혈액암(Hematologic Malignancy)

경희대학교병원 종양혈액내과

조 경 삼

혈액암(종양)(Hematlogic Malignancies)

• 종양

– 양성 종양

– 악성 종양

• 악성 종양(질환) – 암

– 고형암 : 고형 장기 발생 악성 질환

– 혈액암 : 골수 또는 림프조직에서 발생

혈액암

• 분류 : 형태학, 임상 소견

• 백혈병

• 악성림프종

• 형질세포질환

• 골수이형성증후군

• 만성골수증식성질환

• 기타

백혈병 (Leukemia)

• 골수구성– 급성 (AML) : FAB 분류 – M0 – M7– 만성 (CML)

• 림프구성– 급성 (ALL) : FAB 분류 – L1 – L3– 만성 (CLL)

• 기타– Hairy cell leukemia– Prolymphocytic Leukemia– Eosinophilic leukemia

악성 림프종 (Lymphoma)

• 호지킨병[림프종] (Hodgkin’s Disease [Lymphoma]) HD

• 비호지킨 림프종 (Non-Hogkin’sLymhoma) NHL

형질세포질환

• MGUS : Monoclonal Gammopathy of Undetermined Significance

• Plasmacytoma• Multiple myeloma (MM)

– Asymptomatic; smoldering; Stage I– Symptomatic; Stage II, III

• Waldenstrom’s macroglobulinemia• Amyloidosis• POEM syndrome, Plasma cell leukemia

만성골수증식성 질환 (CMPD)

• 진성 적혈구증다증 (PV) Polycythemia vera

• 진성 고혈소판증 (ET)Essential thrombocytopenia

• 특발성골수섬유화증 (IMF)Idiopathic myelofibrosis

• 만성골수구성백혈병 (CML)Chronic myelocytic leukemia

골수이형성 증후군 (MDS) Myelodysplastic syndrome

• RA : refractory anemia (불응성 빈혈)

• RARS : refractory anemia with ringed sideroblasts

• RAEB : refractory anemia with excess of blasts

• RAEB-T : RAEB in transformation

• CMML : chronic myelomonocyticleukemia

Bases of classification

• Morphology : most important part but sometimes not objective

• Immunophenotype : lineage, objective, target (ex. CD20)

• Genetic abnormalities : objective– Specific : BCR-ABL, PML-RARA, – Characteristic but not specific :

MYC, CCND, BCL2 rearrangement, JAK2 mutation– Prognostic : TP53 mutation or FLT3-ITD

• Clinical features : age, nodal versus extranodal presentation, specific anatomic site and history of cytotoxic and other therapies

• Provisional entities, borderline categories

WHO Classification

2001 2008

• I. Myeloid neoplasms

• II. Acute leukemia of ambiguous lineage

• III. Lymphoid neoplasms

• IV. Histiocytic and dendritic cell neoplasms

WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008)

WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008)

• I. Myeloid neoplasms

1. Myeloproliferative neoplasms (MPN)

2. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

3. Melodysplastic/Myeloproliferative neoplasms(MDA/MPN)

4. Myelodysplastic syndrome (MDS)

5. Acute myeloid leukemia (AML) and related precursor neoplasms

1. Myeloproliferative neoplasms (MPN)

1) Chronic myelogenous leukemia, BCR-ABL 1 positive

2) Polycythemia vera

3) Primary myelofibrosis

4) Essential thrombocythemia

5) Chronic neurophilic leukemia

6) Chronic eosinophilic leukemia, NOS (CEL/hypereosinophilic synd.)

7) Mastocytosis① Cutaneous mastocytosis

② Systemic mastocytosis

③ Mast cell leukemia

④ Mast cell sarcoma

⑤ Extracutaneous matocytoma

8) Myeloproliferative neoplasm, unclassifiable

2. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

1) Myeloid and lymphoid neoplasms with PDGFRA rearrangement

2) Myeloid neoplasms with PDGFRBrearrangement

3) Myeloid and lymphoid neoplasms with FGFR1 rearrangement

3. Melodysplastic/Myeloproliferative neoplasms

1) Chronic myelomococytic leukemia

2) Atypical chronic myeloid leukemia, (BCR-ABL1 negative)

3) Juvenile myelomonocytic leukemia

4) Myelodysplastic/Myeloproliferativeneoplasms, unclassifiable

1) Refractory anemia with ring sideroblastsassociated with marked thrombocytosis

4. Myelodysplastic syndrome

1) Refractory cytopenia with unilineage dysplasia 1) Refractory anemia

2) Refractory neutropenia

3) Refractory thrombocytopenia

2) Refractory anemia with ring sideroblasts

3) Refractory cytopenia with multineage dysplasia

4) Refractory anemia with excess blasts I, II

5) Myelodysplastic syndrome associated with isolated del(5q)

6) Myelodysplastic syndrome, unclassifiable

7) Childhood myelodysplastic syndrome 1) Refractory cytopenia of childhood

5. Acute myeloid leukemia (AML) and related precursor neoplasms

1) AML with recurrent genetic abnormalities

2) AML with myelodysplasia-related changes

3) Therapy-related myeloid neoplasms

4) Acute myeloid leukemia, NOS

5) Myeloid sarcoma

6) Myeloid proliferations related to Down syndrome

7) Blastic plasmacytoid dendritic cell neoplasm

II. Acute leukemias of ambiguous lineage(모호한, 애매한, 두가지 이상의 뜻이 있는)

1. Acute undifferntiated leukemia

2. Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1

3. Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged

4. Mixed phenotype acute leukemia, B/myeloid, NOS

5. Mixed phenotype acute leukemia, T/myeloid, NOS

6. Natural killer (NK) cell lymphoblastic leukemia/lymphoma

III. Lymphoid neoplasms

1. Precursor lymphoid neoplasms

2. Mature B-cell neoplasms

3. Mature T-cell and NK-cell neoplasms

4. Hodgkin Lymphoma

5. Post-transplant lymphoproliferativedisorders (PTLD)

IV. Histiocytic and dendritic cell neoplasms

1. Precursor lymphoid neoplasms

1) B lymphoblastic leukemia/lymphoma ① B lymphoblastic leukemia/lymphoma, NOS

② B lymphoblastic leukemia/lymphoma, with recurrent genetic abnormalities a. B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1

b. B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged

c. B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL-AML1(ETV6-RUNX1)

d. B lymphoblastic leukemia/lymphoma with hyperdiploidy

e. B lymphoblastic leukemia/lymphoma with hypodiploidy(hypodiploid ALL)

f. B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32); IL3-IGH

g. B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1(TCF3-PBX1)

2) T lymphoblastic leukemia/lymphoma

2. Mature B-cell neoplasms

1) Chronic lymphocytic leukemia/small lymphocytic lymphoma

2) B-cell prolymphocytic leukemia

3) Splenic marginal zone lymphoma

4) Hairy cell leukemia

5) Splenic B-cell lymphoma/leukemia, unclassifiable① Splenic diffuse red pulp small B-cell lymphoma

② Hairy cell leukemia-variant

각론

• 개별 혈액종양 질환의 설명

AML

• 골수 세포의 악성화로 백혈병세포가 증식하고 말초혈액에서 백혈구가 증가하며 전신 장기에 침윤할 수 있음.정상 혈구세포의 생산은 감소.

• 증상– 빈혈– 감염– 출혈

• 진단– CBC– BM : 세포표지자 검사– 염색체검사, 분자 생물학적 검사

AML 치료

• Chemotherapy :

– Induction CT : anthracycline + Ara-C (AI, AD)

– Consolidation

– Supportive care

– Stem cell transplantation

• APL [M3, t(15;17)]ATRA, arsenic trioxide + chemotherapy

치료 반응

• Hematologic response

– Complete remission : 5%

• BM : blast < 5% with count 500 nucleated cells

• ANC (absolute neutrophil count) : > 1,000/uL

• Platelet : > 100,000/uL

• Cytogenetic remission : 1 ~ 0.5 % • Chromosome analysis, FISH

• Molecular remission : 1/104 ~ 106

• PCR : PML-RARA,

CML

• 증상

– 무증상 (건진에서 발견)

– 복부 증상 : Splenomegaly

– 진행 : accelerating, blastic phase – acute leukemia

• 진단

– CBC

– BM

– Philadelphia 염색체, t(9;22), bcr-abl fusion gene

치료

• Glivec• 2nd generation TKI

– Dasatinib, Nilotinib etc

• Stem cell transplantation• Other chemotherapy, IFN

• Response– Hematologic– Cytogenetic : Ph, FISH (bcr-abl)– Molecular : RT-PCR (bcr-abl)

3 개월

6 개월

12 개월

18 개월

MDS (골수이형성증후군)

• 조혈세포의 이형성(dysplastic) 변화로 효과적인 조혈이 안됨. 골수 세포의 수는 증가하나 정상적인 혈액세포는 감소함.

• 증상 :– Pancytopenia 연관 증상 : 빈혈, 출혈, 감염

– 노년층

• 진단 :– CBC

– BM : 필수

– 염색체, 분자생물학

Cytogenetics : Good = normal, -Y alone, del(5q) alone, del(20q) alone ; Poor = complex (≥ 3 abnormaities) or chr. 7 anormalies ; Intermediate = other abnormalities

Cytopenia : neutrophil < 1,800/mcL, Platelet < 100,000 mcL, Hb < 10g/dLRBC transfusion requirement = having ≥ 1 RBC every 8 weeks over a 4 months period

Low : 0Int-1 : 0.5-1.0Int-2 : 1.5-2.0High : ≥ 2.5

Very low : 0Low : 1Intermediate : 2High : 3-4Very high : 5

치료

• 대증요법 : 수혈, 항생제

• Erythropoietin, G-CSF

• Chemotherapy :

– Vidaza , Dacogen : 반응평가

– Anti-leukemic agents

– isolated del(5q) : lenalidomide

• Stem cell transplantation

MDS/MPN

• CMML

• Atypical CML (aCML)

• JMML

• MDS/MPN, U

• 진단 : BM

• 치료 : CT, SCT, 대증요법

MPN (Myeloproliferative Neoplasms)

• PV : 적혈구증가

• ET : 혈소판 증가

• IMF : 골수 섬유화, 골수외 조혈 (간, 비장)

• CML : 백혈구 증가

• 진단 : CBC, BM, JAK2 mutation

• 치료 : HUA, IFN, anagrelide, SCT

악성 림프종

• 진단 : biopsy

– HD, NHL

– Subtype : B, T cell; precursor, mature

• Staging : Ann Arbor stage

– Stage I, II, III, IV

– Imaging studies

• CT, MRI, PET

– BM

치료

• 항암화학요법

• 방사선치료

• 조혈모세포이식 : 자가, 동종

• 치료 반응 판정

– CR

– PR

ALL

• 소아 : 성인

• ALL : Lymphoblastic lymphoma

• Chemotherapy

• CNS prophylaxis

• Maintenance chemptherapy

• Stem cell transplantation

CLL

• CLL : SLL(Small lymphocytic lymphoma)

• 노년층

• 서양 : 가장 흔한 백혈병

• 치료

– Wait and see

– Chemotherapy

– SCT

형질세포질환

• MGUS : 경과 관찰• Plasmacytoma

– Solitary– Extramedullary

• Multiple Myeloma• Waldenstrom’s macroglobulinemia

– Lymphoplasmocytic lymphoma

• Amyloidosis• POEM syndrome• Plasma cell leukemia

MM (다발성 골수종)

• 증상 : CRAB– Hypercalcemia

– Renal failure

– Anemia

– Bone involvement

• 진단 :– CBC

– M protein : PEP, FLC

– BM

– Bone involvements : X-ray, MRI, bone scan

치료

• Plasmacytoma : single – RT• Asymptomatic MM : wait and see• Symptomatic MM

– Transplantation eligible• Induction Chemotherapy• Autologous SCT : single or tandem• Allogeneic SCT

– Transplantation ineligible• Palliative CT

– RT– Supportive care

향후 전망

• 분류법의 변화– WHO classifcation

• 진단 방법의 발전– 유전자

– 분자생물학

• 치료법의 변화– Target therapy