造血幹細胞移植BMT Overview

台大醫院內科部血液科主治醫師

姚 明

Hematopoietic Stem Cell Transplantation(HSCT)

Cell Therapy

Hematopoietic Stem Cell Transfusion

骨髓暨血液幹細胞移植發展史

1900 年代 ※惡性貧血或骨髓疾患的病人接受口服骨髓細胞或肌肉或骨髓內注射，但未獲成功。1940 年代 ※ 1945 年，由日本廣島、長崎原子彈爆炸，骨髓被發現是最易受輻射傷害的器官，開啟了骨髓移植的研究。1950 年代晚期 ※法國 Mathé 醫生成功以骨髓移植治療在南斯拉夫 Vinca 市遭受輻射意外病人。※美國 Thomas 醫生以同卵雙胞骨髓移植治療急性血癌以及重度再生不良性貧血。※法國 Dausset 醫生發現人類白血球抗原 (HLA) 系統。※美國 McGovern 醫生以高劑量輻射並自體骨髓移植治療急性血癌。

1960 年代晚期 ※美國 Good 醫生完成首例異體親屬骨髓移植治療先天免

疫不全病童。 ※美國 Thomas 醫生完成首例異體親屬骨髓移植治療末期

血癌患者。1970 年代初期 ※美國 Thomas 醫生完成首例異體親屬骨髓移植治療再生

不良性貧血患者。※美國紐約 Memorial Sloan-Kettering 治癌中心 完成首例非

親屬異體骨髓移植。1970 年代晚期 ※以異體骨髓移植治療急性血癌緩解期患者，治癒率超

過 55 ％ ，成為急性血癌標準療法。1980 年代初期 ※由於對高劑量治療的認識骨髓抗排斥藥及抗生素之進

步，及骨髓冰凍技術之成熟，使異體及自體骨髓移植逐漸被廣泛運用在治療血液惡性疾病，固態腫瘤、其他骨髓疾病及先天代謝不全疾病。

1980 年代中期 ※白血球生長刺激素 (G-CSF/GM-CSF) 進入臨床使用。※澳洲 Juttner 醫生完成以自體週邊血液幹細胞移植治療

急性血癌患者。1980 年代晚期 ※美國 Kessinger 醫生進行親屬異體週邊血液幹細胞移植。※法國 Gluckman 醫生成功進行親屬臍帶血移植治療先天

Fanconi 氏貧血患者。1990 年 ※美國 Thomas 醫生因致力骨髓移植之研究而榮獲諾貝爾

醫學獎。1990 年代初期 ※自體 CD34 純化之造血幹細胞移植1990 年代中期迄今 ※非親屬臍帶血移植※非親屬異體週邊血液幹細胞移植※發展迷你移植

Hematopoietic Stem Cell Transplantation造血幹細胞移植

• 骨髓移植 (BMT) Bone marrow transplantation

• 週邊血液幹細胞移植 (PBSCT) Peripheral blood stem cell transplantation

• 血液暨骨髓移植 (BMT) Blood and marrow transplantation

• 臍帶血移植 (CBT)Cord blood transplantation

Type of BMT

• BMT

• PBSCT

• CBT

• Syngeneic 同卵雙胞胎• Allogeneic 異體

– Related 親屬• Sibling 兄弟姐妹• Parent 父母 /Child 子女

– Unrelated 非親屬

• Autologous 自體

Allogeneic BMTIndications:• Malignant hematological diseases

– AML, ALL, CML, lymphoma, myeloma, MDS• Non- malignant hematological diseases

– Severe aplastic anemia, thalassemia major• Malignant non-hematological diseases

– breast ca, NPC• Non- malignant non-hematological

diseases– Metabolic storage disease: eg. 黏多醣症– severe combined immunodefficiency (SCID)

Current Indication of Allo-BMT

• Acute leukemia

– High risk acute

leukemia (AL) in CR1

– Good risk AL in > CR2

– Refractory AL

• CML: TKI-resistant

• high risk MDS

• Myeloma/ Lymphoma

• SAA

• Inherited diseases– Thalassemia major

– SCID

– Osteopetrosis

– Storage diseases

Procedures of Allo-HSCT

• Physical examination• HBV;HCV;HIV checkup• Autodonation

– 2-4 wk prior to BM harvest

• Admission – one day prior to BM harvest

• Bone marrow harvest

• Physical examination• HBV;HCV;HIV checkup• Conditioning High dose therapy/NST

– C/T + total body irradiation (TBI)

• BMT-BM cells infusion• GvHD prophylaxis

– Cyclosporin A/ FK-506– Methotrexate

Donor Recipient

Donor Selection:HLA-A,B,DR matching

Ex: An AMLPatient

D-6 D-5 D-4 D-3 D-2 D-1 D0 D+1 D+2 D+3

TBI TBI TBI Cy Cy BMT

Donor BM Harvest

Conditioning Regimen

Conditioning Regimen• Myeloablative vs Non-myeloablative (RIST)• Reduced Intensity

Allo-PBSC collection• G-CSF adminerstration to donor for PBSC

mobilization– G-CSF 10 ug/Kg/d for 5 days

• Leukapheresis to collect PBSC– Leukapheresis

• aim :CD34+cell > 2x106/Kg patient BW

D-4, D-3, D-2, D-1, D0, D+1 s/p PBSCT

G G G G G

L L

BMT vs PBSCT

• BMT– Donor

• 全身麻醉• 住院

– Recipient• 血液相恢復較慢• cGvHD 機率較低

• PBSCT– Donor

• G-CSF injection• 一般不需住院

– Recipient• 血液相恢復較快• cGvHD 機率較高

Blood component therapy post Allo-BMT

BMT 輸血對照表〈舉例 〉Donor R pRBC Platelet, Plasma

wRBC (FFP, Cryoprecipitate)

O A O A, AB A B O AB

A AB A, O AB

AB O O A, B, AB

All blood product must be irradiated自 preconditioning 起至病人血型改變為止 => 改為 donor type PRBC自 preconditioning 起至血清抗體改變為止 => 改為 donor type Platelets

RBC A B AB O

Plasma Anti-B Anti-A - Anti-APLT - Anti-B

Autologous BMT• Concepts:

– High dose therapy is beneficial for controlling underlying dx

– Auto-BMT is served as rescue for hematopoietic recovery

• Indications:– High dose therapy sensitive malignancies

• Acute leukemia, Lymphoma, Myeloma

• Breast ca, Ovarian ca, NPC, Germ cell tumor, Neuroblastoma, etc.

– Autoimmune diseases

Current Indication of High dose therapy plus Auto-BMT

• Chemotherapy sensitive relapse

Lymphoma (NHL or HD)

• Myeloma

• AML (purged graft)

• Neuroblastoma etc.

Procedures of Auto-BMT

• Auto-BM harvest in remission state

• Patient received high dose therapy– BEAM for Lymphoma; HD Mel for Myeloma

• Auto-BMT

– thawing of DMSO-containing Auto-BM

– transfusion of Auto-BM

Auto –PBSC Collection

• G-CSF injection after chemotherapy

• Leukapheresis when hematopoietic progenitor cells

(HPC) present in PB

• Target: CD34+cell > 2 x 106/kg

• Cryopreservation

ESHAP

G-CSF

5ug/kg/d from D+7

B-NHL in 2nd CR

WBC

Nadir

HPCP+

Leukapheresis

PBSC collection

Complications of BMT

• High dose therapy effect• Veno-occlusive disease of liver (VOD)

– Jaundice, hepatomegaly, ascites, RUQ pain• Hemorrhagic cystitis• Interstitial pneumonitis• Graft versus host disease (GvHD) in Allo-BMT• Infection

Skin Stage Skin involvement0 01 0~25%2 25%~50%3 >50%4 >50% with blisters

Gut Stage Stool volume0 <7 (ml/kg)1 7~142 14~213 21~284 >28

Liver Stage Bilirubin (mg/dL)0 <21 2~32 3~63 6~154 >15

Acute Graft versus Host Disease

aGvHD

移植物抗宿主疾病Overall Grade Organ stage

0 01 S1-2

2S3 or S<3 andG1or L1

3 S>3 and G2 or L24 S4 or G4 or L4

Chronic Graft versus Host Disease

cGvHDLimited Localized skin involvement

Liver dysfunction , or both

Extensive Generalized skin involementLiver dysfunction, or any of the following: Chronic active hepatitis, bridging necrosis or cirrhosis Eye involvement (Schirmer's test <5mm) Mucosal involvement Salivary gland involvement*Scleroderma*Bronchiolitis obliterant (BO)

PNEUMONIA

VIRAL

FUNGAL

BACTERIAL

RISKFACTOR

BACTERIAL

---

marrow infusion

0 50 100 12

NONBACTERIAL(INTERSTITAL)

DAYS AFTER TRANSPLANT MONTHS

HSV CMV ADENO VZV

CANDIADA ASPERGILLUS

GRAM POSGRAM NEG

ENCAPSULATED

neutropenia ACUTE GVHD + Rx CHRONIC GVHD

PCP

Post BMT : Fungal Infection

ASPERGILLUS

CANDIADA

Risk Factors

---

marrow infusion

0 30 100 12

DAYS AFTER TRANSPLANT MONTHS

neutropenia ACUTE GVHD + Rx CHRONIC GVHD

VIRAL

HSV

CMV

VZV

Post BMT : Viral InfectionHerpes Viruses

RISKFACTOR

---

marrow infusion

0 50 100

DAYS AFTER TRANSPLANT MONTHS

neutropenia ACUTE GVHD + Rx CHRONIC GVHD