Hematopoietic Stem Cell Transplantation Koh Liang Piu Adult Stem Cell Transplant Program Department of Hematology Oncology National University Hospital 27 Feb 2009
Year 2007 52 SCT in 45 patients
Type of Hematopoietic Cell Transplantation Autologous Patient serves as a donor Allogeneic Donor HLA Matched Sibling Unrelated Umbilical Cord Blood Syngeneic Identical Twin
Autologous vs Allogeneic HCT
Milestones in the Development of Hematopoietic Cell Transplantation 1949 1957 1962 1968 1972 1977 1987 Jacobson: Spleen shielding experiment Thomas: First human twin transplants for leukemia Storb: Successful allogeneic transplants in dogs Good : First successful HLA-matched sibling transplant for SCID Thomas: First succesful BMT for severe aplastic anemia Thomas: First 100 transplant for refractory acute leukemia from Seattle. 13 long term survivors. 70% relapse. Gluckman: First Umbilical Cord Blood Transplantation
Milestones in the Development of Hematopoietic Cell Transplantation 1990 Dr ED Thomas awarded Nobel Prize for his pioneering work on HSCT 1980-2001 Improvement in supportive care Improvement in GVHD prophylaxis Peripheral blood stem cell Nonmyeloablative conditioning
Annual Numbers of Blood and Marrow Transplantations, 1970-2006 -Worldwide
Number of Allogeneic Transplants Increase
Absolute Numbers of Allogeneic HSCT and RIC HSCT in Europe from 1990-2000 Gratwohl A et al. Bone Marrow Transplant 2002;30:813-31
Diseases commonly treated with HSCT Allogeneic Transplantation Cancers Acute myeloid leukemia Acute lymphoblastic leukemia Chronic myeloid leukemia Myelodysplastic syndromes Myeloproliferative disorders Non-Hodgkin s lymphoma Hodgkin s disease Chronic lymphocytic leukemia Multiple myeloma Juvenile chronic myeloid leukemia Copelan EA. New Engl J Med. 2006; 354:1813-26.
Diseases commonly treated with HSCT Allogeneic Transplantation Other diseases Aplastic anemia Paroxysmal nocturnal hemoglobinuria Fanconi s anemia Blackfan Diamond anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency Wiskott Aldrich syndrome Inborn errors of metabolism Copelan EA. New Engl J Med. 2006; 354:1813-26.
Diseases commonly treated with HSCT Autologous Transplantation Cancers Multiple myeloma Non-Hodgkin s lymphoma Hodgkin s disease Acute myeloid leukemia Neuroblastoma Ovarian cancer Germ-cell tumors Other diseases Autoimmune disorders Amyloidosis Copelan EA. New Engl J Med. 2006; 354:1813-26.
Outcomes of Hematopoietic Stem-Cell Transplantation in Selected Diseases Copelan EA. New Engl J Med. 2006; 354:1813-26.
TRM for AlloSCT in has over time
52 CML patients receiving BMT from HLA matched sibling in SGH 1992-2002 Koh LP, et al. Ann Hematol 2004;82:286-294
AlloSCT Non Relapse causes (GVHD, infection) are the leading causes of death AutoSCT Relapse is the leading cause of death
An Overview of Some Transplant Outcome by Disease Data from CIBMTR
AML
MDS
Myeloma
Aplastic Anemia
Chronic Myeloid Leukemia The Philadelphia Chromosome A 9 22 B A B 22-9 + Ph
Large B Cell Lymphoma
Hodgkin s Disease
HSCT in Singapore
Milestone of Adult HSCT in NUH 1996 First HSCT-Autologous and Allogeneic Jan 2004 First NMSCT Oct 2006 First Unrelated HSCT (BMDP Donor) March 2007 First UCBT Single Unit, Ablative June 2007 First UCBT- Non-ablative Conditioning Aug 2007 First UCBT- Double Unit, Ablative April 2008 First Unrelated HSCT (from NMDP Donor)
Type of Adult HSCT in NUH 1996 2008 60 50 Number 40 30 23 20 30 10 Auto Mini Allo Ablative Allo 20 21 12 8 10 0 19 15 11 8 11 11 12 13 6 10 8 3 1 1 2 3 3 2 2 3 1 2 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year
Type of Adult HSCT (Source of Stem Cell) in NUH 1996-2008 60 50 40 30 Cord MUD Sibling Auto 20 10 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Indications of Adult HSCT in NUH 2004 2008 Number 60 50 40 30 20 10 0 AML/MDS ALL Lymphoma Myeloma CML Others Diagnosis Allo Auto
Autologous Transplantation (High Dose Therapy and Autologous Stem Cell Rescue)
Autologous Hematopoietic Cell Transplantation (HCT) Peripheral Blood Stem Cell Mobilisation Chemotherapy Apheresis WBC WBC >1000-2000 Peripheral Blood CD34 > 10 1000/μL GCSF 10mcg/kg
Autologous Hematopoietic Cell Transplantation (HCT) Why Mobilised Hematolopietic Cell and not unstimulated bone marrow : 1. More Rapid Engraftment Shorter Neutropenia 2. Lower Platelet Transfusion Requirement 3. Shorter Stay in Hospital
Relapsed NHL- Chemotherapy vs Autologous Transplantation Philip T, et al. N Engl J Med 1995; 333:1540
Autologous Transplantation for Multiple Myeloma
Allogeneic Transplantation
The Immunological Barrier in HSCT
The Immunological Barrier GVHD Graft Host 1. T cell Deplete graft 2. Pharmacological Agents to suppress GVHD Graft Failure 1. Immuno- Ablative Conditioning 2. T Deplete the Host
Cause of GVHD No T cell = No GVHD GVHD vs. GVL Relapse GVHD No T cells High dose DLI
Allogeneic Transplantation Schema of Treatment Preparative Regimen (Conditioning Regimen) Allogeneic Stem Cell Infusion Graft-Versus Host Prophylaxis
Allogeneic Transplantation Schema of Treatment Preparative Regimen (Conditioning Regimen) Bu-Cy Cy-TBI Allogeneic Stem Cell Infusion Graft-Versus Host Prophylaxis 1. Myeloablative antileukemic Rx 2. Immunosuppression of host to establish engraftment
Allogeneic Transplantation Conditioning Regimen Regimen Intensity Immunosuppression Nonmyeloablative Flu / TBI 2Gy Flu / Cy FLAG / Ida TBI 2Gy Reduced Intensity Conditioning Flu / Mel /Campath Flu / Bu / ATG BEAM Campath Myeloablative Conditioning Cy / TBI Cy / Bu Tumour Control / Myelosuppression
Allogeneic Transplantation Schema of Treatment Preparative Regimen (Conditioning Regimen) Matched Mismatched PBSC Allogeneic Stem Cell Infusion Related Unrelated Marrow Umbilical Cord Blood Graft-Versus Host Prophylaxis
Allogeneic Transplantation Schema of Treatment Preparative Regimen (Conditioning Regimen) Cyclosporin + Short Course MTX Allogeneic Stem Cell Infusion Tacrolimus + Short Course MTX Graft-Versus Host Prophylaxis Others
Limitations of Myeloablative Conditioning Regimen Preparative Regimen (Conditioning Regimen) 1. Does not prevent leukemic relapse 2. Further intensification is limited by in regimen-related mortality (RRM) 3. Evidence to suggest that cure is achieved by GRAFT- VERSUS- LEUKEMIA (GVL) effect
Demonstration of GVL in Rodents and Humans Mice with leukemia Could not be cure by TBI 9.5 Gy & syngeneic marrow infusion Survived for longer period after allogeneic marrow infusion without evidence of leukemia, but eventually died of lethal secondary or runting disease ( GVHD) Proposed that a reaction of donor marrow killed leukemic cells. Barnes DWH, Loutit JF. British Journal of Hematology 1957;3:241-252
Demonstration of GVL in Rodents and Humans Weiden PL, et al. New England Journal of Medicine 1981;304:1529-33.
Demonstration of GVL in Rodents and Humans Horowitz MM, et al. Blood 1990;75:555-62.
Demonstration of GVL in Rodents and Humans Provides the most compelling evidence that allosct eradicates malignancy via the potent immune-mediated graft-versusmalignancy effect. Also provides rationale of development of the nonmyeloablative conditioning regimen Kolb HJ, et al. Blood 1990;76:2462.
Nonmyeloablative SCT for Metastatic Renal Cell Cancer Child R et al. New England Journal of Medicine 2000;343:750-8
Nonmyeloablative SCT for Metastatic Renal Cell Cancer Child R et al. New England Journal of Medicine 2000;343:750-8
Graft versus tumour effect in mantle cell lymphoma Pre HCT Day 74 HCT Maris et al. Blood 2004;104:3535-3542
Before tranplant. HLA Typing of Potential Donor
HUMAN LEUKOCYTE ANTIGEN (HLA)
Unrelated Cord Blood Registry Search
HLA-A, -B & -DR Serologically Matched Pairs number of allele mismatches HLA-A, -B, -C & -DR National Marrow Donor Program
Choice of Conditioning Regimen
Preparative Regimen Objectives: 1. Eradicate Cancer (for both Auto / AlloSCT) 2. In AlloSCT: to induce immunosuppression and permits engraftment
Non radiation containing Preparative Regimen for BMT
Preparatory Regimens- Radiation Containing
Source of Stem Cell: PBSC vs Bone Marrow
PBSC vs BM Transplant - Engraftment Recovery of both Neutrophil & Platelet was faster with PBSC than with Marrow Besinger WI et al. New England Journal of Medicine 2001; 344:175-81.
PBSC vs BM Transplant - GVHD PBSC recipients had higher incidence of acute GVHD (64% vs 57%) and chronic GVHD (46% vs 35%) Besinger WI et al. New England Journal of Medicine 2001; 344:175-81.
PBSC vs BM Transplant Overall Survival Overall Survival was modestly improved in patients receiving PBSC Transplant (66% vs 54%) Besinger WI et al. New England Journal of Medicine 2001; 344:175-81.
PBSC vs BM Transplant Leukemia Free Survival In patients with advanced leukemia, survival may be improved due to more potent GVL effect after PBSCT. Champlin RE et al. Blood 2000;95:3702-3709
PBSC vs BM Transplant Leukemia Free Survival Long Term Follow up of patients reported to IBMTR & EBMT Acute leukemia Chronic leukemia Leukemia-free survival was similar after PBSC and BM transplantation for acute leukemia. Schimtz N, et al. Blood. 2006;108:4288-4290 LFS rates were higher after PBSC than BM transplantation for patients with advanced chronic myeloid leukemia (33% versus 25%) but lower for those in first chronic phase (41% versus 61%), because of higher TRM
PBSC as risk factor for cgvhd PBSC have been a/w increased incidence of cgvhd (50% -90%) in most studies of HLA matched sibling transplant. Storek J. Blood 1997 Salano C. BMT 1998 Vigorito AC BMT 1998 Scott MA BMT 1998 Champlin RE. Blood 2000 Snowden JA. BMT 2000
PBSC as risk factor for cgvhd Stem cell Trialist. JCO 2005;23:5074-87 9 Randonomised Trials 1,111 patients
Complications of HCT
Complications of Allogeneic Transplantation 1. Toxicity of preparative regimen 2. Graft Rejection 3. Graft-vs-Host Disease Acute (<100 days) Chronic (>100 days) 4. Post transplant Immunodeficiency Infections- Bacteria, Fungal, Virus
1 Year Transplant-Related Mortality (TRM) after HLA-identical Sibling Transplant for Early Leukemia* 1996-1999 Data from MDACC
Complications of Allogeneic Transplantation Mucositis
Acute GVHD
Pathophysiology of of acute GVHD Ferrara JL et al. Biol Blood and Marrow Transplant 1999
Recipient's IL10 promoter region genotype APC of recipient with favorable IL-10 genotype produces large amounts of IL- 10, thereby induce tolerance in donor T cells to alloantigens in recipient. Cooke KR & Ferrara JL. N Engl J Med 2003;349:23
Recipient's IL10 promoter region genotype Analysis of 993 transplant recipients showed that, as compared with the C/C genotype, the IL10 592 A/A genotype was associated with a decreased risk of grade III or IV acute GVHD (hazard ratio, 0.4; 95 percent confidence interval, 0.2 to 0.9; P=0.02) and death in remission (hazard ratio, 0.6; 95 percent confidence interval, 0.3 to 1.0; P=0.05). Lin MT, et al. NEJM 2003; 349:2201-2210.
Complications of Allogeneic Transplantation Acute GvHD
Liver Involvement
Liver Involvement Off IST p210 + STR 95% p210 - STR 100% 23/Chi/Female, CML, 6 months post Allograft, with jaundice
Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with CSP and MTX Nash RA, et al. Blood 1992; 80: 1838-1845. N=325
Etanercept for IPS Yanik G, et al. Blood. 2008;112:3073-3081).
Etanercept for IPS 15 patients with IPS, 8 were intubated 10 achieved CR (off O2) No infectious Pulm Cx Yanik G, et al. Blood. 2008;112:3073-3081).
Ocular sicca Bronchiolitis obliterans Oral ulcers Loss of bile ducts Nail dystrophy Fasciitis Skin sclerosis Deep sclerosis Infections Disability Quality of life Endocrine Metabolism Nutrition Pain Skin ulcers Spectrum of manifestations in chronic GVHD
Impact of cgvhd on Transplant Outcome Relapse NRM DFS A/w lower relapse rates in both early and advanced stage disease Major cause of NRM Negative impact on DFS, esp aplastic anemia, refractory anemia. Lee SJ. Biol Blood Marrow Transplant 2003;9:215-233
Late Effect of AlloSCT
Late Effect of AlloSCT Ades L. Blood Rev 2002;16: 135-146
Late Effect of AlloSCT Ades L. Blood Rev 2002;16: 135-146
Late Effect of AlloSCT Socie G. Blood 2003;101: 3385-73
Socie G. Blood 2003;101: 3385-73
Socie G. Blood 2003;101: 3385-73
Nonmyeloablative SCT Is it really better? Has it fulfilled all its promises?
Nonmyeloablative Allogeneic Therapy Enhancing Engraftment: Modulating Immunosuppressive Treatment TBI Dose (cgy) No. of Dogs Studied % with Sustained Engraftment % with Autologous Recovery 920-immunosuppressive 21 95 0 800 5 80 0 700 5 60 0 600 23 52 17 450-myeloablative and supralethal 39 41 36 Sandmaier B, Storb R. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas Hematopoietic Cell Transplantation. 3 nd ed. Malden, MA: Blackwell Science; 2004:1164-76
Nonmyeloablative Allogeneic Therapy Enhancing Engraftment: Modulating Immunosuppressive Treatment TBI Dose (cgy) 450 450 450 200 200 Post transplant therapy none CSA Pred CSA CSA/MTX % with Sustained Engraftment 6/17 (36%) 7/7 (100%) 0/5 (0%) 0/5 (0%) 3/5 (50%) 200 CSA/MMF 11/12 (92%) Sandmaier B, Storb R. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas Hematopoietic Cell Transplantation. 3 nd ed. Malden, MA: Blackwell Science; 2004:1164-76
The Non-Myeloablative The Seattle Regimen Stem Cell for Transplant Nonmyeloablative Protocol Stem Cell Transplant TBI 200 Rad Fludarabine 25mg/m 2 /d Tab CSA 6.25mg/kg bid D-1 to +56 Day -4-3 -2-1 0 Tab Mycophenolate 30mg/kg D0 to +27 Donor s PBSC 5x10 6 /kg CD34
Nonmyeloablative Allogeneic Therapy 1. Drive Thru Transplant 2. Mixed-Chimerism Transplant 3. Mini-Transplant 4. Reduced Intensity Conditioning Transplant 5. Transplant-Lite
Frequent and commonly transient state of mixed hematopoietic chimerism is a hallmark of RIC
Weeks post-transplant
Chimaera Serpent Goat Lion Greek mythology, the Chimera is a fire-breathing monster, with the head of a lion, the body of a she-goat, and the tail of a serpent. In HCT, Chimerism refers to presence of lympho-hematopoietic cells of donor origin after allogeneic HCT.
Comparison between Myelobalative vs Nonmyeloablative Regimen Hematopoetic Toxicity 100 90 80 70 60 100% 96% 50 40 63% 30 20 10 0 Standard Platelets 23% Standard RBC Nonmyeloablative Nonmyeloablative Platelet and RBC Transfusion Requirement Weissinger F, et al. Blood 2001;97:3390-3400
Comparison between Myelobalative vs Nonmyeloablative Regimen Infectious Complications Bacteremia P=0.01 P=0.01 Myeloablative Myeloablative Nonmyeloablative Nonmyeloablative NMSCT Recipients had fewer episodes of Bacteremia during 1 st 100 days Junghanss C, et al. Biol Blood Marrow Transplant 2002;8:512-520
Comparison between Myelobalative vs Nonmyeloablative Regimen Infectious Complications CMV Infections Incidence at D100; P=0.08 Incidence at D365; P=0.87 P=0.09 Onset of CMV reactivation and disease delayed in NSCFT, similar 1 year overall incidence Junghanss C, et al. Blood 2002;99:1978-85
Comparison between Myelobalative vs Nonmyeloablative Regimen Infectious Complications Fungal Infections 1. Invasive aspergillosis occurs late after NM SCT 2. Median onset D107 Risk factors: 1. Severe agvhd 2. cgvhd 3. CMV disease Fukuda T et al. Blood 2003; 102,827-833
Comparison between Myelobalative vs Nonmyeloablative Regimen GvHD - Related Donor Transplantation Gd 2-4 agvhd Gd 3-4 agvhd Lower in nonablative No difference cgvhd No difference Mielcarek M. Blood 2003;102:756-762
Comparison between Myelobalative vs Nonmyeloablative Regimen GvHD - Unrelated Donor Transplantation Gd 2-4 agvhd Lower in nonablative Gd 3-4 agvhd Lower in nonablative cgvhd No difference Mielcarek M. Blood 2003;102:756-762
Comparison between Myelobalative vs Nonmyeloablative Regimen GvHD Late onset Acute GVHD Time to initiation of prednisolone therapy for GvHD Nonablative SCT 1. a/w fewer systemic immunosuppressants in first 3 mths. 2. a/w delayed initiation of steroids for GVHD (0.95 mths vs 3.0 mths) 3. More prevalent skin and severe gut morbidity 6-12 mths. Mielcarek M. Blood 2003;102:756-762
Comparison between Myelobalative vs Nonmyeloablative Regimen Non Related Mortality NRM Day 100: 3% vs 23% P=0.0001 1 Year 16% vs 30% P=0.04 Diaconescu R, et al. Blood 2004;104:1550-1558.
Nonmyeloablative Allogeneic Transplantation 1 year O.S. Patients with more Indolent Diseases do better Maris MB et al. Blood 2003; 102:2021-30
Nonmyeloablative Allogeneic Transplantation Have the promises been fulfilled? Engraftment Less Toxicity Less GVHD Yes Yes for early acute toxicity Expanded transplant access Long term disease control Yes
Nonmyeloablative Allogeneic Transplantation Have the promises been fulfilled? Engraftment Less Toxicity Less GVHD Less agvhd, no diff in cgvhd Expanded transplant access Long term disease control For some diseases
Our Experience with NMSCT
67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 1999-2004 5 yr OS 43% 5 yr C-PFS 36% 5 yr PFS 28% Koh et al. Biol Blood Marrow Transplant 2007; 13:790-805
67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 1999-2004 OS PFS Patients given MTX/MMF/CsP as GvHD Prophylaxis had superior OS and PFS Koh et al. Biol Blood Marrow Transplant 2007; 13:790-805
67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 1999-2004 Gd III-IV agvhd NRM Patients given MTX/MMF/CsP as GvHD Prophylaxis had : Less severe GvHD Lower NRM Koh et al. Biol Blood Marrow Transplant 2007; 13:790-805
67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 1999-2004 Relapse No statistically significant in relapse (though trend) among patients given MTX/MMF/CsP as GvHD Prophylaxis Koh et al. Biol Blood Marrow Transplant 2007; 13:790-805
67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 1999-2004 65% 85% Subgroup of 21 standard risk patients given MMF/CsP/MTX as GvHD prophylaxis Koh et al. Biol Blood Marrow Transplant 2007; 13:790-805
27 NUH patients undergoing nonmyeloablative allogeneic transplantation 2004-2007 Overall survival Progression free survival Poon LM et al. 2009 BMT Tandem Meeting. American Society of Bone Marrow Transplant February, 11-15, Tampa, Florida
Infections in SCT Recipients
Infection Risks in SCT Recipients Period of immune immune impairment - Early: Neutropenia - Late : T Cell Function Recovery GI Tract Mucositis GVHD and Therapy Intravascular Lines
Allogeneic Myeloablative (with GVHD) Nonmyeloablative (with GVHD) HSV Mucositis related Bacteremia, Candidemia Line related Bacteremia HHV6,Adenoviru s Line related Bacteremia, Candidemia Aspergillosis, CMV Aspergillosis, CMV, VZV HSV Encapsulated Bacteria VZV Encapsulated Bacteria Cord Blood Aspergillosis, HHV6,Adenovirus Candidemia Bacteremia Line related Bacteremia, Candidemia Risks Mucositis, Neutropenia Acute GVHD Mucositis Neutropenia Acute and Chronic GVHD Impaired Cellular & Humoral Immunity, cgvhd Day 0 Day 50 Day 100 Day 360 Day after SCT
Invasive Fungal Infections in HCT Recipients
Fungal Infections in HSCT Recipients Marr KA et al. Clin Infect Disease 2002;34:909-17. Wingard J. Sem Oncol 1993;20:80-7 Schimpff. In Principles and Practice of Infectious Disease. 1995;2666-74
Fungal Infections in BMT Recipients Goodman JL. NEJM 1992 Slavin 1995, Marr 2000 Fluconazole Prophylaxis decreases (1)Fungal Infections (2) Infection-related mortality (3) Overall survival (in the FHCRC study) Goodman JL. NEJM 1992 Slavin MA et al. J Infect Dis 1995. Marr KA et al. Blood 2000 Marr KA. Curr Opin in Inf Dis 2001
Complications of Allogeneic Transplantation Aspergillus Infections in HSCT Recipients
Incidence of Invasive Aspergillosis at FHCRC, 1990-1998 Allograft Recipients Autograft Recipients Marr KA et al. Clin Infect Dis. 2002;34:909-917
Invasive Aspergillosis in HSCT 1682 receiving HSCT from FHCRC 1993-1998 Acute GvHD Steroids for Acute GvHD CMV Probability of developing proven or probable IA late after onset of acute GVHD, diagnosis of CMV disease, or receipt of corticosteroids. Marr KA. Blood 2002;100:4358-66
FHCRC Study 1990-2004 2002-2004 1 year survival after Dx : 30% Upton A et al. Clin Infect Dis 2007;44:531-40
Posaconazole or Fluconazole for Prophylaxis in Severe Graft-versus-Host Disease Ullmann AJ, et al. NEJM 2007; 356:335-347
Posaconazole or Fluconazole for Prophylaxis in Severe Graft-versus-Host Disease 1. Posaconazole and fluconazole appeared to be equally efficacious in preventing all fungal disease (5.3% vs 9%) 2. Posaconazole prevented more cases of proven and probable invasive aspergillosis (2.3%) than did Fluconazole (7%) 3. There were fewer deaths in the posaconazole group 4. Drugs was well tolerated and relatively safe. Ullmann AJ, et al. NEJM 2007; 356:335-347
What do you do if patients do not have matched sibling or URD?
Case Discussion 23 Chinese Female, Poor risk AML, cytogenetics showed 11q23 del Induction failure, CR achieved with 2 nd induction. Has 1 elder brother, HLA typing done. A A B B DRB1* DRB1* Patient 02 03 35 61 1104/44 1404/61 Sister 02 24 35 61 0803/18/ 21/29/32 What would you do next? 1104/44
Unrelated Donor Registry Search BMDP, Singapore: No compatible donor NMDP, Taiwan Tze Chi Registry: No potential matched donor What would you do next?
Clinical Problem Allogeneic Graft Availability Hematology Patients Needing BMT 8/10 2/10 No Compatible Family Donor Compatible Sibling Donor Only 20-35% Receive BMT via Registry Match
Clinical Problem Allogeneic Graft Availability What to do if no matched sibling donor available? Look for alternative donors: Matched unrelated donor Mismatched related donor Umbilical cord blood
Haploidentical HSCT using T-Cell Replete (unmanipulated) graft
Haploidentical Blood Stem Cell Transplantation Advantages - Nearly all patients have a donor - Share major (eg: HLA- C) and minor histocompatibility antigens - Immediate donor availability Disadvantages - HLA barriers: - Graft rejection - GVHD - Immune dysregulation
Early studies using T- cell replete marrow grafts 1. Early 1990s 2. Largely disappointing 3. High incidence of mortality from GVHD and Graft Rejection
Early studies using T- cell replete marrow grafts Fred Hutchinson Cancer Research Center 1. Haploidentical transplant is associated with a higher incidence of GVHD, delayed engraftment and graft failure 2. Patients receiving marrow grafts from HLA-incompatible marrow donors had a relative risk for GVHD of 3.23 as compared with controls Beatty PG, et al. N Engl J Med. 1985;313:765-771. Anasetti C, et al. N Engl J Med. 1989;320:197-204.
T Cell Depletion
T Cell Depletion Ex Vivo TCD In Vivo TCD Positive Selection Negative Selection ATG Alemtuzumab
Allogeneic Peripheral Blood Stem Cell Transplantation Positive selection
Allogeneic Peripheral Blood Stem Cell Transplantation Negative Selection
T cell Depletions Ex vivo TCD Negative Selection Physical - DACS (Density adjusted cell sorting) - Counterflow centrifugal elutriation Immunological Soybean lectin and erythrocyte rosette Monoclonal antibody + rabbit/human complement Monoclonal antibody formulated as immunotoxin Monoclonal antibody bound to magnetic beads Photodynamic Cell Purging
T cell Depletions Ex vivo TCD Positive Selection CD34+ immunoadsorption column (eg: CliniMACS)
T cell Depletions In vivo TCD Monoclonal Antibody (eg: Alemtuzumab/ Campath) Antithymocyte Globulin (eg: Thymoglobulin) In vivo TCD Morris EC. Blood 2003;102:404-6
Haploidentical HSCT using TCD graft
Haploidentical HSCT using TCD graft The Perugia Experience 1. Mega-dose approach by infusing G-CSF mobilized peripheral blood and bone marrow stem cells, both ex vivo depleted of T cells by soybean agglutination and E- rosetting 2. Intensive TBI-based conditioning regimen.
Haploidentical HSCT using TCD graft The Perugia Experience
Haploidentical Transplant for Acute Leukemia Aversa F et al. N Engl J Med 1998;339:1186-93
Haploidentical Transplant for Acute Leukemia 43 patients with high risk leukemia received BM from family with one matched haplotype (3/6 matched) Aversa F et al. N Engl J Med 1998;339:1186-93
Haploidentical Transplant for Acute Leukemia All engrafted TRM 40% Aversa F et al. N Engl J Med 1998;339:1186-93
Haploidentical Blood Stem Cell Transplantation Aversa et al. J Clin Oncol 2005;23:3447
Nonmyeloablative Haploidentical HSCT
Nonmyeloablative Haploidentical Transplant Koh LP, Rizzieri DA et al. American Society of Hematology 2002 Blood 2002; 100: 638a (Abstract 2512)
Nonmyeloablative Haploidentical Transplant Rizzieri DA et al. J Clin Oncol 2006; 25:690-7
Nonmyeloablative Haploidentical Transplant N=29 (59%) are 3/6 matched Rizzieri DA et al. J Clin Oncol 2006; 25:690-7
Nonmyeloablative Haploidentical Transplant Low TRM and Severe GVHD Relapse Survival Subset of standard risk patients Rizzieri DA et al. J Clin Oncol 2006; 25:690-7
Nonmyeloablative Haploidentical Transplant Low TRM and Severe GVHD Relapse With 4.25 years of median follow up, 1 year overall survival in this high risk group was 31%. Subgroup analysis of 19 standard risk patients showed 63% 1 Survival year overall survival and 3 year median survival, which compared favorably to reports using alternative matched unrelated donors or cord blood. Subset of standard risk patients Rizzieri DA et al. J Clin Oncol 2006; 25:690-7
Umbilical Cord Blood Transplant
Advantages of Umbilical Cord Blood (UCB) Lower GVHD Risk Allow 1-2 HLA Ag Mismatch Facilitates Extension of Donor Pool, esp Ethnic Minorities Absence of Risk to Mother Lower CMV Transmission Lack of Donor Attrition Ease of procurement, readily used ( median search time < 1 month )
Disadvantages of Umbilical Cord Blood (UCB) One time donation with finite small volume Prolonged kinetics hematopoietic engraftment Limited graft cell dose in adult recipients
Outcomes among 562 Recipients of Placental-Blood Transplants from Unrelated Donors Neutrophil Recovery Mortality Cell dose Cell dose >2.5 x 10 7 /kg >2.5 x 10 7 /kg HLA mismatch Incidence 0 100 1 78 (72-85) 2 82 (76-88) 3 69 (52-86) HLA mismatch RR Mortality 0 1.0 1 2.0 (1.1-3.6) >2 2.5 (1.4-2.5) Rubinstein P et al. New Engl J Med 1998; 339:1565-1577
Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical cord blood from an HLAidentical sibling Gluckman E, Broxmeyer HE, Auerbach AD, Freidman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P, Cooper S, English D, Kurtzberg J, Bard J, Boyse EA. N Engl J Med 1989;321:1174-1178
Eapen et al. Lancet 2007; 369:1947-54
Comparison of UCBT and Unrelated BMT for Adult Leukemia NEJM : November 25 2004 Takahashi S et al. Blood 2004; 104: 3813-20
Comparison of UCBT and Unrelated BMT for Adult Leukemia 33% 23% 19% Laughlin MJ et al. NEJM 2004; 351: 2265-75 Rocha V et al. NEJM 2004; 351:2276-85 Takahashi S et al. Blood 2004; 104: 3813-20
Comparison of UCBT and Unrelated BMT for Adult Leukemia Results of 3 Comparative Studies (Rocha V NEJM 2004; Laughlin M NEJM 2004; Takahashi S Blood 2004) Engraftment Cord Blood vs Bone Marrow Acute GVHD Chronic GVHD Early TRM Relapse Survival
Recent Development Addressing the Limitations of UCB Transplantation Toxicity of Conditioning Regimen Non-myeloablative (Reduced Intensity) Regimen Limited Cell Dose Delayed Engraftment Multiple Cord Blood Units Ex-Vivo Expansion of Cord Blood Cells
N= 110 Adults Brunstein C, et al. Blood 2007; ;110:3064-3070
Courtesy of John Wagner, University of Minnesota
Courtesy of John Wagner, University of Minnesota
N= 32 ; median age 36 (18-66) Median infused cell dose was 2 6 ~10 7 /kg (range 1 4 4 2) Median time to recovery of neutrophils in 28 patients ( 0 5 ~10 9 /L) was 23 days (range 14 44) Median time to recovery of platelets in 27 patients ( 20 ~10 9 /L) was 36 days (range 16 64). Frassoni F, et al. Lancet Oncol 2008; 9: 831 39.
Graft failure: 0% 45% Acute GVHD II-IV: 4/26 (15%) Ext cgvhd: 1/20 surviving >D 100 TRM 37.5% Frassoni F, et al. Lancet Oncol 2008; 9: 831 39.
Conclusions
Advancement of HSCT over the past few decades: Improving post transplant outcome remains challenging task. Recent advances with effective GVHD prophylaxis and less toxic conditioning regimen have significantly decreased the early TRM and risk of severe GVHD, whereas enabling reliable engraftment, and hence enhancing the therapeutic benefits of allosct. Posttransplant infectious complications / delay in immune reconsitution, relapse remain important barriers to overcome.
Thank You