Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures...

Introduction/Overview

Specific Diseases

Alternative Stem Cell Transplantation

Supportive Measures

Overview of Blood and Marrow Transplantation

History of BMTDefinitions

AML ALLBreast cancerNHL

RationaleStem cell sources

MDSMultiple MyelomaHodgkin’s disease

HEMATOPOIETIC STEM CELL HEMATOPOIETIC STEM CELL DIFFERENTIATIONDIFFERENTIATION

Immunologic Marker ExpressionIn Hematopoiesis

CD34+

PluripotentStem Cell

T Progenitor

BFU-E

B Progenitor

Lymphoid SC

Myeloid SC CFU-Mega

ReticulocyteCFU-E

Myeloblast

Megakaryocyte

MyelocytePromyelocyte

PromonocyteMonoblast

NK Precursor

Pre-B

Sub CorticalCortical Thymocyte

MedullaryThymocyte

Erythrocyte

NK Cell

Platelet

Monocyte

B-Cell

T-Cell

Eosinophil

Basophil

Neutrophil 10

56

7

10,19,24,38

33,61

36

13,15,33,38

9,36,41,42,61

13,16,11b13,16,33

13,14,15,3313,14,15,33

9,10,19,20,24,38

2,3,5,7,38 2,3,5,72,3,5,7

19,20,22

11b,16,56

11b,13,14,15,33,36

HISTORY OF STEM CELL TRANSPLANTATION

Turn of the 20th century, scientists began to formulate the idea that a small number of cells in the marrow, referred to as “stem cells”, might be responsible for the development of all blood cells.

Marrow injury was an important and potentially lethal side effect of exposure to the atomic bomb or to industrial accidents in the atomic weapons industry.

Spurred by the Atomic Energy Commission's and the military’s concern about the spread of nuclear technology and weapons, studies of bone marrow transplantation were initiated.

Lethal TBI Syndromes

Cerebral Syndrome

Intestinal Syndrome

Bone Marrow Syndrome

12,000-1,000,000 cGy

1,200-10,000 cGy

500-700 cGy

Effects of Spleen Shielding on MiceAfter Total Body Irradiation

TBI Dose(cGy)

700

700

1050

1050

1200

SpleenShielding

Yes

No

Yes

No

Yes

Survival

96.3%

0.0%

30.4%

0.0%

0.0%

Rationale for High Dose Therapy and Hematopoietic Stem Cell Transplantation

Incr

easi

ng D

ose

Treatment Necessary for Cure

Death due toother organ toxicity

Death due toMarrow toxicity

CONDITIONING (PREPARATIVE) REGIMEN

To suppress the patient’s To suppress the patient’s immune system from rejecting immune system from rejecting the stem cells.the stem cells.

To eliminate the cancerTo eliminate the cancer

Stem Cell Sources

Bone Marrow

Blood

Umbilical Cord

Fetal Liver

TYPES OF STEM CELL TRANSPLANTSTYPES OF STEM CELL TRANSPLANTS

AUTOLOGOUS TRANSPLANTS - Patients AUTOLOGOUS TRANSPLANTS - Patients receive their own stem cells.receive their own stem cells.

SYNGENEIC TRANSPLANTS - Patients SYNGENEIC TRANSPLANTS - Patients receive stem cells from their identical twin.receive stem cells from their identical twin.

ALLOGENEIC TRANSPLANTS - Patients ALLOGENEIC TRANSPLANTS - Patients receive stem cells from someone other than receive stem cells from someone other than the patient or an identical twin.the patient or an identical twin.

Potential Stem Cell Sources

Autologous stem cells

HLA-matched related donors

HLA-matched unrelated donors

Haploidentical related donors

Umbilical cord blood

Criteria

Tumor with dose response curve

Tumor sensitive to myelosuppressive agents

Purging techniques if marrow is contaminatedwith tumor - Preserve stem cells - Eradicate tumor

Technique for peripheral stem cell collections

Minimal tumor burden

Marrow ablation

Autologous Bone Marrow Transplantation

Allogeneic Engraftment

With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-and accessories cells) to overcome rejection.

Graft

Stem cell doseT-cell dose (CD8)Graft facilitating cellsStromal stem cells?

HostImmunosuppressionPreparative regimenPost-transplant RxDisease effectsSensitization

Engraftment

With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-and accessories cells) to overcome rejection.

Graft

Stem cell doseT-cell dose (CD8)Graft facilitating cellsStromal stem cells?

Host

ImmunosuppressionPreparative regimenPost-transplant RxDisease effectsSensitization

Graph Rejection/GVHD

RecurrentDisease

HUMAN LEUKOCYTE-ASSOCIATED (HLA) ANTIGENS

A set of proteins on the surface of their cells.

A set of HLA proteins are inherited equally from patients.

Chances of having a full match are ~ 1 in 3.

The higher the number of matching HLA antigens, the greater the chance that the patient’s body will accept the donor’s stem cells.

HUMAN LEUKOCYTE ANTIGEN HUMAN LEUKOCYTE ANTIGEN INHERRITANCEINHERRITANCE

IDENTIFICATION OF A RELATED IDENTIFICATION OF A RELATED ALLOGENEIC DONORALLOGENEIC DONOR

Identical TwinIdentical Twin < 1%< 1%

HLA-matched SiblingHLA-matched Sibling

6 antigen6 antigen 25 - 30%25 - 30%



3 antigen3 antigen > 90%> 90%

Stem Cell Source

Donor Availability

Tumor Content

GVHD/GVL

Tx-related Mortality

Limited

None

Possible

10-40%

Majority

Possible

None

0-10%

Allogeneic Autologous

Alternatives to HLA-matched Related Donors


Cord Blood Transplantation-Related-Unrelated

HLA-mismatched related Donors(Haplo-identical)

(Autologous stem cell transplantation)

Stem Cell Source

Donor Availablity

Tumor Content

GVHD/GVL

Tx-related Mortality

Allogeneic

Limited

None

Possible

10-40%

Autologous

Majority

Possible

None

0-10%

Advancements in AllogeneicStem Cell Transplantation

Alternative donors - Unrelated bone marrow donors - Stored cord blood

Ganciclovir

Hematopoietic growth factors

Blood as stem cell product

Donor lymphocyte infusions

Stem Cell Donor Availability

HLA-matched relative

Unrelated donor

Cord blood

HLA-mismatched relative

25-30%

10-40%

50%

10%50%90%

1 Ag2 Ag3 Ag

Alternatives to HLA-matchedRelated Donors


Cord blood transplantation - Related - Unrelated

HLA-mismatched related donors(Haplo-identical)

Autologous stem cell transplantation

The NMDP Network

114Collection

Centers(15 foreign)

Coordinating CenterMinneapolis, MN 112

TransplantCenters

(23 foreign)

ASCO 1998

98Donor Center

(8 foreign)

Volunteer Marrow Donors

ASCO 1998

40

30

20

10

0

Year

Vol

unte

ers

in R

egis

try

(Mill

ions

)

Total Donors3,134,601

Fully TypedDonors

89 90 91 92 93 9488 95 96 97 98

Probability of Finding a Six-antigen HLA Matched Donor

100

1000

10,000

100,000

500,000

1,000,000

0.0%

11.9%

54.2%

90.6%

99.9%

99.9%

0.0%

3.3%

20.7%

60.0%

85.7%

93.7%

Pool Size Japanese North America Caucasian

Beatty et al., 1995

1.6%15.8%

20.2%

43.5%

54.7%

7.2%

2.1%

25.6%DR Typing

Confirmatory Typing

Work-Up

Transplant

Work-Up

Confirmatory Typing

Formal Search

Preliminary Search

Cord Blood Transplantation

Advantages Disadvantages

Waste product of normal deliveries

Readily available

Increased availability for minorities

Decreased transmission of viruses (e.g. CMV)

One unit rescues one patient/no DLI

Theoretical risk of genetic disease transmission

Theoretical risk of maternal cell contamination (GVHD)

Efficacy in adults unknown

Haplo-identical HSCT

Advantages Disadvantages

Nearly all patients have a donor

Share major (e.g. HLA-C) and minor hitocompatibility antigens

Immediate donor availability

HLA Barriers:

-Graft rejection -GVHD -Immune dysregulation

Strategy for Donor Selection

BMT

No

Urgent

Referral

Simultaneous Search URD, BM and UCB

Non-urgent orNon-malignant

Diagnosis

Yes Yes

UCBT

6/6 HLA-matched BMDonor Available?

4-6 HLA-matched UCB(s)Identified with Cell Dose

>1.5 x 107 NC/kg?

Choice of Stem Cell Source

Diagnosis

Urgency of transplant

HLA typing

Cell dose available in UC units(s)

Age

Chemo-sensitivity

Diseases Treated by Bone Marrow Transplantation

Aplastic anemiaThalassemiaSickle cell anemiaImmunodeficiency

disordersAcute myelogenous

leukemiaMyelodysplastic

syndromeMultiple myeloma

Armitage, NEJM 1994

Acute lymphocytic leukemia

Chronic myelogenous leukemia

Chronic lymphocytic leukemia

Non-Hodgkin’s lymphoma

Hodgkin’s disease

Indications for Blood and Marrow Transplantation in North America

(2000)4,500

3,000

2,000

1,000

0AML Hodgkin

DiseaseCML MDS/

OtherLeukemia

CLL

OvarianCancer

Non-Hodgkin

Lymphoma

Tra

nspl

ants

Allogeneic (Total N=67,000)Autologous (Total N=11,000)

4,000

2,500

1,500

500

3,500

Non-MalignantDisease

ALLOtherCancer

BreastCancer

MultipleMyeloma

Annual Numbers of Blood and Marrow Transplants Worldwide

(1970-2000)40

30

20

10

01975 1980 1985 1990 1995 20001970

Year

Num

ber

of T

rans

plan

ts(T

hous

ands

) Autologous

Allogeneic

Advancements in Allogeneic Stem Cell Transplantation

Alternative donors

Unrelated bone marrow donors

Stored cord blood

Ganciclovir

Hematopoietic growth factors

Blood as a stem cell product

Donor lymphocyte infusions

Donor Lymphocyte Infusions

Efficacy varies:

High incidence of GVHD (40-60%)

High correlation of GVHD and response

Optimal dose, frequency and timing remain undetermined

CML = 50-90%AML = 25-50%

Allogeneic Hematopoietic Stem Cell Transplantation

The allograft is a rescue product to replace the defective stem cells following ablation with cytotoxic therapy.

Main therapeutic component of an allogeneic stem cell transplant is the “graft vs. leukemia” effect mediated by T-cells in the allograft.

Old Paradigm New Paradigm

Non-myeloablative Regimens in Allo SCT

Advantages:

-Decreased acute toxicity

-Application to older and/or morbid patients

-Application to broader spectrum of diseases

Disadvantages:

-Toxicity of the procedure (GVHD)

-Loss/decrease in anti-tumor activity from cytotoxic chemotherapy/radiation

Non-myeloablative HematopoieticCell Transplant

± DLIHSCT

A

BB

B BB B

B B

B B

A BALA

AA

ALAL

A A

B B B

B BB

Recipient Donor MixedChimera

CompleteChimera

Host

Donor

Preparative Regimen

CLINICAL COURSE ON ABP1 (CC 00-C-0119)

• Multiple SclerosisMultiple Sclerosis

• Rheumatoid Rheumatoid ArthritisArthritis

• SclerodermaScleroderma

Hematopoetic Stem Cell Transplantation for Auto-immune Diseases

ETIB RESEARCH HEMATOPOIETIC STEM CELL TRANSPLANTATION

StrategyStrategy TacticTactic

RejectionRejection Immune-depleting Immune-depleting chemochemo

Tc2 cellsTc2 cells

GVHDGVHD Th2 cellsTh2 cells

GVLGVL Tc2 cellsTc2 cellsId vaccinesId vaccines

Immune reconstitutionImmune reconstitution Cytokines (IL-7)Cytokines (IL-7)

“Diseases desperate grown

By disparate appliance Are reliev’d,

Or not at all”

After Shakespeare

Introduction/Overview Specific Diseases Alternative Stem Cell Transplantation Supportive Measures...

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