Advances in SCT in Acute Leukemia 충남대학교병원 혈액종양내과 조 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, * Data incomplete 0 2,000 4,000 6,000 8,000 10, Non-myeloablative Traditional 2003*2002 TRANSPLANTS

* Data incomplete ,200 1,500 TRANSPLANTS *2002 Related Unrelated NON-MYELOABLATIVE ALLOTRANSPLANTS REGISTERED WITH THE IBMTR,

AML 12, ,000 4,000 6,000 8,000 10,000 Other Non-Malignant Disease CMLALLMDS/MPS Other Leukemia NHLMultiple Myeloma CLLHodgkin Disease Renal Cell Other Cancer SAA TRANSPLANTS Non-myeloablative (N=4,944) Traditional (N=36,192) INDICATIONS FOR ALLOGENEIC BLOOD AND MARROW TRANSPLANTS REGISTERED WITH THE IBMTR, Worldwide -

AGE OF ALLOTRANSPLANT RECIPIENTS REGISTERED WITH THE IBMTR, Non-MyeloablativeTraditional >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, ,000 8,000 16,000 20,000 Traditional Non-myeloablative SOURCES 18, ,841 14,451 12,000 Bone MarrowPeripheral 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- AuthorsaGVHDcGVHDExtensive cGVHD TRMnRef Heldal (Norway) Equal PB > BMEqual61BMT 2003 Couban (Canada) Equal PB < BM228Blood 2002 Powles (UK) Equal 39Lancet 2000 Bensinger (USA) Equal -175NEJM 2000

Allo-PBSCT vs. Allo-BMT in Leukemia - Randomized Studies: Survival- AuthorsLFSOSRelapseRef Heldal (Norway) Equal BMT 2003 Couban (Canada) (Equal)PB > BMEqualBlood 2002 Powles R (UK) -EqualPB < BMLancet 2000 Bensinger (USA) PB > BMEqualPB < BMNEJM 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 PBSCTP aGvHD1.16 ( )0.006 cGvHD1.53 ( )< Extensive cGvHD 1.66 ( )< Relapse0.81 ( )NS

Allo-PBSCT vs. allo-BMT in AML Influence 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 stem 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) typed16 – 56%50 – 80% Median search time3 – 6 months<1 month Donors identified but not available30%<1% Rare haplotypes represented a 2%29% Major limiting factors to graft acquisitionHLA matchCell dose and HLA Ease of rearranging date of cell infusionDifficultEasy Potential for second HSC graft or DLIYesNot from the same donor Potential for viral transmission to recipientYesNo Potential for congenital diseasesNoYes Risk to donorYesNo 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-DRB1 Eurocord, 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, DQ 10/10 or 9/10 Cell Dose 2x10 7 /kg 1 or 2 HLA mismatched A, B, DR 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 expansion 1)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 al Blood 2004

Ichinohe T et al: Blood 2004 Haploidentical SCT T-cell-replete NIMA-complementary SCT (n=35) aGVHD III-IVaGVHD II-IV OS

NUMBER OF TRANSPLANTS 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, ,000 CMLALL Lymphoma MDS/MPS Other Leukemia Other Cancer Aplastic Anemia Other Non- malignant Disease AML INDICATIONS FOR ALLOGENEIC BLOOD AND MARROW TRANSPLANTATION, 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 HLA-ID SIB Infection (17%) Other (12%) Organ toxicity (14%) Relapse (34%) IPn (8%) GVHD (15%) AUTO AUTO Infection (5%) Other (7%) Organ toxicity (7%) Relapse (78%) IPn (3%) UNRELATED 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 mHag-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

TRANSPLANTS 4, ,000 1,500 2,000 Allogeneic (Total N = 7,200) Autologous (Total N = 10,500) 2,500 3,000 4,000 3,500 Breast Cancer NHLMultiple Myeloma AMLALLCML MDS / Other Leukemia CLL Other Cancer Neuroblastoma Hodgkin Disease Non- Malignant Disease 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 Minimize Treatment-related morbidity & mortality Relapse Maximize Cure

Thank you for your attention !