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인간생명과질병 백혈병 강원대학교의학전문대학원내과학교실혈액종양내과분과이희영

ㄴ 림프구 백혈구 백혈구 적혈구 혈소판

http://www.youtube.com/watch?v=fjoyaaygqfe

원인 AML 의발병원인을밝히는것은대부분의환자에서불가능하나, 유전성소인, 방사선조사, 화학약품등에대한직업성노출과항암제등치료약제들이원인이될수있는것으로알려지고있다. Progression to acute leukemia may require a series of genetic events beginning with clonal expansion of a transformed leukemic stem cell. The specific mutational event(s) required for this progression are not currently well defined.

원인 (1) 유전성소인 Down 증후군 : 유전과 AML 이가장뚜렷한연관성을보이는예 체성염색체의이수배수체 (aneuploidy) 와연관된 AML 의발생 : Down 증후군, Klinefelter 증후군 (XXY), Patau 증후군 (D-trisomy) 등 손상에취약한염색체와유전자재배열을특징으로하는유전성질환 : Fanconi 증후군, Bloom 증후군, ataxia telangiectasia

원인 (2) 방사선조사 일본에서원폭이투여되었던지역의주민과강직척추염 (ankylosing spondylitis) 치료를위하여 X 선조사를받았던환자들에서 AML 의발생률이증가 P32 치료를받은진성적혈구증다증환자와라듐에노출된노동자들에서도 AML 발생빈도가증가 alkylating agents 와 radiation 을병용시발생위험증가 (3) 화학약품과그밖의직업성노출 벤젠 : 혈액세포의유전자손상을초래하여재생불량빈혈을일으키며, 대부분환자에서혈구감소증소견을보인지 5 년이내에 AML 이발생한다. 페트로레움제품과페인트, 방부제, ethylene oxide, 제초제, 살충제와전자장의노출

원인 (4) 항암화학요법제 1. alkylating agents - 초기투여후평균 4-6 년후발생 종종 myelodysplastic syndrome 이선행 chromosome 5 혹은 7 의이상이동반 (-5,-7, 5q-,7q-) 2. topoisomerase II inhibitors - 투여후 1-3 년의비교적짧은잠복기 dysplasia 가선행되는일은흔하지않음 특징적인 11q23 과관련된염색체이상이발견 [t(6;11), t(9;11),t(11;19)]

http://www.youtube.com/watch?v=fjoyaaygqfe

ㄴ 림프구 백혈구 백혈구 적혈구 혈소판

증상 (1) 백혈구의암적증식으로인한증상 혈액내의백혈구가비정상적으로많아지면혈액이끈적끈적해짐으로써혈액순환이잘되지않아머리가아프고, 어지럽고, 피로를자주느끼면서전신쇠약감을느끼게됩니다. 또한비정상적으로증식한백혈구가혈관을넘쳐나와림프절, 간, 비장, 잇몸등의여러곳에쌓임. 백혈구가비정상적인증식으로발생하는여러대사산물들이간이나콩팥에서미처처리되지못하여피에쌓임 ( 고뇨산혈증, 고칼륨혈증, 고인산혈증, 저칼슘혈증, 급성신부전증, 범발성혈관내응고증등의대사이상 )

증상 (2) 정상적인적혈구, 백혈구, 혈소판등의골수의다른세포들이자라지를못하여발생하는증상 적혈구생성이감소 -> 어지럽고, 피로를자주느끼고, 호흡이곤란한등의빈혈증상 혈소판감소 -> 출혈성증상을일으켜외상이없는상황에서코피, 잇몸출혈, 피부나구강및장출혈, 비정상적인월경, 피부의멍등의출혈증상 백혈구가아무리많아도비정상적인것만있지, 정상적인기능을하는백혈구는거의없기때문에세균또는진균 ( 곰팡이 ) 감염이잘발생함.

http://www.youtube.com/watch?v=fjoyaaygqfe

Diagnosis Detailed medical history and physical examination A sample of blood is examined under a microscope to see what the cells look like and to determine the number of mature cells and blasts. A bone marrow aspiration is one way to collect a bone marrow sample. The doctor inserts a needle into hip, and removes a small amount of liquid bone marrow. http://www.youtube.com/watch?v=fjoyaaygqfe

Initial diagnostic evaluation of AML

Diagnosis Morphology Cytochemistry Immunophenotype Chromosomal Classification Molecular classification

Morphology 혈액과골수검체로진단 모세포의형태와수를진단 Ex) Auer rods

Cytochemistry Myeloperoxidase (MPO) Sudan black B (SBB) non-specific esterase (NSE)

FAB classification M0 The blasts lack differentiating features and were nonreactive to Sudan Black B and myeloperoxidase staining. More than 20 percent of the blasts expressed myeloid antigens CD13 and CD33. The blasts were terminal transferase negative and nonreactive with antibodies to lymphocytes. Auer rods were not found.

FAB classification M1 The majority of cells have a rim of pale to slightly basophilic agranular cytoplasm. The nuclei have finely dispersed chromatin and prominent nucleoli.

FAB classification M2 The WBC count was 70,000/ L and was comprised almost entirely of myeloblasts with numerous azurophilic granules.

FAB classification M3 The cell in the top center and far left are "faggot" cells, with numerous intertwining Auer rods (arrows).

FAB classification M4EO Bone marrow smear from a patient with acute myelomonocytic leukemia with increased marrow eosinophils (FAB classification M4EO) and an associated inv(16) chromosome abnormality. (Wright-Giemsa stain). The two eosinophilic precursors in this field (arrows) show prominent basophilic-staining granules.

FAB classification M5B Bone marrow smear from a patient with acute monocytic leukemia with maturation (FAB M5B). This field shows a range of maturation of monocytic cells.

FAB classification M6 Bone marrow smear from a patient with erythroleukemia (FAB classification M6). A megaloblastoid erythroblast (blue arrow) is shown along with three myeloblasts (black arrows).

FAB classification M7 Bone marrow smear from a patient with acute megakaryoblastic leukemia Panel A shows large blasts and promegakaryocytes; the latter cells are larger than the blasts and have coarse nuclear chromatin and irregularly shaped nuclei (Wright- Giemsa stain). Panel B shows staining of these cells with a monoclonal antibody to platelet glycoprotein IIIa (CD61).

Immunophenotype 면역표현형검사의일차적목적 골수계로의분화가아주적은 Minimally differentiated AML 과 Acute lymphoblastic leukemia 을감별진단 그외급성거대핵모세포백혈병 (acute megakaryoblastic leukemia) 의진단에도필수적 진단방법 유세포분석 (flow cytometry) 면역조직화학법 (immunohistochemistry)

Immunophenotype Myeloid marker: CD13, CD33. c-kit, CD64 & CD14(monocytic markers), glycophorin A(erythroblasts), D41(megakaryoblasts) B-lymphocyte 혹은 pre B-lymphocyte markers: CD19,CD10, CD22, surface immunoglobulin T-cell marker: CD2, CD3, CD4, CD5, CD7, CD8 단지한개의 myeloid marker 혹은 marker 가없으면 acute undifferentiated leukemia(aul) 로진단

Chromosomal Classification AML 의예후는대개세포유전학검사 (cytogenetic studies) 에의해서결정된다. 약 50% 의환자는예후와밀접한관계가있는특징적인염색체이상을보이며, 환자의 30-35% 는정상염색체, 20% 는기타의여러형태의염색체, 그리고 10% 에서는 karyotyping 을할수없게된다.

Chromosomal Classification 좋은예후 : inv(16), t(8;21), t(15;17) 은표준요법에대한예후가비교적좋으나환자의 30% 미만에서나타난다. 중간예후 : 정상핵형 (normal karyotype) 혹은 cytogenetic analysis 가불가능한경우는예후가중간에놓인다. 나쁜예후 : 그외다른염색체이상에서는예후가나쁘다.

Cytogenetic abnormalities 와 FAB 분류사이에는관련 t(15;17): M3, inv(16): M4Eo, t(8;21): M2, t(9;11) 을포함한 11q23 abnormalities: M5 임상적인특징과도연관 younger age: t(8;21), t(15;17) older age: del(5q), del(7q) Granulocytic sarcomas: t(8;21) DIC: t(15;17) diabetes insipidus, fever, infection: monosomy 7

Molecular classification

치료 항암치료없이 supportive care 만으로는 median life expectancy 가 6 개월에지나지않음 전신상태와수행능력이비교적좋은노인에서도 chemotherapy 와비교하여 supportive care 는 survival 혹은 morbidity 에서열등 나이가매우많거나혹은쇠약한환자를제외하고는모두항암화학요법을받는것이권장

1. 항암화학요법 AML 환자의치료 (2 phases) complete remission(cr) 을획득하기위한 induction 과 postremission management CR( 완전관해 ) 의정의 leukemia 와관련된 symptom, sign 의소실 PB: blast 는관찰되지않아야하며, platelet count 는 100,000/uL 이상, neutrophil count 는 1,500/uL 이상 BM: blast 는 5% 미만, cellularity > 20%, nl maturation No extramedullary leukemia 최소 4 주간지속

2. Transplantation ( 골수이식 ) Allogeneic hematopoietic stem cell transplantation 은 hematopoietic support 뿐만아니라 antileukemiceffect(graft-versus-leukemia effect) 제공 chemotherapy 와비교하여 recurrence rates 는낮으나치료에따른 mortality 는높아서 overall survival rate 는크게차이가없음 일반적으로젊은환자 (<20-25 세 ) 에서는 allogeneic transplantation 이유리하고 55 세이상에서는불리함 autologous transplantation: complete remission 동안에환자자신으로부터채취된 hematopoietic cells 을이용

만성골수성백혈병 (Chronic myeloid leukemia; CML)

발생빈도 소아에서 40 대중반까지서서히증가하다중년이후급격히증가 전백혈병의 12.5%, 만성백혈병의 95% 서구 : 전백혈병의 15%, 만성백혈병의 40%

병태생리 1960 년 : 만성골수백혈병 (CML) 환자의백혈구에서비정상적으로짧아진염색체발견 -> 22 번염색체 (Philadelphia chromosome) 1973 년 : 9 번염색체의장완과 22 번염색체사이의상호전이로발생

필라델피아염색체 22 번염색체의장완과 9 번염색체의장완의상호전위 t(9:22)(q34:q11) 9 번염색체의암유전자인 c-abl 이 22 번염색체의 bcr 에결합 ; bcr/abl 재배열

임상증상 대개증상은서서히발생 일부환자는건강검진을위해시행한혈액검사에서진단 증상으로는비장의비대로인한상복부팽만감팽만감, 때로는피로감로감, 미열미열, 야간발한야간발한 (night sweat), 체중감소또는뼈의통증통증 (bone tenderness) 병이진행되면 80-90% 의환자에서비장비대를동반 10-15% 가속기나급성기에진단 말기에가서는급성백혈병에서와같이빈혈빈혈, 출혈출혈, 감염등으로사망

PBS in CML Atlas of Hematology

임상경과 대다수의진단후에도수년간은거의정상 3-5 년간의만성기 (chronic phase) 가속기가속기 (accelerated phase) 백혈구수와비장의비대는치료에대해 response (-) 빈혈심화심화, 혈소판감소 백혈구는점점 immature 급성전환기 (blast crisis, blastic phase) 말초혈액에전골수세포 (promyelocytes) 와골수아세포 (myeloblast) 발견 50% myeloid, 1/3 lymphoid, 10% erythroid, 나머지 undifferentiated blast 3-6 개월개월후에는결국사망

치료 1. 동종골수이식 현재완치를이룰수있는유일한치료법 조기에높은사망률이문제 장기기능 65-70세이하 적합한공여자 만성기초기

Imatinib mesylate (Gleevec, Glivec TM ; STI571) 새로운모델을제시 현재처음치료에있어표준요법으로인정 주부작용은 myelosuppression 이며이외에 fluid retention, nausea, muscle cramps, diarrhea, skin rash 등

글리벡용량증가 글리벡저항성일때다음단계의치료 조혈모세포이식 새로운약제시도 ( 다사티닙, AMN) Change to INF Ara-C