대한내과학회지 : 제 73 권제 5 호 2007 종 설 청소년급성림프구성백혈병 전남대학교의과대학내과학교실 김형준 =Abstract= Adolescents and young adults (AYA) with acute lymphoblastic leukemia Hyeoung-Joon Kim, M.D., PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwang-ju, Korea Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) constitute a distinct population from children and older adults. However, AYA represent a minority of patients enrolled onto either adult or pediatric clinical trials. As a result, little information is available regarding complete remission (CR), event-free survival (EFS) and overall survival (OS) rates for this age group, and the appropriate treatment regimen for this group of patients remains elusive. A systematic review of all published clinical trials, which provide data on treatment and outcome of AYA with ALL, has been summarized in an effort to determine whether they should be treated on pediatric or adult protocols. AYA with ALL have far superior outcomes when treated on more intensive pediatric regimens and are required specific collaborative trials in order to optimize and improved outcomes.(korean J Med 73:459-463, 2007) Key Words : Adolescents and young adults (AYA), Acute lymphoblastic leukemia (ALL) 환자의나이는급성백혈병치료에있어중요한치료관련예후인자로알려져있다. 또한, 성인과소아에서발생되는급성백혈병의임상적양상및치료반응에차이가있어소아에서는급성림프구성백혈병이호발하며성인에서는급성골수구성백혈병의빈도가더많은것으로보고되었다. 성인급성림프구성백혈병의무사고생존율은 (event-free survival) 40% 미만이데반해 10세미만소아급성림프구성백혈병의무사고생존율은 80% 에준한다 1-3). 그러나이러한소아의치료성적이청소년, adolescents and young adults (AYA) 시기에발생된급성림프구성백혈병의치료성적으로이어지지는못하고있다. 특히, 급성림프구성백혈병치료방침에서청소년이란연령의특성상, 성인의치료방침 (adult protocol) 에따라치료한환자와소아의치료방침 (pediatric protocol) 에따라치료한환자의치료결과에서도차이를보일수있 다. 청소년급성림프구성백혈병에대한치료성적에대하여 1983년에서 1989년까지 Children's Cancer Group (CCG) ALL trials의 6년무사고생존율 59%, 이후 Cancer and Leukemia Group B (CALGB) 및 UKALL X and Xa trials 등에의해 15세에서 21세사이의연령에대한치료성적및임상적특성에대한연구결과가보고되었다 1, 3). 이에본논문에서는청소년급성림프구성백혈병을대상으로생물학적및임상적특징과성인과소아치료방침에따른치료결과의차이를분석하였다. 청소년급성림프구성백혈병에대한연령의정의청소년백혈병에대한연령의정의는명확한연령기준은없으나소아치료방침과성인치료방침의치료를받은환자의분석을위하여 15세에서 21세사이를기준으 - 459 -
-The Korean Journal of Medicine : Vol. 73, No. 5, 2007 - Table 1. Prognostic factors in childhood acute lymphoblastic leukemia (ALL) Leukemic Subtype Favorable Prognostic Factors Unfavorable Prognostic Factors B cell precursor T cell Hyperdiploidy TEL-AML1 fusion Trisomies 4,10, and 17 HOX11 overexpression t(11;19) with MLL-ENL fusion Poor early response MLL rearrangement in infants Philadelphia chromosome Leukocyte count >50 10 9 /L Age > 10 years at diagnosis Poor early response Low dose-intensity chemotherapy 로하였는데, 이는성인치료방침에서의최소연령기준이 15세까지였고, 소아치료방침의최고연령기준이 21세까지로구성되어있기때문이다. 청소년급성림프구성백혈병의임상적및생물학적특성청소년급성림프구성백혈병중 T-세포림프구성백혈병의발생빈도는 23.2% 로보고되며높은백혈구수치 (>50 10 9 /L) 와헤모글로빈수치 (>11 g) 를보이는반면, 소아에서흔히보이는간비종대나림프선증대소견등은보이지않는것으로보고된다. 급성림프구성백혈병의다양한임상경과는염색체이상과연관된백혈병세포의약제민감성과약제내성과연관되어진다. Pre-B 세포급성림프구성백혈병에서좋은예후를보이는염색체이상은 hyperdiploidy (>50 chromosomes) 과 TEL-AML1 fusion 이며, MLL rearrragnement나필라델피아염색체등은불량예후인자로알려져있다 ( 표 1). Medical Research Council (MRC) 분석에따르면, 16-21세의급성림프구성백혈병에서 t(9;22) 염색체이상 (Ph+) 의빈도는 7.5% 로 1~9세의 1.3% 와 1 0~19세의 3.4% 에비해연령이증가할수록빈도가증가됨을보였고, 반면에소아에서흔히관찰되는 t(12;21) 및 hyperdiploidy 의염색체이상빈도는매우낮은것으로분석되었다 4, 5). 또한, 연령의증가에따른백혈병세포의약제저항의빈도는증가되어지고항암제의약동학적유효성은감소하게된다. 백혈병치료에대한반응은백혈병세포의유전학적특징과환자의약물유전학적요인에의해결정되며이는환자의중요한예후인자로작용한다 6). 환자의골수내미세잔존질환 (minimal residual disease) 의측정은백혈병세포의면역표현형에따른유세포분석 (flow cytometry) 및 polymerase chain reaction (PCR) 분석을이용하여시행할수있으며이는골수내형태학적검사보다더욱민감하고특이적으로질환을추적관찰할수있다. 특히, 관해유도치료가종료된환자에서형태학적및분자생물학적관해 (leukemic involvement of <0.01% nucleated bone marrow) 를획득한환자에서그렇지못한환자보다우월한치료성적을보여줌을알수있다. 또한, 형태학적관해를이룬환자에서도미세잔존질환의수치가관해유도치료종료후 1% 이상으로유지되는경우높은재발율을보이며동종조혈모세포이식술의적응을고려할수있다. 이러한미세잔존질환 (MRD) 의측정을통해치료위험군의분류를시행하고, 각각의위험군에따른치료방침을정함으로써환자의치료경과를향상시킬수있다 4). 급성림프구성백혈병환자에서는중추신경계재발을방지하기위한치료 (CNS-directed therapy) 가필요하며두개방사선치료 (cranial irradiation) 나척수강내항암치료 (intrathecal chemotherapy) 를시행하고있다. 중추신경계재발의고위험환자로는 Ph+ 급성림프구성백혈병을포함한고위험유전학적소견을가진환자나 T-세포급성림프구성백혈병, 많은백혈병세포의증식소견 ( 백혈구수치 >100 10 9 /L), 남성인경우, 그리고진단당시뇌척수액내백혈병세포의침윤을보인경우등을들수있다 7). 청소년급성림프구성백혈병의치료방침에따른치료성적급성림프구성백혈병에서연령의증가에따른생물학적차이는명확하게차이가나며연령에따른치료결과의차이는 1~5세연령대의무사고생존율은 80% 에달하나 15~19세사이의연령대는무사고생존율이 60% 로감소되고성인에이르러서는 40% 까지감소된다. 급성림프구성백혈병환자에서가장중요한예후인자로생각되 - 460 -
- Hyeoung-Joon Kim : Adolescents and young adults (AYA) with acute lymphoblastic leukemia - Figure 1. The event-free survival (EFS) of young adults ages 16-21 with acute lymphoblastic leukemia (ALL) treated on CCG and CALGB trials from 1988-1995. (Reprinted from Blood. 2000;96:467a) 어지는것은백혈병세포의유전학적및분자생물학적특성으로결정된다. 염색체이상들에따른연령에따른빈도와치료결과는표 2에정리되었으며가장중요한염색체이상은 Ph+ 염색체이상이다. Ph+ 급성림프구성백혈병의빈도는연령에비례하고치료의성적또한매우불량하다. 대표적인성인치료방침으로 MD Anderson Cancer Center에서보고한 Hyper-CVAD 항암치료법은 30세미만의환자에서관해율은 98% 및 5년무질환생존율 (disease-free survival) 과전체생존율은 54% 로 30 49세환자군의관해율 89% 와전체생존율 42% 에비해매우좋은성적을보고하고있다 8, 9). 이러한성인치료방침의항암치료는대부분 15세이상을대상으로하고있으며 79세까지의고연령환자도대상으로포함하고있다. 젊은연령층의전체생존율이고연령층의환자보다월등히높음을보였지만, 이연구의제한점은똑같은치료방법으로젊은연령을치료하는것보다젊은연령층에서치료의강도를강화시킴으로서더욱향상된치료결과가도출될수있음을배제할수없다. 또한, 다양한성인치료방침에서개개항암치료제의역할이명확히규명되어지지않은반면, 소아치료방침에서는중추신경계재발의방지에 dexamethasone 이 prednisolone보다우월하게작용하고, 비골수억제항암제 (vincristine, corticosteroids, L-asparaginase) 의용량강화를통한치료가청소년급성림프구성백혈병의전체생존율을증가시킨다는연구등이규명되어있다 2, 10, 11). 성인치료방침에따른청소년급성림프구성백혈병의치료의성적은구체적으로언급된보고는없으며, 대부분 15~30세사이의연령에대한치료결과가보고되었다. 후향적치료성적보고로서 French ALL cooperative group (FRALLE) 93 소아치료방침군과 Leucemie Aigue Lymphoblastique de L' Adulte (LALA) 94 성인치료방침군의비교에따르면소아의치료방침에따라치료한군에서보다좋은치료성적을보고하였다 12). FRALLE93 치료방침은 LALA94와비교하여 20배의 asparaginase 및 5배의 prednisolone을사용하였고, anthracyclines의치료용량도성인에비해많았었다. 항암치료후관해율 (remission rate) 에서소아치료방침으로치료한군이높았으며, 다변량분석 (multivariate analysis) 에서도진단당시의백혈구수치 (>50 10 9 /L) 와치료방침의차이가통계적으로유의한인자로분석되었다. 또한 Dutch-Belgian Haemato-Oncology Cooperative Study Group (HOVON) 연구에서도소아치료방침으로치료한청소년급성림프구성백혈병환자에서높은무사고생존율과낮은재발율 (25% vs 55%) 이관찰되었으며이연구에서도 asparaginase와 vincristine 등의항암제치료용량이소아치료방침에서훨씬더많이사용되었다 13). 성인치료방침에따른항암제구성은 vincristine, prednisolone, daunorubicin, cyclophosphamide 및 L-asparaginase 로구성되었으며중추신경계예방치료를동반하였다. 또한, 관해유도후조직적합항원이일치하는공여자가있을경우동종조혈모세포이식술을시행하였고이식의공여자가없는경우, 자가조혈모세포이식술이나공고항암요법을지속하는방침으로치료하였다. CALGB와 Children s Cancer Group (CCG) 의보고에의하면, 1988년에서 1998년까지 10년동안 16~21세의급성림프구성백혈병환자 103명과 196명을대상으로비교대조분석을시행한바, 양군간의연령, 성비, 면역학적표현형, 백혈구수치및염색체이상은일치하였으며, 완전관해율에서도 CCG 96% 와 CALGB 93% 로유사한소견을나타냈다. 그러나 6년무사고생존율에서 CCG 군에서는 64% 였으나 CALGB군에서는 38% 로소아치료군인 CCG 치료성적이우월한비슷한연구결과를보고하였다 14) ( 그림 1). 또한소아와성인치료방침에서항암제치료용량의차이를없애고같은치료방법을통한연령의차이에따른 UKALL X (14세미만소아 ) 및 UKALL Xa (15세이상청소년 ) 의분석에따르면, 10~14세의 5년무질환생존율 - 461 -
- 대한내과학회지 : 제 73 권제 5 호통권제 567 호 2007 - Table 2. Comparison of adolescent/young adults with acute lymphoblastic leukemia (ALL) on pediatric versus adult clinical trials Cooperative Group/Study Period No. of Patients CR (%), 5-year EFS (%), 5-year North America 1988-1998 Age of patients (yrs): 16-21 CCG 1882 (peds) 196 96 64 * CALGB 8811-9511 (adult) 103 93 38 * French 1993-1994 Age of patients (yrs): 15-20 FRALLE-93 (peds) 77 94 67 LALA-94 (adult) 100 83 41 Dutch 1985-1999 Age of patients (yrs): 15-20 DCOG ALL (peds) 15-18 yrs 47 98 69 HOVON (adult) 15-18 yrs 44 91 34 19-20 yrs 29 90 34 Italian 1996-2000, Age of patients (yrs): 14-18 AIEOP (peds) 153 94 83 GIMEMA (adults) 95 95 55 * 6-year EFS, DFS CR, complete remission; EFS, event-free survival; DFS, disease-free survival (Reprinted from Hematology Am Soc Hematol Educ Program. 2005) 은 49% 였으나 15~19세의 5년무질환생존율은 (DFS) 35% 로연령의차이가중요한예후인자로작용함을보여주었다 1). 결론결론적으로청소년급성림프구성백혈병은소아에비해높은빈도의 T세포면역형과 t(9;22) 염색체이상및높은빈도의나쁜염색체예후인자발현과낮은빈도의림프종형태의임상양상을보임으로써소아와다른임상결과를보이고있다. 또한, 성인과소아의치료방침에따른생존률과무사고생존률의차이는치료방침의항암제성분및용량의차이를보이고있으며성인치료방침에서는초기관해후동종또는자가조혈모세포이식술의적극적인도입에차이가있다. 그리고성인에서급성림프구성백혈병의발생빈도에비해소아의급성림프구성백혈병의빈도는매우높고성인에서의급성림프구성백혈병은매우다양한형태로나타나는특징을가지고있다. 이에향후소아및성인치료방침의적절한조합을통한청소년연령에맞는치료방침의제시와정확한치 료반응의평가를통한예후를판정하여개개의환자에게맞는치료방침의제시가필요할것으로사료된다. 중심단어 : 청소년급성림프구성백혈병, 성인및소아치료방침, 치료성적 REFERENCES 1) Chessells JM, Hall E, Prentice HG, Durrant J, Bailey CC, Richards SM. The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties. Leukemia. 12:463-473, 1998 2) Schrappe M, Reiter A, Ludwig WD, Harbott, J., Zimmermann, M., Hiddemann, W., Niemeyer, C., Henze, G., Feldges, Z., Zintle, F., Kornhuber, B., Ritter, J., Welte, K., Gadner, H. Riehm. H. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German- Austrian-Swiss ALL-BFM Study Group. Blood. 95:3310-3322, 2000 3) Gaynon PS, Trigg ME, Heerema NA, Sensel, MG, - 462 -
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