Advances in SCT in Acute Leukemia

충남대학교병원 혈액종양내과조 덕 연

Allo-SCT

• Conditioning

• Source of stem cells

• Type of donors

• Complications

• Allotransplant immunology

Conditioning

• Traditional (myeloablative)

• Reduced intensity conditioning (non-myeloablative)

Reduced Intensity Conditioning SCT (RIST)

ALLOTRANSPLANTS REGISTERED WITH THE IBMTR, 1998-2003

* Data incomplete

0

2,000

4,000

6,000

8,000

10,000

1998 1999 2000 2001

Non-myeloablative

Traditional

2003*2002

TR

AN

SP

LA

NT

S

* Data incomplete

0

300

600

900

1,200

1,500

TR

AN

SP

LA

NT

S

1998 1999 2000 2001 2003*2002

Related

Unrelated

NON-MYELOABLATIVE ALLOTRANSPLANTS REGISTERED WITH THE IBMTR, 1998-2003

AML

12,000

0

2,000

4,000

6,000

8,000

10,000

OtherNon-Malignant

Disease

CML ALL MDS/MPSOther

Leukemia

NHL MultipleMyeloma

CLL HodgkinDisease

RenalCell

OtherCancer

SAA

TR

AN

SP

LA

NT

S

Non-myeloablative (N=4,944)

Traditional (N=36,192)

INDICATIONS FOR ALLOGENEIC BLOOD AND MARROW TRANSPLANTS REGISTERED WITH THE IBMTR, 1998-2003

- Worldwide -

AGE OF ALLOTRANSPLANT RECIPIENTS REGISTERED WITH THE IBMTR, 1998-2003

11166

5441

6539

7484

4670

798

56

0 2000 4000 6000 8000 10000 12000 14000

575

282

527

964

1659

872

62

04008001200160020002400

Non-Myeloablative Traditional

>70y

60-69y

50-59y

40-49y

30-39y

20-29y

< 20y

RIST

• Less regimen-related toxicities

• Less bone marrow depression

• Less tissue damage - less cytokine storm - less GvHD

• More GvL

Questions

• The best reduced intensity conditioning ?

• DLI ?– Necessary ? When ? How ?

• Up-front RIST ?– RIST can replace conventional SCT ?

Source of Stem Cells

• Bone marrow

• Mobilized peripheral blood

• Cord blood

Allo-PBSCT

ALLOGENEIC STEM CELL SOURCES FOR ALLOTRANSPLANTS REGISTERED

WITH THE IBMTR, 1998-2003

0

4,000

8,000

16,000

20,000

Traditional

Non-myeloablative

SO

UR

CE

S

18,861

929

3,841

14,451

12,000

Bone Marrow Peripheral Blood

Mobilized Peripheral Blood

Advantages

• Large number of cells

• Early engraftment

• No anesthesia

Disadvantages

• More GvHD (?)

• Donor safety (?)

Allo-PBSCT vs. Allo-BMT in Leukemia- Randomized Studies: GvHD & TRM-

Authors aGVHD cGVHD Extensive cGVHD

TRM n Ref

Heldal (Norway)

Equal Equal PB > BM Equal 61 BMT 2003

Couban (Canada)

Equal Equal Equal PB < BM

228 Blood 2002

Powles (UK)

Equal Equal Equal Equal 39 Lancet 2000

Bensinger (USA)

Equal Equal Equal - 175 NEJM 2000

Allo-PBSCT vs. Allo-BMT in Leukemia- Randomized Studies: Survival-

Authors LFS OS Relapse Ref

Heldal (Norway)

Equal Equal Equal BMT 2003

Couban (Canada) (Equal) PB > BM

Equal Blood 2002

Powles R (UK)

- Equal PB < BM Lancet 2000

Bensinger (USA)

PB > BM Equal PB < BM NEJM 2000

Allo-PBSCT vs. Allo-BMT in Leukemia- A Meta-Analysis -

5 Randomized & 11 Cohort Studies

Culter B et al, JCO 2001

Relative Risk for PBSCT

P

aGvHD 1.16 (1.04-1.28) 0.006

cGvHD 1.53 (1.25-1.88) < 0.001

Extensive cGvHD 1.66 (1.35-2.05) < 0.001

Relapse 0.81 (0.62-1.05) NS

Allo-PBSCT vs. allo-BMT in AMLInfluence of dose and stem cell source shows

better outcome with rich marrow (EBMT)

Blood 2002

LFS

TRM

Relaspe

OS

Cord Blood Transplantation

Cord Blood

Advantages• Enriched in primitive ste

m cells

• Immaturity of the immune system

– less GvHD

– less stringent criteria for HLA

• Easy and quick access

Disadvantages

• Limited number of cells

– Delayed engraftment

• Less GvL effect

Bone marrow

Cord blood

Information of A+B+DRB1(DNA) typed

16–56% 50–80%

Median search time3–

6 months<1 month

Donors identified but not available 30% <1%

Rare haplotypes representeda 2% 29%

Major limiting factors to graft acquisition

HLA match Cell dose and HLA

Ease of rearranging date of cell infusion

Difficult Easy

Potential for second HSC graft or DLI YesNot from the same

donorPotential for viral transmission to recipient

Yes No

Potential for congenital diseases No Yes

Risk to donor Yes No

Advantages and Disadvantages in the Search and Identification

Grewal SS et al, Blood 2003

UCBT vs. UBMT in Adult Leukemia - Non-Leukemic Death -

Matched pair analysis, Eurocord 2004

n=81

n=162

UCBT vs. UBMT in Adult Leukemia - Relapse -

Matched pair analysis, Eurocord 2004

n=81

n=162

UCBT vs. UBMT in Adult Leukemia - Overall Survival -

Matched pair analysis, Eurocord 2004

n=162

n=81

ANC Recovery in Hematologic Malignancies- According to the number of HLA disparities -

Eurocord 2004

n=550

100-day TRM in Hematologic Malignancies- According to the number of cells -

Eurocord 2004

n=550

Overall Survival in Hematologic Malignancies - According to the number of HLA disparities -

HLA-A and HLA-B by serology and allelic typing of HLA-DRB1Eurocord,Exp Hematol 2004

n=550

Strategies of Alternative donor search

Proposed by Gluckman E (2004)

High resolution HLA typing of patient and family

No donor: Alternative donor search

Bone Marrow Donor Registries Cord Blood Bank

HLA indentical A, B, C, DR, DQ10/10 or 9/10

Cell Dose 2x107/kg1 or 2 HLA mismatched

A, B, DR

Transplant Transplant

Perspectives to Improve UCBT

• Identification of risk factors for outcomes in homogenous groups of disease

• Establishment of criteria for CB selection

• To improve engraftment

1. Prophylactic hematopoietic growth factors

2. Ex vivo expansion1) Stem cells

2) Early or late progenitor cells

3. Transplant with multiple units

4. Reduced intensity conditioning

Type of Donors

• Related

– HLA-matched

– Haplotype-identical

• Unrelated

– Matched

– Mismatched

Haplo-identical SCT• T-cell depleted, megadose SCT

Aversa F et al (Int J Hematol, 2002) EFS 18 AML in CR: 60% 10 ALL in CR: 38% NK alloreactivity (+) – GvL: better EFS

• T-cell replete SCT Ichinohe T et al (Blood 2004) 25 patients (12 AML, 12 ALL) TRM 11/35; 3 Yr-OS 38%

Can be offered as a viable option to candidates with high-risk leukemias !

A Scheme of three different types of NIMA-complementary HLA-haploidentical SCT

Ichinohe T et alBlood 2004

Ichinohe T et al: Blood 2004

Haploidentical SCT T-cell-replete NIMA-complementary SCT (n=35)

aGVHD III-IVaGVHD II-IV

OS OS

NU

MB

ER

OF

T

RA

NS

PL

AN

TS

0

1,000

2,000

3,000

3,500

4,500

Related donor (Total N=10,700)

Unrelated donor (Total N=5,300)

2,500

1,500

500

4,000

CMLALL

Lymphoma

MDS/MPS

OtherLeukemia

Other Cancer

AplasticAnemia

Other Non-malignantDisease

AML

INDICATIONS FOR ALLOGENEIC BLOOD AND MARROW TRANSPLANTATION, 2002

- Worldwide

Unrelated Donor Selection

• Resolution of HLA typing– High resolution HLA typing

• Extent of HLA typing– HLA-A, B, & DR– HLA-A, B, C, DR, & DQ (?)– Plus Minor histocompatibility (?)

Prevention & Management of Complications

• GvHD

• Infection

• Organ toxicity

CAUSES OF DEATH AFTER TRANSPLANTS DONE

IN 1996-2000

HLA-ID SIBHLA-ID SIB

Infection (17%)

Other (12%)

Organ toxicity (14%)

Relapse (34%)

IPn (8%)

GVHD (15%)

AUTOAUTO

Infection (5%)

Other (7%)

Organ toxicity (7%)

Relapse (78%)

IPn (3%)

UNRELATEDUNRELATED

Infection (21%)

Other (17%)

Organ toxicity 15%)

Relapse (23%)

IPn (9%)

GVHD (15%)

GvHD

• New agents

• New strategies

Infections

• New antiviral agents

• New antifungal agents

Allotransplant Immunology

• Donor lymphocyte infusion

• GvHD vs. GvL

• Co-transplantation with mesenchymal stem cells

Donor Lymphocyte Infusion

• Disease-specific responses in post-SCT relapse– CML-CP: 70-80%, CML-BP: 12-28%– AML and MDS: 15-30%– ALL: rare

• Unrelated donors– Similar with related donors in CML, AML (?)

• Effector cells and target antigens• Separating GvL from GvHD• NST protocols

Current and Potential Strategies to Separate GvL from GvHD (I)

Reduction in number of potentially harmful alloreactive cells

• Administration of graded T-cell doses

• Depletion of T-cell subsets

• Depletion based upon activation marker expression in MLC

• Enrichment for antigen-specific T-cells– In vitro expansion of tumor-specific or lineage-restricted mHa

g-specific CTL

– MHC-peptide tetramer complex selection

Reduction in function of potentially harmful alloreactive cells

• Reduce exposure to inflammatory cytokines-delay time to prophylactic infusion

• Induction or anergy by blockade of co-stimulatory pathways

• Transduction with suicide gene

• Alteration of type 1/type2 T-cell balance

• Blockade of specific cytotoxic pathways preferentially used by GvHD mediators

• Sublethal irradiation of T cells

Current and Potential Strategies to Separate GvL from GvHD (II)

Mesenchymal Stem Cells

• Can be expanded for as many as 40 generations; No MHC expression

• In vitro & animal models– Enhance HSC engraftment

– Inhibits allo-reactive T-cells: GvHD

• In human ? : still open

Advantages

• Fewer infections

• No GvHD

Disadvantages

• Higher relapse rate

• Toxicity of high-dose chemotherapy

• No GvL effect

Auto-SCT

TR

AN

SP

LA

NT

S

4,500

0

500

1,000

1,500

2,000

Allogeneic (Total N = 7,200) Autologous (Total N = 10,500)

2,500

3,000

4,000

3,500

BreastCancer

NHLMultipleMyeloma

AML ALL CMLMDS / Other

Leukemia

CLL OtherCancer

NeuroblastomaHodgkinDisease

Non-MalignantDisease

INDICATIONS FOR BLOOD AND MARROW TRANSPLANTATION IN NORTH AMERICA

2002

In Vitro Purging

• A promise not quite fulfilled !

• Methods– Pharmacological agents– Monoclonal antibodies with complement– Toxins– Antibody-coated beads: magnetic sorting– Suicide gene transfer

Perspectives

MinimizeTreatment-related morbidity & mortality

Relapse

MaximizeCure

Thank you for your attention !