untitled

Size: px

Start display at page:

Download "untitled"

세은 강
5 years ago
Views:

1 Clinical Pediatric Hematology-Oncology Volume 24 ㆍ Number 1 ㆍ April 2017 ORIGINAL ARTICLE 다운증후군에서일과성골수증식질환과백혈병의임상적특성의차이에대한단일기관연구 황인찬ㆍ양새미ㆍ천은재ㆍ황금빛ㆍ정현주ㆍ이장훈ㆍ박문성ㆍ박준은 아주대학교의과대학소아과학교실 Differences in Clinical Characteristics of Transient Myeloproliferative Disease and Leukemia in Down Syndrome: A Single University Hospital Study Inchan Hwang, M.D., Saemi Yang, M.D., Eunjae Cheon, M.D., Gumbich Hwang, M.D., Hyun Joo Jung, M.D., Jang Hoon Lee, M.D., Ph.D., Moon Sung Park, M.D., Ph.D. and Jun Eun Park, M.D., Ph.D. Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea Background: Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing leukemia. However, in some patients, leukemia does not become apparent despite significant number of blast cells in the peripheral blood. This condition is called Transient myeloproliferative disorder (TMD), and is a disease entity unique to DS newborns and defined as the morphologic detection of blasts in DS less than three months of age. The present study investigated whether there was a difference between leukemia and TMD, and determined prognostic and risk factors. Methods: We collected blood samples from 317 patients of 433 DS confirmed patients. We found 18 patients who had blast cells in their peripheral blood. Results: Twelve patients were positive for blasts during the neonate period, and only one patient progressed to leukemia. The other 11 patients were later diagnosed with TMD. Six more patients were later diagnosed with leukemia, therefore, 7 patients were diagnosed with leukemia in total. All patients diagnosed with leukemia had anemia at the time of diagnosis, which was not found in TMD patients. All leukemia patients developed their disease after three months of life. Acute Myeloid Leukemia (AML) patients had additional chromosome mutation to trisomy 21 when they were diagnosed. Conclusion: In patients with Down Syndrome, anemia at diagnosis and age of onset could be helpful in distinguishing TMD from acute leukemia. Cancerous mutations in the chromosomes of peripheral and marrow blast cells of Down syndrome patients may foreshadow acute leukemia. Key Words: Down syndrome, Transient myeloproliferative disorder, Acute myeloid leukemia pissn / eissn Clin Pediatr Hematol Oncol 2017;24:49 54 Received on March 19, 2017 Revised on March 26, 2017 Accepted on April 12, 2017 Corresponding Author: Jun Eun Park Department of Pediatrics, Ajou University School of Medicine, 164, WorldCup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: Fax: pedpje@ajou.ac.kr ORCID ID: orcid.org/

2 Inchan Hwang, et al 서론 21번세염색체증인다운증후군은 600-1,000명중한명꼴로발생하는가장흔한염색체질환으로, 심장기형부터갑상선기능저하등의내분비질환, 혈액학적질환까지다양한질병을동반할수있다. 그중에서도백혈병의발생률은일반인구에서의발생률보다 10-20배, 특히 5세미만에서는 50배까지도달하는것으로알려져있으며, 그중에 French-American-British (FAB) 분류에서급성골수성백혈병 M7 (AML M7) 으로분류되는급성거대핵모세포백혈병의경우일반인구보다약 500배가량많이발생하는것으로알려져있다. 다운증후군에서백혈병의양상은나이에따라다소차이가있어서, 생후 4세까지는급성골수성백혈병이대부분이며, 4세이후로는급성골수성백혈병과급성림프모구백혈병의발생비율은정상소아들과비슷하여지나, 발생률은 10배정도높다 [1-3]. 또, 다운증후군환자들에서만특별하게나타나는질환으로일과성골수증식질환이있는데, 이질환은생후 3개월이내에말초혈액에서모세포들이발견되나, 특별한치료없이저절로소실되는것을특징으로한다 [4,5]. Berlin-Frankfurt-Munster (BFM) 의연구에서는말초혈액에서 5% 이상의모세포가관찰될때일과성골수증식질환으로진단한경우도있으나, Pediatric Oncology Group (POG) 와 Children s Oncology Group (COG) 의경우처럼사전적의미대로말초혈액에서모세포가관찰되기만해도진단하는경우가많으며 [5-8], 이런진단기준의차이때문에발생률이좀다르게보고되기는하나, 일반적으로알려진바로는다운증후군환자들의 7-10% 에서발생하며 10-30% 의환자들에서급성골수성백혈병으로진행할가능성이있다고알려져있다 [4,5,9,10]. 대부분의환자에서저절로호전되지만 10% 정도는이질환으로사망하는것으로알려져있다. 그 러나이질환의정확한치료기준이나치료방법은아직까지도확립되어있지않다 [4,5,7]. 저자들은본원에서시행한말초혈액검사결과에서모세포들이관찰된다운증후군환자들을대상으로임상적경과가어떻게되는지를평가하고, 이를통해백혈병과일과성골수증식질환의연관성및예후인자에대해알아보고자하였다. Table 1. Patients characteristics Leukemia (n=7) TMD (n=11) Sex (M:F) 5:2 8:3 Age 2 years 2 months 1 day-11years 1 day 1 day-54 days Initial symptoms/sign Fever Petechiae, bruise Respiratory symptom Hepatosplenomegaly 대상및방법 1998년 10월부터 2016년 9월까지아주대학교병원에서염색체검사를통해진단되어진료받은다운증후군환자의총수는 433명이었으며, 이중 317명이한번이라도전체혈구계산검사를진행하였고, 생후 3개월이내에검사를환자는 116명이었으며, 18명 (4.1%) 의환자의말초혈액에서모세포가확인되어이들의의무기록을후향적으로분석하였다. 18명의환자들중에서 3개월이내에혈액검사를시행한환자는 12명이었다. 백혈병의진단및분류는 FAB 분류에의거하였으며, 일과성골수증식질환의진단은 POG와 COG의기준과동일하게말초혈액에서모세포가관찰되기만하여도진단하는것으로하 TMD, transient myeloproliferative disorder Table 2. CBC profiles when the first blasts were revealed in peripheral blood WBC (/ L) Hgb. (g/dl) Plt. (/ L) Blast a) (%) Leukemia (n=7) TMD (n=11) T-test (P-value) 42,700 5,100-73, ,300 1,100-38, ,800 6,800-43, ,4000 4, , CBC, complete blood count; WBC, white blood cell; HgB, hemoglobin; Plt, Platelet; TMD, Transient myeloproliferative disorder. a) Percentage of blast in peripheral blood Vol. 24, No. 1, April 2017

3 TMD and Leukemia in Down Syndrome 였다 [5,6,8]. 결과 18명의대상환자들중백혈병으로진단된환자는 7명, 일과성골수증식질환으로진단된환자는 11명이었으며, 처음모세포가확인된때를기준으로하여각질환의연령중간값은각각 2년 2개월, 1일로백혈병으로진단된경우가나이가많은것을확인할수있었다. 3개월미만의다운증후군환자중에혈액검사를 1회라도시행했던경우는 116명으로, 혈액검사를시행한환아들중에서일과성골수증식성장애가확인된경우는 9.4% 였다. 호소하는증상으로는백혈병은발열, 멍과자반, 호흡증상, 간비비대등의전형적인백혈병의증상이더흔했던것에반해, 일과성골수증식질환에서는호흡증상외의증상은거의관찰되지않았으며, 무증상으로우연히발견된환자도 4명 ( 일과성골수증식질환환자의 36.4%) 이나되었다 (Table 1). 말초혈액에서모세포가처음으로관찰될때의백혈구, 헤모글로빈, 혈소판, 모세포의중간값을비교하였을때, 백혈구는두질환모두에서증가하여있었으며, 헤모글로빈수치는백혈병에서통계적으로유의하게감소되어있었다. 혈소판은백혈병에서더감소되어있으나통계적인유의를가지지는못하였으며, 모세포도백혈병이일과성골수증식질환의경우보다더높은것으로나타났으나혈소판의경우와마찬가지로통계적인유의점을나타내지는못하였다 (Table 2). 각질환에서의특징을살펴보면, 백혈병환자들의진단시기는모든환자에서 3개월이후였다. 급성림프모구백혈병은골수의세포유전학검사에서다운증후군이외의추가적인돌연변이가관찰되지않았으며 4세이후에모두진단된것에반해, 모든급성골수성백혈병은 FAB 분류의차이와상관없이다운증후군에추가적인돌연변이가동반되었다가치료예후판정을위한추적골수검사결과에서는소실되었으며진단시기가 4세이전인것을확인할수있었다 (Table 3). 일과성골수증식질환환자들의말초혈액에서모세포출현시기는생후 1일째가가장많았고, 가장늦게나타난환자는 54일째에처음발견되었으며, 급성골수성백혈병으로진행한한명의환자를제외한 11례모두특별한치료없이 3개월이전에말초혈액에서모세포가소실되었다. 또모세포가처음으로확인될때시행한말초혈액의염색체검사에서다운증후군외의추가적인돌연변이가동반되어있는경우는없었다 (Table 4). 백혈병과일과성골수증식질환환자들중에서증례한명씩특별한경과를가졌던환자들이있는데, 백혈병환자중에증 Table 3. Characteristics of down syndrome leukemia patients Cytogenetics in bone marrow After treatment Event and timing Status/follow-up (month) Case no. FAB Age At diagnosis 1 ALL 4 years Transfer to other hospital Unknown 21 months Transfer to other hospital AML M1 29 months Alive/12 Relapse 9 months +21[17]/48,sl,+8[3] ALL 11 years Alive/ AML M2 2 years 2 months Alive/22-49,XX,der(1)del(1)(p13.2)del(1)(q41),+11,+21? 6 AML M7 10 months Alive/ [14]/47,sl,add(7)(p22)[6] TMD to AML M7 99 days Dead of disease/12 - i(21)(q10)[13]/88-92,xxyy,+i(21)(q10),+i(21)(q10)[7] i(21)(q10) FAB, french-american-british; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; TMD, transient myeloproliferative disorder. Clin Pediatr Hematol Oncol 51

4 Inchan Hwang, et al Table 4. Characteristics of TMD patients and their Blast at first and peak Case no. Age at diagnosis (day) Sex Cytogenetics at first examination Period which blasts is visible in PB (day) Blast in PB (%) Initial result Peak result 7 1 M I(21)(q10) Progress to AML M M M M +21[18]/46, XY[2] F M M F 47,XX,+21[11]/46,XX[9] M +21* F M 46,XY,+21,der(14;21)(q10;q10) TMD, transient myeloproliferative disorder; PB, peripheral blood; AML, acute myeloid leukemia. 례 6번의경우, 생후 3개월이내에시행한전체혈구계산검사는정상소견으로모세포는관찰되지않았다. 생후 24주부터혈소판감소증이발생하였고, 10개월경추적검사로시행한검사에서모세포가출현하여골수검사시행후 AML M7으로진단되었다. 그러나이후특별한치료없이말초혈액에서모세포가소실되었고, 추적골수검사결과에서도완전관해소견확인되어현재특별한치료없이 2개월동안추적관찰중이다. AML M7으로진단당시의골수검사에서이전에말초혈액에서다운증후군진단될당시에확인되지않던추가적인돌연변이가확인되었고, 다른급성골수성백혈병환자들과동일하게이돌연변이는치료후완전관해판정시의골수검사에서호전되었다. 일과성골수증식질환에서백혈병으로진행한증례 7번의경우는생후 1일째말초혈액에서모세포가관찰되었으나, 이후검사결과에서줄어드는양상으로일과성골수증식질환으로생각하여경과관찰하였으나, 99일째까지도모세포관찰되며혈소판감소증, 빈혈, 황달, 처짐증상있어시행한골수검사에서 AML M7으로진행되는것이확인되었다. 이환자도생후 1일째시행한혈액검사결과에서모세포가관찰됨에도다운증후군이외에유전학적돌연변이는없었다가, AML M7으로진단된당시의골수검사결과에서추가적인돌연변이가관찰되고마찬가지로치료후소실되는것을확인할수있었다. 고찰다운증후군은특정인종, 지역별로유병률의차이는없으 나산모연령에따른위험요인은존재한다고알려져있다. 국내의경우에는출산연령이지속적으로올라감에따라고위험산모의비율또한높아지고있어다운증후군출생아의비율또한높아질것으로예상된다. 또한, 다운증후군환자들의출생초기사망의주된원인이었던심장기형과다른질환들에의한사망률또한줄어들면서기대수명이늘어나게되어출생초기의문제뿐아닌이후에발생하는질환에대한대책또한중요하게되었다 [11]. 과거에는다운증후군환자들에서백혈병의치료성적이좋지않다는보고가많았으나, 최근에는급성골수성백혈병과급성림프모구백혈병모두에서이전보다좋은치료법들이제시되고있다 [12-14]. 일과성골수증식질환은 1950 년대에처음으로보고되고제시된개념으로, 일과성백혈병, 일과성이상골수혈구형성으로도불리는데, 3개월미만다운증후군환자에서모세포가발견될때로정의한다 [5,15]. 발병률은예전연구에서는 10% 에달하는것으로알려져있으며, 태아의유병률또한상당할것으로예상이되고있으나대부분의경우사산또는유산이되며그런경우부검이이루어지지않는한확인이불가하여정확한발생률은더높을것으로생각된다 [5,16]. 일과성골수증식질환이침범하는장기로는간, 심장, 골수, 췌장, 피부, 비장, 신장, 폐등다양하며나타나는증상또한태아수종등의출생전증상부터, 폐, 신장침범과응고장애에의한사망, 무증상까지매우다양하다 [5,17]. 일과성골수증식질환이다운증후군에서만특징적으로나타나는이유는다운증후군에서의급성골수성백혈병이갖는특징과도큰연관이있는데, GATA1 유전자의돌연변이가비다 52 Vol. 24, No. 1, April 2017

5 TMD and Leukemia in Down Syndrome 운증후군환자에비해흔하며, 그표현형이삼염색체 21의유무에따라다르게나타나기때문인것으로알려져있다 [5,17,18]. GATA1 유전자의돌연변이는다운증후군환자에게서는백혈병유발인자로의역할을하며 cytarabine의높은치료효과와독성을동시에유발하는원인이되기도한다. 또, 다운증후군환자에서 FAB 분류중 AML M7에해당하는급성거대핵모세포백혈병이많은것이 GATA1 돌연변이의역할때문인것으로알려져있다 [17,19-21]. 일과성골수증식질환에서는이 GATA1 돌연변이의표현정도와추가적인돌연변이발생유무가증상발현정도나급성골수성백혈병으로의진행여부에영향을끼친다는보고가있다 [17,22]. 두질환은굉장히비슷해보이나차이점은분명존재하는데, 일과성골수증식질환의경우에는대부분의경우에서골수보다말초혈액에서모세포가더많거나비슷하게관찰된다는것과, 일과성골수증식질환의모세포는다른세포들로분화기능이있다는것등이여러연구를통해차이점으로제시되고있다 [6,17,23,24]. 일과성골수증식질환의진단은 Berlin-Frankfurt-Munster (BFM) 같은연구에서는말초혈액에서 5% 이상의모세포가나오는것을기준으로하는경우도있으나대부분의경우에는사전적인정의그대로말초혈액에서모세포가존재하기만해도진단하는것이일반적이다 [5]. 대부분의경우에서별다른치료없이호전되는것에대해서는두가지가설이있는데, 첫째로는간침범이많이되며태아단계에서의조혈이주로간에서이루어지는것을생각해보았을때에조혈기능이간에서골수로옮겨가며호전이된다는가설이있고, 두번째로는헤모글로빈을이루는소단위가태아시기와성인이다르듯유전적인기전에의한것이라는가설이있다 [25-27]. 일과성골수증식질환의치료는저용량 cytarabine 치료가효과가있다고알려져있으나연구자료마다제시하고있는치료용량이다달라이에대한추가적인연구가필요할것으로보인다 [5]. 치료기준도생명을위협하는증상이외에도모세포상승이동반될때등을추가적인치료기준으로제시하는연구가있었으나확립된치료기준은없다. 다만치료유무가추후백혈병으로의진행에상관이없는것으로되어있어높은치료독성을고려하였을때에치료에는신중을가해야할것으로생각된다 [5,7]. 예후는질병자체로인한사망률이 10% 정도에달하며추후백혈병으로진행될확률이 20-25% 에서존재하는것으로알려져있다 [5,28]. 본연구에서도환자의연령과질환과의연관성에대해서는대부분의연구를통해알려진것과같이일과성골수증식질환에서는 1예의백혈병으로진행한증례를제외하고는 3개월이전에말초혈액의모세포가모두호전이되는것을확인할수 있었고, 이를통하여생후 3개월이후에나타나는미성숙세포는백혈병으로의진행, 또는백혈병의발병일가능성이높다는것을알수있었다. 또상술한다운증후군백혈병의연령별분포와유사하게 4세이전백혈병환자들은모두급성골수성백혈병으로, 4세이후로는모두급성림프모구백혈병으로진단이됨을확인할수있었다 [5]. 다기관연구를통해제시된일과성골수증식질환의백혈병으로의진행예측인자는연구기관별로제시하는것에차이가있었는데, 먼저 POG의경우 21번세염색체외의추가적인핵형이상이발생할경우백혈병 ( 특히급성골수성백혈병 ) 으로의진행을의미한다는보고를하였다 [6]. 본원연구결과에서도이와동일하게급성골수성백혈병환자에서만다운증후군외추가적인유전학적돌연변이가확인되었으며일과성골수증식질환에서급성골수성백혈병으로진행한환자의증례에서백혈병으로진단될때돌연변이가추가되는것을확인할수있었다. BFM의연구에서는혈소판감소증과흉막삼출이백혈병으로의진행예측인자가됨을발표하였으나 [7], 본연구에서는혈소판감소증의경우에는통계적유의를갖지못하였으며, 흉막삼출이확인된환자가없어이에관하여는확인이불가능하였다. COG에서는 47일을기준으로그이상모세포가지속될경우백혈병이나타날확률이 29%, 그이전에소실될경우 18% 로모세포의지속기간이길수록백혈병이나타날확률이높아진다고보고하였다 [5,8]. 본연구에서도모세포가 47일미만으로지속된 8예에서는백혈병으로의진행이없었고 47일이상지속된 4례중 1예에서만백혈병으로의진행이확인되었다. 최근발표된한연구에서는일과성골수증식질환환자들보다백혈병환자들이나이가더많고더낮은헤모글로빈, 혈소판수치를가지는것과, 급성골수성백혈병에서는빈혈이더심한경우에사망한환자가더많음을나타내는보고가있었다 [29]. 본연구에서는백혈병환자들에서통계적으로유의하게헤모글로빈수치가낮은것을확인할수있었으나 (P=0.018), 혈소판의경우에는통계적인유의성을갖지는못하였으며, 백혈병에서빈혈의사망예측인자로의활용여부는추적관찰이길게된증례가적어확인이불가능하였다. 결론으로, 다운증후군환자에서모세포가관찰될때연령, 빈혈의정도및말초및골수에서발견되는모세포의염색체검사에서추가적인돌연변이의발생유무가일과성골수증식질환과백혈병의감별진단에도움이됨을보여주었다. 본연구는후향적으로진행되었으며연구대상의수가적다는제한점이존재하므로좀더적절한평가도구를찾기위해서는다기관협력연구가필요할것이다. Clin Pediatr Hematol Oncol 53

6 Inchan Hwang, et al References 1. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 2000;355: Lange B. The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br J Haematol 2000;110: Centers for Disease Control and Prevention (CDC). Improved national prevalence estimates for 18 selected major birth defects-united States, MMWR Morb Mortal Wkly Rep 2006;54: Zipursky A. Transient leukaemia-a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 2003; 120: Gamis AS, Smith FO. Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 2012;159: Massey GV, Zipursky A, Chang MN, et al. A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG Blood 2006;107: Klusmann JH, Creutzig U, Zimmermann M, et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008;111: Gamis AS, Alonzo TA, Gerbing RB, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 2011;118:6752-9; quiz Massey GV. Transient leukemia in newborns with Down syndrome. Pediatr Blood Cancer 2005;44: Seewald L, Taub JW, Maloney KW, McCabe ER. Acute leukemias in children with Down syndrome. Mol Genet Metab 2012;107: Lee W. Down syndrome. J Korean Pediatr Soc 2003;46: Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J, Zimmermann M. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005;19: Arico M, Ziino O, Valsecchi MG, et al. Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 2008; 113: Tigay JH. A comparison of acute lymphoblastic leukemia in Down syndrome and non-down syndrome children: the role of trisomy 21. J Pediatr Oncol Nurs 2009;26: Choi JK. Hematopoietic disorders in Down syndrome. Int J Clin Exp Pathol 2008;1: Henry E, Walker D, Wiedmeier SE, Christensen RD. Hematological abnormalities during the first week of life among neonates with Down syndrome: data from a multihospital healthcare system. Am J Med Genet A 2007;143A: Roy A, Roberts I, Norton A, Vyas P. Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis. Br J Haematol 2009;147: Ahmed M, Sternberg A, Hall G, et al. Natural history of GATA1 mutations in Down syndrome. Blood 2004;103: Ge Y, Jensen TL, Stout ML, et al. The role of cytidine deaminase and GATA1 mutations in the increased cytosine arabinoside sensitivity of Down syndrome myeloblasts and leukemia cell lines. Cancer Res 2004;64: Malinge S, Izraeli S, Crispino JD. Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 2009;113: Xavier AC, Ge Y, Taub JW. Down syndrome and malignancies: a unique clinical relationship: a paper from the 2008 william beaumont hospital symposium on molecular pathology. J Mol Diagn 2009;11: Kanezaki R, Toki T, Terui K, et al. Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. Blood 2010;116: Miyauchi J, Ito Y, Tsukamoto K, et al. Blasts in transient leukaemia in neonates with Down syndrome differentiate into basophil/mast-cell and megakaryocyte lineages in vitro in association with down-regulation of truncated form of GATA1. Br J Haematol 2010;148: Maroz A, Stachorski L, Emmrich S, et al. GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia. Leukemia 2014;28: Miyauchi J, Ito Y, Kawano T, Tsunematsu Y, Shimizu K. Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down's syndrome: a report of four autopsy cases and proposal of a hypothesis. Blood 1992;80: Gamis AS, Hilden JM. Transient myeloproliferative disorder, a disorder with too few data and many unanswered questions: does it contain an important piece of the puzzle to understanding hematopoiesis and acute myelogenous leukemia? J Pediatr Hematol Oncol 2002;24: Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer 2005;5: Cantor AB. Myeloid proliferations associated with down syndrome. J Hematop 2015;8: Li MJ, Lee NC, Yang YL, et al. Long-term outcome for Down syndrome patients with hematopoietic disorders. J Formos Med Assoc 2016;115: Vol. 24, No. 1, April 2017

7.Æ¯Áýb71ÎÀ¯È« š

7.Æ¯Áýb71ÎÀ¯È« š J KMA Special Issue Myelodysplastic Syndrome June Won Cheong, MD Yoo Hong Min, MD Department of Internal Medicine, Yonsei University College of Medicine E mail : jwcheong70@yumc.yonsei.ac.kr minbrmmd@yumc.yonsei.ac.kr