異體造血幹細胞移植簡介(Allogeneic hematopoietic stem

cell transplantation)

李 啟 誠 醫 師

E. DONNALL THOMAS, M.D.

Nobel Prize in Physiology or Medicine, 1990

for his pioneering work on bone marrow transplantation

造血幹細胞移植的歷史19571957: Thomas ED et.al.:

1st attempt of BMT in human beings (failure; HLA was identified in 1960+)

19591959: Thomas ED et.al.: 2nd attempt of BMT in identical twin

(hematological recovery occurred in 2 weeks, but

leukemia recurred months later)

Allogeneic HSCT, for What?

To replace incorrigible hematopoietic defectsTo replace incorrigible hematopoietic defects:• Quantitative defect: 再生不良性貧血 /Fanconi’s

anemia• Qualitative defect:

– 惡性疾病 : 各種急性或慢性, 骨髓性或淋巴球性白血病 ,淋巴癌 , 多發性骨髓瘤

– 非惡性疾病 :•骨髓造血幹細胞缺陷疾病 : 重度免疫不全症候•造血細胞基因缺損 : 嚴重型地中海型貧血•酵素相關基因缺陷 : 大理石症, 高雪氏症, 黏寶寶

造血幹細胞移植的種類

• 自體移植 (Autologous)

• 異體移植 (Allogeneic)

• 同卵雙胞胎移植 (Syngeneic)

異體移植 (Allogeneic Transplantation)

異體移植 : 捐贈者免疫基因須與病人相符

淋巴球

•MHC–Major HLA (MHC)

•Class I: A, B, C, E, H, G, F•Class II: DR, DQ, DP, DM, •Class III: not so important

–Minor HLA (mHC)•Non-MHC

–KIR–NOD

Resolution

• Low resolution– Serologically antigen (ex. A01)– CREG (cross-reactive groups)

• Intermediate resolution (ex. A0101/ 0102/ 0105)

• High resolution (ex. *A0101)

異體移植

• 親屬間異體移植 (sibling or other

family donors)

• 非親屬間異體移植 (unrelated donor;

MUD: HLA-matched unrelated donor)

造血幹細胞的來源

• 骨髓幹細胞 (Bone marrow; BMT)

• 週邊血液幹細胞 (Peripheral blood stem cell; PBSCT)

• 臍帶血幹細胞 (Cord blood stem cell; CBT)

異體造血幹細胞移植之步驟

正常骨髓

急性血癌

殲滅療法

死傷殆盡

造血幹細胞移植

FHCRC 大廳服務中心

Allogeneic HSCT

• Conditioning therapy ( 殲滅療法 ): 高劑量化學治療或放射治療

TBI + Cy: Total body irradiation + Cyclophosphamide

BuCy: Busulfan + Cyclophosphamide

• Stem cell transplantation: Day 0

Evaluate engraftment

Evaluate GVHD

Control infection

四個階段• Conditioning to engraftment: D-7 to D30

• Early stage after engraftment: D30-D100

• Late stage after engraftment: D100 – 1yr

• Chronic stage after engraftment: > 1yr

Chimera

Tests for chimerism

• Erythrocyte Ag (ABO, Rh, MN…)• Cytogenetics of metaphase for sex

chromosome• FISH• STR(microsatellite)/VNTR(minisatellite) of

nuclear cells—even lineage-specific STR analysis (after FACS with sorting)

西雅圖華盛頓大學

Three major complications after allo-HSCT

• Infection

• Acute GVHD

• Chronic GVHD

Immunosuppressant

GVHD (GVT)

Immunosuppressant

Infection: bacteria, fungus, virus

GVHD (GVT)

Dilemma post allogeneic HSCT

Life-threatening

Disease relapse

Infection complications after allogeneic HSCT

Day 0 Day 100

Bacterial

Fungal

HSV CMV

PCP

1 year (or more)

Day 0 Day 100 1 year (or more)

Day 30

Life-threatening infection

• Invasive fungal infection

• CMV infection

Aspergillus pneumonia

CMV pneumonia

CMV colitis: edema, congestion and multiple ulcers in the sigmoid colon

Inclusion body

To prevent aGVHD:↓conditioning intensity ↓cytokine storm

To prevent aGVHD: Suppress T T-depletionLater DLI

PB BM

CD34 cells 3-4X 1X

T-cells 10X 1X

GVHD Mechanism

Changing Concepts: GVHD Syndrome After AlloHCT

Day 0 50 100 180 1 y 2 y 3 y 5 y

Acute GVHD: rash, GI, liver Chronic GVHD: skin, eyes, mouth, GI liver, musculoskeletal, lungs, GU

- Classic acute - Late acute - Classic chronic - Chronic overlap

Activity Damage(inflammation) i n j u r y r e p a i r (fibrosis)

AlloreactivityAutoimmunity

Immunodeficiency

All I m

ages Ar e C

opy righ t Pro t ec t ed

Acute GVHD

• Engraftment to D+100• Alloreactive T-cells against HLA-bearing host tissue

• General performance decreased• Skin rash• Oral mucositis• Gastritis• Colitis• Hepatobiliary: hepatitis, jaundice• Cytopenia, thrombocytopenia• Impaired immunity

Skin GVHD

Severe oral GVHD: multiple ulcers

Chronic GVHD

• After D+100

• Appear as auto-immune phenomenon

• Sicca syndrome: dry eye, dry mouth

• Scleroderma

• Esophageal dysmotility

• Lung: obstructive lung disease (BO, BOOP)

• Hepatobiliary

• Cytopenia, thrombocytopenia

• Impaired immunity

Chronic GVHD of Skin: Day 170

InfectionsDisabilityQuality of lifeEndocrineMetabolismNutritionPain

Ocular sicca

Oral ulcers

Nail dystrophy

Skin sclerosis

Deep sclerosis

Bronchiolitis obliterans

Loss of bile ducts

Fasciitis

Skin ulcers

Spectrum of manifestations in chronic GVHD

All I m

a ge s Ar e C

op y ri gh t Pro t ec te d

Immunosuppressant

GVHD (GVT)

Immunosuppressant

Infection: bacteria, fungus, virus

GVHD (GVT)

Dilemma post allogeneic HSCT

Life-threatening

Disease relapse

Tulip

Patient evaluation toward medical staff

• Competence

• Courtesy

• Compassion

Neutral

Satisfied

Very satisfied

Thank You!