.03 for Asian). There was no association between C3435T polymorphisms and imatinib response in African, Asian, and Caucasian CML patients. Keywords ABCB1 C1236T polymorphism, ABCB1 G2677T polymorphism, ABCB1 C3435T polymorphism, chronic myeloid leukemia, imatinib, response 만성골수성백혈병은조혈모세포의이상으로과립구백혈구가과도하게증식하는만성골수증식성암이다. 만성골수성백혈병환자에서발견되는중요한특징인필라델피아염색체 (Philadelphia chromosome) 는 9번염색체의 ABL 유전자와 22 번염색체의 BCR 유전자의상호전위에의한융합으로생성된다. 이때생성된 BCR-ABL 융합유전자에의해합성되는발암단백질 P210 BCR-ABL은강력한티로신키나아제 (tyrosine kinase) 활 # Corresponding Author Pusoon Chun College of Pharmacy, Inje University, 197 Inje-ro, Gimhae, Gyeongnam 50834, Korea Tel.: 055-320-3886 Fax.: 055-320-3940 E-mail: pusoon@inje.ac.kr 성을가지며골수구전구세포의세포자멸사 (apoptosis) 를억제하여이세포들의비정상적인증폭을일으켜결국백혈병을초래한다. 1) 만성골수성백혈병은병기에따라급성기 (blastic phase, BP), 가속기 (accelerated phase, AP), 그리고만성기 (chronic phase, CP) 로나뉜다. 급성기는말초혈액혹은골수에서모세포 (blasts) 의비율이 30% 를넘거나간, 비장, 임파절을제외한골수외에서모세포의침윤이발견되는상태이며가속기는다음의기준중어느하나에속하는경우에해당된다 : 말초혈액또는골수에서의모세포비율이 10~30%; 모세포와전골수세포 (promyelocytes) 를합하여말초혈액또는골수에서의비율이 30% 미만 ; 말초혈액의호염기구 (basophils) 비율이 20% 이상 ; 치료와무관한혈소판감소증 (<100 10 3 /μl) 또는치료에반응하지않는혈소판증 118

ABCB1 유전적다형성이만성골수성백혈병환자의 Imatinib 치료반응에미치는영향 : 체계적문헌고찰및메타분석 119 가증 (>1,000 10 3 /μl); 비장비대 ; 필라델피아염색체외의염색체이상 ; 지속적인백혈구증가 (>10 10 3 /μl). 반면골수외에서모세포의침윤이없이말초혈액혹은골수에서모세포가 15% 미만, 호염기구가 20% 미만, 모세포와전골수세포를합하여 30% 미만, 그리고혈소판수가 100 10 3 /μl 이상인경우는만성기에속한다. 2) 만성골수성백혈병의치료에대한반응은혈액학적 (hematologic response, HR), 세포유전학적 (cytogenetic response, CR) 그리고분자적반응 (molecular response, MR) 으로분류한다. 완전혈액학적반응 (complete HR) 은다음의기준에해당하는경우이다 : 백혈구수 <10 10 3 /μl; 호염기구 <5%; 골수세포, 전골수세포, 골수모세포가발견되지않음 ; 혈소판 <450 10 3 /μl; 비촉지성비장. 세포유전학적반응은골수에서발견되는필라델피아염색체양성세포의비율에따라완전반응 (complete CCyR; 0% Ph+ cells), 주요반응 (major CyR; 0~35% Ph+ cells), 부분반응 (partial CyR; 1~5% Ph+ cells), 소반응 (36~65% Ph+ cells, 최소반응 (minimal CyR; 66~95% Ph+ cells), 그리고무반응 (>95% Ph+ cells) 으로분류한다. 반면분자적반응은골수에서보이는 BCR-ABL 단백질의양에따라완전반응 (complete MR; BCR/ ABL mrna의미검출 ) 및주요반응 (major MR; BCR-ABL/ ABL 0.1%) 으로분류한다. 3) 이매티닙 (imatinib, STI-571) 은 BCR-ABL 티로신키나아제 (tyrosine kinase) 의 ATP 결합부위에경쟁적으로결합하여 BCR- ABL 단백질을불활성구조로유지시킴으로써필라델피아염색체에의해생성되는비정상적 BCR-ABL 티로신키나아제의활성을억제한다. 이매티닙이필라델피아염색체양성만성골수성백혈병 (Philadelphia-chromosome-positive CML, Ph+ CML) 만성기환자의치료에서탁월한성과를거두고 1차치료제로사용이권고되고있음에도불구하고상당수의환자는이약물에대해내성을가지는것으로보고되고있다. 4,5) 이매티닙치료에대해내성을형성하는가장중요한원인이 BCR-ABL 유전자의돌연변이및증폭에의한것으로알려져있지만 P-당단백 ((Pglycoprotein, P-gp) 및 ABCG2 같은약물배출펌프의증가, 유기양이온수송체 (organic cation transporter 1, OCT1) 및유기음이온수송펩타이드 (organic anion transporting polypeptide, OATP) 1A2 등약물흡수수송체의감소또한이매티닙의치료반응소실의중요한영향인자가된다. 6) ATP-binding cassette subfamily B member 1(ABCB1) 은다약제내성단백 (multidrug resistance 1, MDR1) 으로도불리는유전자단백질로 P-당단백이라는약물의배출에주요한역할을하는세포막수송체를인코딩한다. P-당단백은장상피 (intestinal epithelium), 간세포, 신장의근위세뇨관, 혈액뇌장벽 (blood-brain barrier) 및혈액고환장벽의모세혈관내피세포등에광범위하게존재하면서약물의흡수를억제하거나배설을촉진한다. P-당단 백은또한암세포에서다량발현하여암세포내의항암제농도를감소시켜약제내성을형성한다. 7) ABCB1 단일염기다형성이만성골수성백혈병환자에서이매티닙치료반응에영향을미친다는많은연구결과가발표되어왔으나연구결과들에일관성이없다. 근래에 Zu 등은메타분석을통해아시아인에서 MDR1 C1236T 다형성은이매티닙의치료성과가나쁜위험인자가되지만 MDR1 G2677T와 C3435T 다형성은만성골수성백혈병환자의이매티닙반응성에유의한영향이없다고발표했다. 8) 반면최근에발표된 Zheng의메타분석연구에서는 2677G 혹은 3435T allele을지닌만성골수성백혈병환자는이매티닙의치료에대해저조한반응을보였고 1236CC 유전형을지닌아시아인만성골수성백혈병환자는 1236CT 혹은 1236TT 유전자형을가진환자에비해이매티닙의치료에대해더좋은반응을보였다. 9) 하지만더최근에 Wang 등이발표한메타분석에서는 MDR1 다형성인 C1236T, G2677T, 그리고 C3435T 모두만성골수성백혈병환자의이매티닙치료반응에영향을미치지않은것으로나타났다. 10) 따라서본연구는메타분석을통해 ABCB1 단일염기다형성중가장빈번히발견되는 C1236T, G2677T, 그리고 C3435T이이매티닙의치료반응에미치는영향을규명하고자수행되었다. 연구방법문헌검색만성골수성백혈병환자에서 ABCB1 단일염기다형성이이매티닙치료반응에대한영향을보고하는출판물의검색을위해체계적문헌고찰을수행하였다. 2015년 12월말현재까지발표된출판물을대상으로다음의용어를사용하여 PubMed, Embase, 그리고 Cochrane Library 데이터베이스를검색하였다 : ABCB1 polymorphism, chronic myeloid leukemia, imatinib, response. 또한출판물의면밀한조사를위해초기에선택된논문들의참고문헌목록을직접수기로검토하였다. 연구의선정및자료추출본연구에포함할논문의선정및선정된각연구들로부터의자료추출은공저자 2인이독립적으로수행하여공통으로선정한연구및추출된자료만을활용하였으며의견이불일치하는부분이있는경우충분한논의를통하여의견이합일되는자료를사용하였다. 본연구에포함한문헌의선정기준은다음과같다 : (1) 만성골수성백혈병환자에서 ABCB1 단일염기다형성과이매티닙치료반응에관한연구 ; (2) ABCB1 단일염기다형성의이매티닙치료반응의비교를위한오즈비 (Odds ratio, OR) 의산출이가능한데이터의발표 ; (3) 이매티닙치료반응에대한기준제시. 반면종설, 논평, 중복되어출판된연구, 초록만발표된 Vol. 60, No. 3, 2016

120 하혜민 천부순 연구, 임상적치료성과를보여주지않는논문, 그리고이매티닙에대한반응성비교를위한오즈비의산출이가능한유전자형빈도를나타내고있지않은연구는배제하였다. 선정된연구로부터추출한자료는다음을포함한다 : 연구에참여한만성골수성백혈병환자의병기 (disease phase), 투여한이매티닙의용량, 이매티닙의복용기간, 각연구에서사용한치료에대한반응기준, 그리고이매티닙치료에대한반응군및내성군의유전자형빈도. 문헌의질평가선정된연구의질평가를위해관찰연구의질평가도구인 Newcastle-Ottawa Quality Assessment Scale(NOS) 척도를사용하였다. 11) 각연구의질은 0~9점사이의점수로매겨졌으며 0~3점은 낮음, 4~6점은 보통, 그리고 7~9점은 우수 로평가했다. 12) 연구의질평가는공저자 2인이독립적으로수행한후두연구자가동일한점수를부여한경우최종평가하였으며불일치하는평가를받은연구의경우충분한논의를통하여의견이합일되는점수를부여하였다. 통계분석만성만성골수성백혈병환자에서 ABCB1 C1236T, G2677T, 그리고 C3435T이이매티닙치료반응에미치는영향을평가하기위해본연구에포함된개별연구들로부터가중평균오즈비 (Odds ratio, OR) 를산출하여통합된요약추정치 (pooled estimate) 를구하고오즈비와 95% 신뢰구간 (confidence intervals, CIs) 으로나타내었다. 요약추정치는 Z-test의 P값이 0.05 미만일때통계적으로유의한것으로판단하였다. 단일염기다형성의이매티닙치료에대한영향은 CC vs. TT 및 GG vs. TT, 우성모델 (dominant genetic model, CC vs. CT+TT 혹은 GG vs. GT+TT), 그리고열성모델 (recessive genetic model, TT vs. CC+CT 혹은 TT vs. GG+GT) 로분석하였으며민족성에의한영향은개별연구가이루어진국가별로하위집단분석 (subgroup analyses ) 을수행하여관찰하였다. 본메타분석에포함된개별연구들간의이질성은 Chisquare-based Q test에의해 Chi 2 >df ( 자유도 ) 일때연구들간이질성이있는것으로의심하고 P값이 0.1 미만일때통계적으로유의한것으로판정하였다. 연구들간의이질성은또한 Higgin s I² 통계량으로도분석하였으며 I² 의값이 25% 미만인경우이질성이 없음 으로, 25~50% 인경우 낮음 으로, 50~75% 인경우 중등도 로, 그리고 75% 이상인경우를 높음 으로해석했다. 13,14) 모든통계분석은 Review Manager Version 5(Cochrane Collaboration, Oxford, United Kingdom) 를이용하여 Mantel-Haenszel method의고정효과모형 (fixed effect model) 로분석하였고출판비뚤림은 funnel plot으로관찰하였다. 연구결과문헌검색데이터베이스의검색으로총 244개의문헌이수집되었다. 제목과초록의검토를통해선정및배제기준을만족하는 28편의 Fig. 1 Flowchart of the study selection process. J. Pharm. Soc. Korea

ABCB1 유전적다형성이만성골수성백혈병환자의 Imatinib 치료반응에미치는영향 : 체계적문헌고찰및메타분석 121 논문을 1차적으로선택하고전문 (full-test) 을검토하여본메타분석에포함할최종논문을선정하였다. 만성골수성백혈병환자에서 ABCB1 단일염기다형성이이매티닙치료에대한임상적반응에미치는영향을오즈비의산출이가능한유전자형빈도를보여주지않은논문 12개와논평 (Letter) 형태의논문 2개를본연구에서배제하였으며 1차적으로선택된논문의참고문헌목록을직접수기로검토하는과정에서찾은논문 1개를추가하여최종적으로 2개의전향적코호트연구와 15,16) 13개의환자-대조군연구 (case-control studies) 를 17-29) 본연구에포함하였다 (Fig. 1). 문헌의질평가를수행한결과 6개의연구가 17-22) NOS 등급으로 9점을, 7개의연구가 15,16,23-27) 8점을, 그리고 1개의연구가 28) 7점 을얻어 우수 로평가되었으며 1개의연구는 29) 5점을얻어 보통 으로평가되었다. ABCB1 C1236T이이매티닙치료에대한반응에미치는영향총 9개의연구가 ABCB1 C1236T의이매티닙반응성에대한영향분석에포함되었으며 3개의연구가아시아에서, 20,21,24) 3개의연구는유럽에서, 17,19,28) 2개의연구는아프리카에서, 15,27) 그리고나머지 1개의연구는아메리카에서 18) 수행되었다. 본분석에포함된 814명의환자중 349명 (42.9%) 은아시아인, 177명 (21.7%) 은유럽인, 170명 (20.9%) 은아프리카인, 그리고 118명 (14.5%) 이아메리카인이었다. 모든환자가이매티닙 400 mg을 Table I Characteristics of the included studies and genotype frequencies of ABCB1 C1236T polymorphism according to response to imatinib Study Country CML phase Dose/day Treatment Duration (months) Response criteria Genotypes (n) Responsive Resistant CC CT TT CC CT TT Kassogue et al., 2015 Morocco CP 400 mg (N=70) 48 CR 15 13 08 16 13 05 Ali et al., 2014 Egypt CP 400 mg (N=100) 3 MR 20 30 05 19 23 03 Au et al., 2014 Malaysia CP 400 mg (N=215) 6 MR 12 66 40 19 44 34 Seong et al., 2013 Korea CP 400 mg (N=82) 6 CR 15 30 18 02 07 10 Gromicho et al., 2012 Portugal NA 400 mg (N=33) 2-73 (46, median) MR 6 06 03 03 12 03 Vivona et al., 2012 Brazil CP 400 mg (N=118) 18 MR 24 46 15 33 Ni et al., 2011 China CP 400 mg (N=52) 12 CR 10 12 05 03 07 15 Maffioli et al., 2011 Spain CP 400 mg (N=59) 16.7-110.9 (60.6, median) Response 46 13 5 00 Dulucq et al., 2008 France AP, CP 400 mg (N=85) 12 MR 11 20 17 16 18 03 AP, accelerated phase; CML, chronic myeloid leukemia; CP, chronic phase; CR, cytogenetic response; MR, molecular response; NA, not applicable. Fig. 2 Forest plot of the association between ABCB1 C1236T polymorphism and imatinib response stratified by country under the recessive genetic model. Squares represent study-specific OR; horizontal lines represent 95% CIs; diamond represents a summary odds ratio estimate with corresponding 95% CI. Vol. 60, No. 3, 2016

122 하혜민 천부순 매일복용했으며 85.5% 이상의환자가만성골수성백혈병의만성기에있었다 (Table I). 9개의연구결과를종합한결과 ABCB1 C1236T은이매티닙반응성에유의한영향을미치지않는것으로드러났다 (CC vs. TT, OR: 0.84; 95% CI: 0.53, 1.33; p=0.46; CC vs. CT+TT, OR: 0.90; 95% CI: 0.64, 1.25; p=0.53; CC+CT vs. TT, OR: 1.03; 95% CI: 0.72, 1.47). 그러나개별연구가이루어진국가별하위집단분석에서 1236CC 혹은 1236CT 유전자형을가진아시아환자는 1236TT 유전자형을가진아시아환자에비해이매티닙에대한반응성이유의한수준으로우수한반면아프리카환자에서는반대의결과가관찰되었다 (CC+CT vs. TT: 아시아, OR: 1.65; 95% CI: 1.05, 2.59; p=0.03; 아프리카, OR: 0.41; 95% CI: 0.21, 0.80; p=0.008). 하위집단분석에포함된연구들간이질성이높았으며출판비뚤림이관찰되었다 (Fig. 2, Fig. 3). Fig. 3 Funnel plot for publication bias of the included studies in the subgroup analysis of the effect of ABCB1 C1236T polymorphism on imatinib response stratified by country under the recessive genetic model. Table II Characteristics of the included studies and genotype frequencies of ABCB1 G2677T polymorphism according to response to imatinib Study Country CML phase Dose/day Treatment Duration (months) Response criteria Genotypes (n) Responsive Resistant GG GT TT GG GT TT Kassogue et al., 2015 Morocco CP 400 mg (N=67) 48 CR 21 12 NA 24 10 NA Ali et al., 2014 Egypt CP 400 mg (N=155) 3 MR 48 46 06 25 25 05 Elghannam et al., 2014 Egypt AP, BP, CP 400-600 mg (N=96) 3 MR 16 11 16 17 34 02 Maffioli et al., 2011 Spain CP 400 mg (N=59) 16.7-110.9 (60.6, median) Response 14 40 4 1 Ni et al., 2011 China CP 400 mg (N=40) 12 CR 08 07 02 05 14 04 Sailaja et al., 2010 India AP, BP, CP NA 24 CR 24 44 68 20 29 21 AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; CR, cytogenetic response; MR, molecular response; Response, cytogenetic, molecular, and hematological responses. Fig. 4 Forest plot of the association between ABCB1 G2677T polymorphism and imatinib response stratified by country under the allele contrast model. Squares represent study-specific OR; horizontal lines represent 95% CIs; diamond represents a summary odds ratio estimate with corresponding 95% CI. J. Pharm. Soc. Korea

ABCB1 유전적다형성이만성골수성백혈병환자의 Imatinib 치료반응에미치는영향 : 체계적문헌고찰및메타분석 123 Fig. 5 Forest plot of the association between ABCB1 G2677T polymorphism and imatinib response stratified by country under the recessive genetic model. Squares represent study-specific OR; horizontal lines represent 95% CIs; diamond represents a summary odds ratio estimate with corresponding 95% CI. ABCB1 G2677T이이매티닙치료에대한반응에미치는영향총 6개의연구가 ABCB1 G2677T의이매티닙반응성에대한영향분석에포함되었으며 3개의연구가아프리카에서수행되었고, 15,16,27) 2개의연구는아시아에서, 24,29) 나머지 1개의연구가유럽에서 17) 수행되었다. 본분석에는전체 623명의환자가포함되었다 : 아프리카인 318명 (51%); 아시아인 246명 (39.5%); 유럽인이 59명 (9.5%). 반이상의환자가매일이매티닙 400 mg을복용했으며만성골수성백혈병의만성기에있었다 (Table II). ABCB1 G2677T의이매티닙치료반응에대한영향을우성모 델로분석한결과유의한영향을미치지않는것으로나타났다 (GG vs. GT+TT, OR: 0.87; 95% CI: 0.61, 1.25; p=0.46). 그러나개별연구가이루어진국가별로하위집단분석을수행했을때아시아와아프리카환자중 2677GG 혹은 2677GT 유전자형을가진환자는 2677TT 유전자형을가진환자에비해이매티닙에대한치료반응이유의한수준으로저조하였다 (GG vs. TT, OR: 0.32; 95% CI: 0.19, 0.54; p<0.0001; GG+GT vs. TT, OR: 0.44; 95% CI: 0.27, 0.70; p=0.0005)(fig. 4, Fig. 5). 본분석에포함된연구들간에통계적으로유의한이질성은발견되지않았으나출판비뚤림이관찰되었다 (Fig. 6, Fig. 7). Fig. 6 Funnel plot for publication bias of the included studies in the subgroup analysis of the effect of ABCB1 G2677T polymorphism on imatinib response stratified by country under the allele contrast model. Fig. 7 Funnel plot for publication bias of the included studies in the subgroup analysis of the effect of ABCB1 G2677T polymorphism on imatinib response stratified by country under the recessive genetic model. Vol. 60, No. 3, 2016

124 하혜민 천부순 Table III Characteristics of the included studies and genotype frequency of ABCB1 C3435T polymorphism according to response to imatinib Treatment Genotypes (n) Response Study Country CML phase Duration Responsive Resistant Dose/day criteria (months) CC CT TT CC CT TT Kassogue et al., 2015 Morocco CP 400 mg (N=70) 48 CR 18 12 06 21 11 02 Salimizand et al., 2015 Iran AP (N=11), 400 mg (N=56) CP (N=59) 600 mg (N=14) 64 CR 06 10 33 03 08 10 Ali et al., 2014 Egypt CP 400 mg (N=155) 3 MR 44 47 09 23 28 04 Au et al., 2014 Malaysia CP 400 mg (N=215) 6 MR 30 69 19 27 53 17 Seong et al., 2013 Korea CP 400 mg (N=82) 6 CR 30 28 05 05 10 04 Shinohara et al., 2013 Japan CP 400 mg (N=143); 3.2-106 600 mg (N=1) (16.5, median) MR 25 31 16 28 33 11 Anthony et al., 2012 Malaysia AP, CP 400 mg (N=45) 6 Response 06 13 03 10 09 04 Vivona et al., 2012 Brazil CP 400 mg (N=70), 600 or 800 mg (N=48) 18 MR 24 46 19 29 Maffioli et al., 2011 Spain CP 400 mg (N=63) 16.7-111 (60.6, median) Response 11 48 04 00 Ni et al., 2011 China CP 400 mg (N=52) 12 CR 15 12 01 05 14 05 Takahashi et al., 2010 Japan CP 400 mg (N=31); 300 mg (N=17); <300 mg (N=14) NA MR 07 21 06 08 16 04 AP, accelerated phase; CML, chronic myeloid leukemia; CP, chronic phase; CR, cytogenetic response; MR, molecular response; Response, cytogenetic, molecular, and hematological responses; NA, not applicable. Fig. 8 Funnel plots for publication bias of the included studies in the meta-analysis of the effect of ABCB1 C3455T polymorphism on imatinib response stratified by country under the allele contrast model (a), dominant model (b), and recessive model (c), respectively. ABCB1 C3435T이이매티닙치료에대한반응에미치는영향총 1,076명의환자를대상으로한 11개의연구가 ABCB1 C3435T의이매티닙치료반응에대한영향분석에포함되었다 : 아시아에서수행된 7개의연구에서 20-26,29) 670명 (62.3%) 이, 아프리카에서수행된 2개의연구에서 15,27) 225명 (20.9%) 이, 그리고유럽에서수행된 1개의연구와 17) 아메리카에서수행된 1개의연구에서 18) 각각 63명 (5.9%) 과 118명 (11%) 이본연구에서분석되었다. 80%(839명 ) 가넘는환자가이매티닙 400 mg을매일복용하였으며 4.6%(49명 ) 는 600~800 mg을, 그나머지는 400 mg 이하를매일복용하였고 95% 이상 (1020명이상 ) 의환자가만성골수성백혈병의만성기에있었다 (Table III). 11개의연구결과를종합한결과 C3435T은이매티닙의치료효과에유의한영향을미치지않는것으로나타났다 (CC vs. TT, OR: 0.93; 95% CI: 0.61, 1.43; p=0.75; I²=16.1%; CC vs. CT+TT, OR: 0.91; 95% CI: 0.70, 1.19; p=0.51; I²=21.1%; CC+CT vs. TT, OR: 0.90; 95% CI: 0.62, 1.30; p=0.56; I²= 3.4%). 본분석에포함된연구들간에이질성은발견되지않았지만출판비뚤림이관찰되었다 (Fig. 8). 고찰본연구는 ABCB1 단일염기다형성중가장빈번히발견되는 C1236T, G2677T, 그리고 C3435T이만성골수성백혈병환자의이매티닙치료에대한반응에미치는영향을규명하기위해수행되었다. 이매티닙이필라델피아염색체양성만성골수성백혈병만성기환자의치료에서 1차치료제로사용이권고되고있음에도불구하고많은환자가이약물에반응하지않거나내성을형성하는것으로보고되고있으며이매티닙의사용으로치료 J. Pharm. Soc. Korea

ABCB1 유전적다형성이만성골수성백혈병환자의 Imatinib 치료반응에미치는영향 : 체계적문헌고찰및메타분석 125 에실패한경우나사티닙이나닐로티닙을사용하여우수한세포유전학적반응과분자적반응을거두므로이매티닙치료에대한반응을예견하는바이오마커의규명은만성골수성백혈병환자의치료를결정하는데있어중요한요소라고할수있다. 30) 본메타분석의결과 ABCB1 1236TT 유전자형을가진아시아환자는 1236CC 혹은 1236CT 유전자형을지닌환자에비해이매티닙치료에대한반응이유의한수준으로저조한반면동일유전자형을지닌아프리카환자에서는오히려이매티닙치료에대한반응이유의한수준으로우수한것으로나타났다. 아시아환자에서관찰된본연구의결과는 ABCB1 1236TT 유전자형이아시아환자에서이매티닙의치료성과를나쁘게하는위험인자가된다고발표한 Zu 등의메타분석과 8) 1236CC 유전형을지닌아시아의만성골수성백혈병환자는이매티닙의치료시더좋은반응을보일것이라고발표한 Zheng 등의메타분석 9) 결과와일치하지만, C1236T가만성골수성백혈병환자의이매티닙치료성과에영향을미치지않음을보여준 Wang 등의메타분석 10) 결과와는일치하지않는다. 본메타분석의결과가 Wang 등의연구결과와다른이유는두메타분석에포함된연구의차이때문으로보인다. Wang 등의메타분석에포함된 Kim 등의연구와 31) Marin 등의연구는 32) 이매티닙의치료에대한 ABCB1 C1236T (rs1128503) 의영향을보고하지않아본메타분석에는포함되지못했으며, Deenik 등의연구는 33) 논평 으로발표되어본메타분석에서배제되었다. 또한본메타분석은 Wang 등이분석하지않은 Ali 등의연구, 15) Maffioli 등의연구, 17) Gromicho 등의연구를 19) 포함시켜분석하였다. 한편, 본연구에서 ABCB1 2677GG 혹은 2677GT 유전자형을가진아시아와아프리카환자는 2677TT 유전자형을가진환자에비해이매티닙에대한반응성이유의한수준으로저조한것이관찰되었으며이결과는 Zheng 등이발표한연구결과와일치한다. 9) 그러나이결과는 G2677T이만성골수성백혈병환자의이매티닙치료성과에영향을미치지않는다고주장한 Wang 등의메타분석 10) 결과와는상반된다. 두메타분석간에보이는이러한결과의차이는각메타분석에포함된연구의차이에서기인한것으로보인다. Wang은 ABCB1 G2677T/A(rs2032582) 가이매티닙의치료반응에미치는영향을분석하기위해 Ali 등의연구, 15) Elghannam 등의연구, 16) Ni 등의연구 24) 만을분석했으나본연구는이 3개의연구에더하여 Maffioli 등의연구, 17) Kassogue 등의연구, 27) Sailaja 등의연구 29) 도포함하여분석하였다. 본연구에서 ABCB1 C3435T은이매티닙의치료반응에유의한영향을미치지않는것으로나타났으며이결과는최근에 Wang 등이발표한메타분석연구 10) 결과와일치한다. 본연구는선행메타분석연구에서분석되지않은연구와 29) 가장최근의연구를 15,22,27) 포함하여분석하였으나 논평 으로발 표한 Deenik 등의논문과 33) Dulucq 등의논문은 34) 배제하여분석에포함시키지않았다. Deenik 등은만성골수성백혈병만성기초기의네덜란드인 46명에게매일이매티닙 800 mg을투여한후 ABCB1 다형성이이매티닙치료에분자적반응에미치는영향을관찰한결과 1236CT 혹은 1236TT 유전자형을지닌환자는 1236CC 유전자형을지닌환자에비해반응이저조했다고발표하였고이결과는본연구가관찰한 1236TT 유전자형을가진아시아환자에서의저조한반응과일치한다. 반면 Dulucq 등은프랑스환자에서 C1236T 다형성은이매티닙치료반응에영향을미치지않았다고주장했다. 본연구에포함된거의대부분의환자가만성골수성백혈병의만성기에있었으므로환자의병기에있었으므로연구들간에동질성이보장되었고대다수의환자가하루 400 mg의이매티닙을복용하여이매티닙의사용량에있어서도연구들간에차이가거의없었다는장점이있으나본연구에는몇가지한계점이있다. 이매티닙치료에대한반응을평가하기위한기준으로세포유전학적반응과분자적반응을구분없이사용했으며이매티닙의복용기간이짧게는 3개월, 길게는 111개월로연구들간에매우다양하였다. 또한아시아외의지역에서수행된연구결과가빈약했다. 그럼에도불구하고본연구는만성골수성백혈병의만성기에있는아시아및아프리카환자에서이매티닙치료에대해저조한치료반응을예견할수있는수있는바이오마커로서 ABCB1 C1236T와 G2677T 단일염기다형성을제안하는것에그의의가있다고하겠다. 결론만성골수성백혈병의만성기환자중 ABCB1 1236TT 유전자형및 2677G allele을지닌아시아환자와 1236C 및 2677G allele을지닌아프리카환자는이매티닙치료에대해저조한성과를보일위험이있다. 반면 ABCB1 C3435T은만성골수성백혈병만성기환자의이매티닙치료반응에유의한영향을미치지않는것으로보인다. References 1) Kurzrock, R., Kantarjian, H. M., Druker, B. J. and Talpaz, M. : Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann. Intern. Med. 138, 819 (2003). 2) Talpaz, M., Shah, N. P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., Cortes, J., O Brien, S., Nicaise, C., Bleickardt, E., Blackwood-Chirchir, M. A., Iyer, V., Chen, T. T., Huang, F., Decillis, A. P. and Sawyers, C. L. : Dasatinib in imatinibresistant Philadelphia chromosome-positive leukemias. N. Vol. 60, No. 3, 2016

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