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1 병원약사회지 (2013), 제 30 권제 4 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 30, No. 4, 304 ~ 319 (2013) 회원학술보고 만성골수성백혈병치료제의효과 : 메타분석 동덕여자대학교약학대학 The Effect of Treatment for Chronic Myeloid Leukemia: Meta- Analysis Ki Yon Rhew College of Pharmacy, Dongduk Women's University, 23-1 Wolgok-dong, Seoungbuk-gu, Seoul, , Korea Abstract : Chronic myeloid leukemia (CML) is one of the myeloproliferative disorders which is associated with the Philadelphia chromosome t(9;22)(q34;q11) resulting in a BCR-ABL gene. This abnormal gene produces a specific product BCR-ABL tyrosine kinase. Therefore, tyrosine kinase inhibitors (TKIs) could be used for long term controls of CML progression for most patients, and these have good tolerance and low adverse drug reaction rates. The present study was performed to evaluate the efficacy and safety of imatinib, dasatinib, and nilotinib as a first, second, third line therapy for CML. This meta-analysis was taken on August 31st 2012, the Medline and Embase searches were used to access the appropriate studies. Twenty-six studies, which suggested the cytogenetic, hematologic and molecular responses, were selected for this analysis. (0.839, 95% CI: ) and nilotinib (0.797, 95% CI: ) were analyzed as to having superior cytogenetic responses for patients of newly diagnosed CML-CP (chronic 투고일자 ; 심사완료일자 ; 게재확정일자 교신저자유기연 Tel: kiyon@dongduk.ac.kr

2 유기연 : 만성골수성백혈병치료제의효과 : 메타분석 phase) when compared to imatinib (0.676, 95% CI: ). The ADR, however were less shown in the imatinib group as compared to the second generation TKIs. For imatinib resistant or intolerant patients, the dasatinib 100 mg qd (CCgR 95% CI: , CHR 95% CI: , MMolR 95% CI: ) were analyzed with the most suitable therapy option as compared to dasatinib 70 mg (CCgR 95% CI: , CHR 95% CI: , MMolR 95% CI: ) or nilotinib 400 mg bid (CCgR 95% CI: , CHR 95% CI: , MMolR 95% CI: ). In the third line therapy for CML, there are no significant differences between dasatinib 70 mg bid and nilotinib 400 mg bid groups. [Key words] Chronic myeloid leukemia, Imatinib,, Nilotinib, Tyrosine kinase inhibitors 만성골수성백혈병 (Chronic myeloid leukemia, CML) 은악성혈액질환으로, 모든연령에서발생할수있으나일반적으로성인에게서나타나며, 미국에서인구 10만명당약 1-2명에게서발병하고대체로남성에게조금더많이나타나게된다. 1) 우리나라에서는 2009년에 1,819건으로전체암의 0.89% 를차지하는암으로남자에게서 1.3배더많이발생하였다는보고가있었다. 2) CML은특히 t(9;22)(q34;q11) 의전위로인해발현되는필라델피아 (Philadelphia) 염색체에기인한 BCR-ABL 유전자가형성되어나타나는골수증식성질환 (myeloproliferative disorders) 으로, 티로신키나아제 (tyrosine kinase) 의활성을가지는 BCR-ABL 유전자에의해조혈모세포의클론이비정상적으로확장하고골수내에비정상적세포가과도하게증식한다. CML의치료는, 만성안정기 (chronic stable phase), 가속기 (accelerated phase), 급성전환기 (blast crisis) 로구분되는, 그특정질병상태에따라달라지게된다. 만일환자가비교적젊고안정적인질병상태를유지하고있으며적절한기증자가있고환자의상태가가속기와급성전환기등의상태라면동종조혈줄기세포이식 (allogeneic hematopoietic cell transplantation) 이가장적절한 CML의치료방법이다. 3,4) 그러나티로신키나아제억제제 (tyrosine kinase inhibitors, TKIs) 는질병을잘조절할뿐아니라내약성도비교적양호하기때문에동종조혈줄기세포이식이어렵거나만성안정기의경우초기치료적접근으로많이사용된다. 5) TKIs는 BCR-ABL 경로 (pathway) 의시작을억제하고다른신호경로에도영향을미쳐 CML의진행을억제하며, 이러한표적경로는 imatinib에대한내성의발현기전차이에의한임상적인효과도다양하게한다. 6)-8) 1세대 TKIs인 imatinib은 ATP 결합부분을차단함으로써활성형태로의전환을예방하므로경쟁적으로 BCR-ABL 단백질티로신키나아제의비활성배열형태를억제한다. 9)-11) Imatinib은많은수의환자들에서오랜기간 CML의진행을막고우수한관해 (remission) 효과를나타냈다. 12)-15) 그러나 imatinib에내성을갖거나약물에내약성이낮은환자들은 imatinib을계속해서사용할수없었고, 이에대한 2차선택제로 dasatinib과 nilotibnib 등의 2세대 TKIs가 imatinib 1차치료에실패한환자들에게사용되어그효과를입증받았다. 16)-21) 이후 2010년에는 2세대 TKIs 중 dasatinib과 nilotinib

3 JKSHP, VOL.30, NO.4 (2013) 이미국 FDA에서 CML의 1차선택치료제로사용하도록허가를받았으며, 22),23) 우리나라에서도 2011년에 CML의 1차선택제로허가받아사용되고있다. 24) CML 1차선택치료제로의임상시험은 imatinib과 dasatinib, imatinib과 nilotinib의비교연구로진행되었고, dasatinib과 nilotinib의효능을직접적으로비교한연구는아직시행되지않았다. 또한두임상시험을간접적으로비교한논문은있으나, 25) 이는 1차선택치료제에대한효과를단순비교한것이기때문에본연구에서는메타분석기법을활용하여 TKIs의 1차선택치료제, 2차선택치료제, 3차치료제로서의효과를개별적으로분석하여, 그효과와안전성을평가하고자한다. 연구방법문헌의수집및선정방법 Medline, EMbase의 database를통해논문을검색하였다. (2012년 8월 1일검색 ) 검색어는 [(imatinib OR dasatinib OR nilotinib) AND chronic myeloid leukemia ] 를사용하였다. 문헌의선정기준은다음과같았다 (1) 임상연구 (2) imatinib, dasatinib, nilotinib의 CML 효과를평가변수로제시 (3) 결과변수로혈액학적반응또는세포유전학적반응또는분자학적반응, 약물유해반응 (ADR) 등을관찰한논문. 동일한임상시험에대해중복출판된논문의경우분석에적절한평가변수를제시한연구를사용하여결과를도출하였다. 문헌제외기준은 (1) 다른질병에 imatinib, dasatinib, nilotinib 의효과를평가한경우, (2) 약물의약동학적지표를평가변수로본경우, (3) 약물의이상반응을 1차변수로본연구, (4) 진단이나약물기전을규명하는목적으로진행된연구, (5) 동일용량에대해제시된결과 ( 제시된반응종류및치료기간 ) 가 2개이상일치하지않은연구등이다. CML에서의혈액학적반응, 세포학적반응, 분자반응에대한정의는일반적인 CML에서의정의를사용하였고, 이는다음에해당한다. 26),27) (1) 혈액학적반응 - Complete Hematologic response, CHR: WBC <10 x 10 9 /L, basophils <5 percent, no myelocytes, promyelocytes, myeloblasts in the differential, Platelet count <450 x 10 9 /L, Spleen nonpalpable (2) 세포유전학적반응 - Complete cytogenetic response (CCgR): no Ph+ metaphases, partial cytogenetic response (PCgR): 1 percent to 35 percent Ph+ metaphases, major cytogenetic response (MCgR): CCgR plus PCgR, minor cytogenetic response (mcgr): 36 percent to 65 percent Ph+ metaphases, minimal cytogenetic response (mincgr): 66 percent to 95 percent Ph+ metaphases, none (nocgr): >95 percent Ph+ metaphases (3) 분자학적반응-complete molecular response (CMolR): PCR (polymerase chain reaction) 에의한 BCR-ABL mrna의미검출, major molecular response (MMolR): ABL에대한 BCR-ABL 비가 0.1 percent 이하통계분석선정된논문에서대상피험자정보, 치료용량및용법, 치료기간및혈액학적세포유전학적검사의시기등을추출하여정리하였고, 이러한과정은 2명의연구자가시행하여일치하는결과를사용하였다. 만일불일치하는정보에대해서는재논의를통해의견이일치하는사항을사용하였다. 가장많은연구에서치료율로제시한것을분석하고자하여, 결과변수로 CHR, MMolR, CCgR의발현율로분석하였다. 1차선택치료제로서사용된경우에서는이상반응도분석에포함하였다. 동질성검정은 Chi-square test를통해실시하고, I2값으로제시하였고, 만일동질성이확보된다면, fixed effect model을사용하고, 그렇지않은경우 random effect model을사용하여분석하였다. 출판된논문이 3편이상인경우 publication bias를 Begg s rank correlation method 와 Egger s regression method를사용하여 funnel plot으로분석하도록하였고, 모든통계분석은 Comprehensive Meta-analysis Software, Version 2 (Biostat, Englewood, USA) 을사용하여, 양측검정으로실시되었다

4 유기연 : 만성골수성백혈병치료제의효과 : 메타분석 Table 1. Characteristics of studies included in this meta-analysis Target subjects Study name Study medication No. of pts Outcomes Kantarjian H, et al. (2010) 28), imatinib 519 CCgR, MMolR Saglio G, et al. (2010) 29) Nilotinib, imatinib 565 CCgR, MMolR 1st line therapy Cortes JE, et al. (2010)a 30) Rosti G, et al. (2009) 31) Nilotinib CCgR, MMolR Yusuf B, et al. (2012) 32) Imatinib 31, MMolR Cortes JE, et al. (2010)b 33) Imatinib 476, MMolR Maya KM et al. (2010) 34) Nilotinib 88, MMolR Giuseppe S, et al. (2010) 35) 210, MMolR Klamova H, et al. (2010) 36) 71, MMolR Neil P, et al. (2010) 37) 670, MMolR Vinogradova O, et al. (2009) 38) 18, MMolR Timothy H, et al. (2009) 39) Nilotinib 321, MMolR Kantarjian H, et al. (2009) 40), imatinib 150, MMolR Apperley JF, et al. (2009) 41) 174 2nd line therapy Arinobu T, et al. (2009) 42) Nilotinib 27, MMolR Sakamaki H, et al. (2009) 43) 30 Cortes J, et al. (2008) 44) 157 CCgR Coutre P, et al. (2008) 45) Nilotinib 119 Kantarjian H, et al. (2007)a 19) Nilotinib 280, MMolR Roberto L, et al. (2011) 46) 125 CCgR, MMolR Kantarjian H, et al. (2007)b 47) 49 Cortes J, et al. (2007) 48) 116 Hochhaus A, et al. (2007) 16) 186 Giles FJ, et al. (2010) 49) Nilotinib 60 3rd line therapy Garg RJ et al. (2009) 50) Nilotinib, dasatinib 48, MMolR Alfonso Q et al. (2007) 51) 23 연구결과문헌검색을한결과총 131편의논문이검색되었으며, 해당논문들은선정및제외기준에의해분류되었다. 이중 1차선택치료제로서 6편, 2차치료제로서 17 편, 3차치료제로서 3편이수집되었다 (Table 1). 16),19),28)- 51) 같은임상시험에대해서는가장많은환자를포함하고적절한결과변수를제시한논문에대해자료를정리하였고, 제외된논문은기전이나진단관련한논문 27 편, CML이아닌다른질환에의해사용한연구 59편, 이상반응관련논문 5편, 약동학관련논문 6편, 동일임상시험에의한논문 8편이었다 (Fig. 1)

5 JKSHP, VOL.30, NO.4 (2013) Fig. 1 Flow diagram of literature search and trial selection process Fig. 2 Complete cytogenetic response(ccgr) rates at 12months with imatinib, dasatinib, and nilotinib for the patients newly diagnosed CML 1차치료선택제 CML의 1차치료선택제로서임상시험을진행한연구에서 imatinib 400 mg qd, dasatinib 100 mg qd, nilotinib 400 mg bid를분석하였으며각연구에서제시된치료율중가장많은빈도로제시된결과변수는 12개월의 CCgR, MMolR로수집되었 다. 먼저 CCgR의발현율을볼때 imatinib 400 mg qd에서는 (95% CI: 0.641, 0.709) 으로나타났고, dasatinib 100 mg qd에서는 (95% CI: 0.790, 0.878), nilotinib 400 mg bid 에서는 (95% CI: 0.749, 0.838) 로나타났다 (Fig. 2). 또한 MMolR은 imatinib, dasatinib,

6 유기연 : 만성골수성백혈병치료제의효과 : 메타분석 nilotinib의순으로 (95% CI: 0.233, 0.299), (95% CI: 0.426, 0.541), (95% CI: 0.374, 0.489) 로나타났으며 (Fig. 3), 즉 2세대 TKIs의효과가 CCgR, MMolR 모두에서 imatinib 400mg qd 보다더높은유효성이가진것으로분석되었다. 이상반응은 grade 3 or 4 neutropenia와 grade 3 or 4 non hematologic adverse reaction을분 Fig. 3 Major molecular response (MMolR) rates at 12months with imatinib, dasatinib, and nilotinib for the patients newly diagnosed CML Fig. 4 Grade 3 or 4 neutropenia ADR event rates of imatinib, dasatinib, and nilotinib in the patients newly diagnosed CML

7 JKSHP, VOL.30, NO.4 (2013) Fig. 5 Grade 3 or 4 non hematologic adverse reaction rates of imatinib, dasatinib, and nilotinib in the patients newly diagnosed CML Fig. 6 Complete cytogenetic response(ccgr) rates between dasatinib and nilotinib for the patients that are intolerance or resistant to imatinib therapy 석하였다. Grade 3 or 4 neutropenia에대해서 imatinib의경우 (95% CI: 0.199, 0.265), dasatinib (95% CI: 0.426, 0.541), nilotinib (95% CI: 0.071, 0.135) 로나타났다. 즉, nilotinib 400 mg bid 의경우다른두치료제에비해 grade 3 or 4 neutropenia은유의한차이로적게나타났다 (Fig. 4). Non hematologic adverse reaction의경우에는 imatinib (95% CI:

8 유기연 : 만성골수성백혈병치료제의효과 : 메타분석 Fig. 7 Major molecular response (MMolR) rates between dasatinib and nilotinib for the patients that are intolerance or resistant to imatinib therapy 0.032, 0.069), dasatinib (95% CI: 0.117, 0.268), nilotinib (95% CI: 0.059, 0.148) 으로나타나 dasatinib에비해서는 imatinib이훨씬적은이상반응을나타냈다 (Fig. 5). 2차치료선택제 Imatinib의치료후내성이생기거나, 내약성이적어 dasatinib 이나 nilotinib으로치료한환자군에대한연구는총 17편으로수집되었다. 이연구에서는각각 dasatinib 100 mg qd, dasatinib 70 mg bid, nilotinib 400 mg bid로사용하였고그결과변수로는, MMolR에대해서분석하였다. CCgR을결과변수로본연구는 dasatinib 100 mg qd 3건, dasatinib 70 mg bid 9건, nilotinib 400 mg bid로치료용량을투여한연구 5건으로총 17편이었고, CCgR의발현빈도는 dasatinib 100 mg qd는 (95% CI: 0.474, 0.597), dasatinib 70 mg bid (95% CI: 0.377, 0.436), nilotinib 400 mg bid (95% CI: 0.283, 0.353) 으로분석되었고 (Fig. 6), MMolR을결과변수로제시한연구는총 6편이며, 용량에따라서 dasatinib 100 mg qd 2편, dasatinib 70 mg bid 2편, nilotinib 400 mg bid 2편으로검색되었다. 그효과는 dasatinib 100 mg qd, dasatinib 70 mg bid, nilotinib 400 mg bid 순으로 (95% CI: 0.253, 0.376), (95% CI: 0.274, 0.410), (0.187, 0.292) 로나타났다 (Fig. 7). CHR에대해서는총 15편의논문이제시하였고, 각약물에대해서는 dasatinib 100 mg qd 2건, 70 mg bid 8건, nilotinib 400 mg bid 5건으로수집되었다. 100 mg qd (95% CI: 0.877, 0.953), dasatinib 70 mg bid (95% CI: 0.557, 0.639), nilotinib 400 mg bid (95% CI: 0.570, 0.659) 으로 CHR의발현율이분석되었다 (Fig. 8). 즉, CCgR로분석하여보았을때 dasatinib 100 mg qd의효과가통계적으로유의하게다른두약물보다좋은결과로나타났고, 이어서 dasatinib 70 mg bid 군이 nilotinib 군에비교하여도유의하게좋은결과를보여주었다. CHR에대해서는 nilotinib 400 mg bid, dasatinib 70 mg bid에비교하여 dasatinib 100 mg qd가더높은빈도로나타났고, MMolR에대해서는 nilotinib 400 mg bid, dasatinib의 100 mg qd, 70 mg bid 모두에서유의한차이가나타나지는않았다

9 JKSHP, VOL.30, NO.4 (2013) Fig. 8 Complete Hematologic response (CHR) rates between dasatinib and nilotinib for the patients that are intolerance or resistant to imatinib therapy Fig. 9 Complete cytogenetic response (CCgR) rates [A] and complete Hematologic response (CHR) [B] rates and between dasatinib and nilotinib for the patients that are intolerance or resistant to imatinib therapy and another second generation TKIs

10 유기연 : 만성골수성백혈병치료제의효과 : 메타분석 3차치료선택제 Imatinib에치료실패한환자가 dasatinib에의한치료가다시실패하였을때 nilotinib 400 mg bid로치료한후그결과를제시한연구와, 1차 imatinib에의한치료실패이후 nilotinib의치료에도적절한효과가나타나지않은환자들에대해서 dasatinib 70 mg bid로치료를하여그효과를제시한연구들을대상으로분석을실시하였으며, 이는각각 2편의논문이수집되었다. 먼저 CCgR에대한분석으로는 dasatinib 70 mg bid로치료하였을때, (95% CI: 0.121, 0.346) 의발현율을나타내었고, nilotinib 400 mg bid 로치료하였을때 (95% CI: 0.092, 0.269) 로나타났다. CHR에대해서는 dasatinib 70 mg bid의효과가 (95% CI: 0.455, 0.715), nilotinib 400 mg bid는 (95% CI: 0.347, 0.586) 으로두약물의 3차치료선택치료제로서의효과는통계적으로유의하지않았다 (Fig. 9). 민감도분석및 Publication bias 민감도분석결과하나의연구에의한현저한차이는나타나지않았으며 3편이상출판된연구에대해서 publication bias를분석하였을때, funnel plot 역시명확한비대칭이나타나지않았고, Begg s test 와 Egger s test 모두에서 publication bias가보여지지않았다. 고찰및결론 1차치료선택제로서 dasatinib과 nilotinib에대한직접적인비교임상연구가아직진행된바없는시점에서본연구는여러연구들에서의 TKIs의약물효과를혈액학적, 세포유전학적, 또는분자학적반응으로분석하여그효과를비교하고자하였다. 두임상시험만을비교한연구 25) 에서는 nilotinib에서 dasatinib보다 MMolR의효과가유의하게높은것으로나타났으나, 본연구에서는 1차치료선택제로 nilotinib과 dasatinib, imatinib의효과를비교하였을때 2세대 TKIs의효과 (CCgR, MMolR) 가 imatinib 400 mg qd 보다더유의하게높게나타났으나 2세대 TKIs 사이에서는유의한차이를보여 주지않았다. 이는다른임상시험도포함하여분석하였기때문에그결과가다른것으로판단되며, CCgR 역시함께분석하여보다객관적인근거를제시하였다고할수있겠다. 또한 Elias Jabbour의연구 52) 에서와마찬가지로 imatinib과의비교에서는 2 세대 TKIs가확연히더높은효과를보여주었다. 미국 FDA 22),23) 와우리나라식약처 24) 에서는 imatinib에내약성이적거나내성이있어치료에실패한환자에게 2차선택치료제로 dasatinib 70 mg bid, 100 mg qd 모두허가를받았다. 그러나본연구에서는 dasatinib 100 mg qd에서더높은빈도의 을보여주는것으로나타났고, MMolR 에서는그결과가유의하게다르지않은것으로나타났다. 또한 Shah NP 53) 의연구에서는이상반응역시훨씬적은것으로나타나 dasatinib 70 mg bid 보다는 100 mg qd 용법이더적절하다고사료된다. 2차선택치료제로서 dasatinib 100 mg qd와 nilotinib 400 mg bid를비교하였을때는 CCgR은 nilotinib보다 dasatinib 100 mg qd에서더우세하게나타났고, CHR의빈도는 dasatinib 100 mg qd에서 dasatinib 70 mg bid, nilotinib 400 mg bid 보다우세한것으로나타났으며, MMolR은모두에서비슷한결과로나타나, Tam의연구 32) 에서 을용량을고려하지않은단순히두약물을비교하였을때 nilotinib에서더높은효과로보고한것과는상이한결과가나타났다. 3차치료제로서의약물의효과는, dasatinib과 nilotinib 두약물을직접적으로비교한 Garg RJ, et al 50) 에서는 dasatinib의효과가더좋은경향성을나타내었지만통계적으로는유의한차이를보여주지않았던것처럼다른연구들과함께메타분석을실시하였을때에도두약물에서유의한차이는나타나지않았다. 향후이약물에서직접적인비교연구가보다많이진행되어약물간효과및이상반응을다양한측면에서제시할수있을것이다. 결론적으로만성골수성백혈병에서 1차치료선택제로서는 2세대 TKIs가 imatinib 보다더좋은치료율을나타내었지만, 이상반응은보다높은빈도로나타나는경향을보였고, 2차치료선택제로서는 dasatinib 100 mg qd에서가장효과가좋은경향

11 JKSHP, VOL.30, NO.4 (2013) 성을나타내었으며, 3차치료제에서는 2세대 TKIs 인두약물에서통계적으로유의한차이가나타나지않은것을볼수있었다. 향후 2세대 TKIs의 1차, 2 차, 3차 CML 치료제로서무작위비교임상이진행되어그효과를비교분석하여 2세대 TKIs 효과의경향성을제시할수있다면약물사용에긍정적인역할을할수있을것이라사료된다. 감사의말씀본연구의자료수집및검토과정에있어서수고해준대학원생정지현, 윤상이에게감사하며, 또한본연구는 2011년동덕여자대학교연구비지원에의하여수행된것으로이에감사드립니다. 참고문헌 1) Faderl S., Talpaz M., Estrov Z., and Kantarjian H.M. : Chronic myelogenous leukemia: biology and therapy, Annals of Internal Medicine, 131(3), (2006) 2) 013/ _5873.html (Accessed on November 30th (2012) 3) Biggs J.C., Szer J., Crilley P., Atkinson K., Downs K., Dodds A., Concannon A.J., Avalos B., Tutschka P., and Kapoor N. : Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2., Blood, 80(5), (1992) 4) Pavlu J., Kew A.K., Taylor-Roberts B., Auner H.W., Marin D., Olavarria E., Kanfer E.J., MacDonald D.H., Milojkovic D., Rahemtulla A., Rezvani K., Goldman J.M., Apperley J.F., and Szydlo R.M. : Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase, Blood, 115(20), (2010) 5) Cortes J., and Kantarjian H. : How I treat newly diagnosed chronic phase CML, Blood, 120(7), (2012) 6) Verstovsek S., Golemovic M., Kantarjian H., Manshouri T., Estrov Z., Manley P., Sun T., Arlinghaus R.B., Alland L., Dugan M., Cortes J., Giles F., and Beran M. : AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells, Cancer, 104(6), (2005) 7) Kantarjian H.M., Giles F., Quint?s- Cardama A., and Cortes J. : Important therapeutic targets in chronic myelogenous leukemia, Clin Cancer Res, 13(4), (2007) 8) Weisberg E., Manley P.W., Cowan-Jacob S.W., Hochhaus A., and Griffin J.D. : Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia, Nat Rev Cancer, 7(5), (2007) 9) Mauro M.J., and Druker B.J. : STI571: targeting BCR-ABL as therapy for CML, Oncologist, 6(3), (2001) 10) Savage D.G., and Antman K.H. : Imatinib mesylate-a new oral targeted therapy, N Engl J Med, 346(9), (2002) 11) Tsao A.S., Kantarijian H., and Talpaz M. : STI-571 in chronic myelogenous leukaemia, Br J Haematol, 119(1), (2002) 12) Druker B.J., Guilhot F., O'Brien S.G., Gathmann I., Kantarjian H., Gattermann N., Deininger M.W., Silver R.T., Goldman J.M., Stone R.M., Cervantes F., Hochhaus A., Powell B.L., Gabrilove J.L., Rousselot P., Reiffers J., Cornelissen J.J., Hughes

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