Hematopoietic Stem Cell Transplantation

Transcription

1 Hematopoietic Stem Cell Transplantation Koh Liang Piu Adult Stem Cell Transplant Program Department of Hematology Oncology National University Hospital 27 Feb 2009

2 Year SCT in 45 patients

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4 Type of Hematopoietic Cell Transplantation Autologous Patient serves as a donor Allogeneic Donor HLA Matched Sibling Unrelated Umbilical Cord Blood Syngeneic Identical Twin

5 Autologous vs Allogeneic HCT

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7 Milestones in the Development of Hematopoietic Cell Transplantation 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

8 Milestones in the Development of Hematopoietic Cell Transplantation 1990 Dr ED Thomas awarded Nobel Prize for his pioneering work on HSCT Improvement in supportive care Improvement in GVHD prophylaxis Peripheral blood stem cell Nonmyeloablative conditioning

9 Annual Numbers of Blood and Marrow Transplantations, Worldwide

10 Number of Allogeneic Transplants Increase

11 Absolute Numbers of Allogeneic HSCT and RIC HSCT in Europe from Gratwohl A et al. Bone Marrow Transplant 2002;30:813-31

12 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:

13 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:

14 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:

15 Outcomes of Hematopoietic Stem-Cell Transplantation in Selected Diseases Copelan EA. New Engl J Med. 2006; 354:

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18 TRM for AlloSCT in has over time

19 52 CML patients receiving BMT from HLA matched sibling in SGH Koh LP, et al. Ann Hematol 2004;82:

20 AlloSCT Non Relapse causes (GVHD, infection) are the leading causes of death AutoSCT Relapse is the leading cause of death

21 An Overview of Some Transplant Outcome by Disease Data from CIBMTR

22 AML

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25 MDS

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27 Myeloma

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29 Aplastic Anemia

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31 Chronic Myeloid Leukemia The Philadelphia Chromosome A 9 22 B A B Ph

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33 Large B Cell Lymphoma

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35 Hodgkin s Disease

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37 HSCT in Singapore

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39 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)

40 Type of Adult HSCT in NUH Number Auto Mini Allo Ablative Allo Year

41 Type of Adult HSCT (Source of Stem Cell) in NUH Cord MUD Sibling Auto

42 Indications of Adult HSCT in NUH Number AML/MDS ALL Lymphoma Myeloma CML Others Diagnosis Allo Auto

43 Autologous Transplantation (High Dose Therapy and Autologous Stem Cell Rescue)

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46 Autologous Hematopoietic Cell Transplantation (HCT) Peripheral Blood Stem Cell Mobilisation Chemotherapy Apheresis WBC WBC > Peripheral Blood CD34 > /μL GCSF 10mcg/kg

47 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

48 Relapsed NHL- Chemotherapy vs Autologous Transplantation Philip T, et al. N Engl J Med 1995; 333:1540

49 Autologous Transplantation for Multiple Myeloma

50 Allogeneic Transplantation

51 The Immunological Barrier in HSCT

52 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

53 Cause of GVHD No T cell = No GVHD GVHD vs. GVL Relapse GVHD No T cells High dose DLI

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55 Allogeneic Transplantation Schema of Treatment Preparative Regimen (Conditioning Regimen) Allogeneic Stem Cell Infusion Graft-Versus Host Prophylaxis

56 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

57 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

58 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

59 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

60 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

61 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:

62 Demonstration of GVL in Rodents and Humans Weiden PL, et al. New England Journal of Medicine 1981;304:

63 Demonstration of GVL in Rodents and Humans Horowitz MM, et al. Blood 1990;75:

64 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.

65 Nonmyeloablative SCT for Metastatic Renal Cell Cancer Child R et al. New England Journal of Medicine 2000;343:750-8

66 Nonmyeloablative SCT for Metastatic Renal Cell Cancer Child R et al. New England Journal of Medicine 2000;343:750-8

67 Graft versus tumour effect in mantle cell lymphoma Pre HCT Day 74 HCT Maris et al. Blood 2004;104:

68 Before tranplant. HLA Typing of Potential Donor

69 HUMAN LEUKOCYTE ANTIGEN (HLA)

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74 Unrelated Cord Blood Registry Search

75 HLA-A, -B & -DR Serologically Matched Pairs number of allele mismatches HLA-A, -B, -C & -DR National Marrow Donor Program

76 Choice of Conditioning Regimen

77 Preparative Regimen Objectives: 1. Eradicate Cancer (for both Auto / AlloSCT) 2. In AlloSCT: to induce immunosuppression and permits engraftment

78 Non radiation containing Preparative Regimen for BMT

79 Preparatory Regimens- Radiation Containing

80 Source of Stem Cell: PBSC vs Bone Marrow

81 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:

82 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:

83 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:

84 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:

85 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: 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

86 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

87 PBSC as risk factor for cgvhd Stem cell Trialist. JCO 2005;23: Randonomised Trials 1,111 patients

88 Complications of HCT

89 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

90 1 Year Transplant-Related Mortality (TRM) after HLA-identical Sibling Transplant for Early Leukemia* Data from MDACC

91 Complications of Allogeneic Transplantation Mucositis

92 Acute GVHD

93 Pathophysiology of of acute GVHD Ferrara JL et al. Biol Blood and Marrow Transplant 1999

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96 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

97 Recipient's IL10 promoter region genotype Analysis of 993 transplant recipients showed that, as compared with the C/C genotype, the IL 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:

98 Complications of Allogeneic Transplantation Acute GvHD

99 Liver Involvement

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101 Liver Involvement Off IST p210 + STR 95% p210 - STR 100% 23/Chi/Female, CML, 6 months post Allograft, with jaundice

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106 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: N=325

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109 Etanercept for IPS Yanik G, et al. Blood. 2008;112: ).

110 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: ).

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114 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

115 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:

116 Late Effect of AlloSCT

117 Late Effect of AlloSCT Ades L. Blood Rev 2002;16:

118 Late Effect of AlloSCT Ades L. Blood Rev 2002;16:

119 Late Effect of AlloSCT Socie G. Blood 2003;101:

120 Socie G. Blood 2003;101:

121 Socie G. Blood 2003;101:

122 Nonmyeloablative SCT Is it really better? Has it fulfilled all its promises?

123 Nonmyeloablative Allogeneic Therapy Enhancing Engraftment: Modulating Immunosuppressive Treatment TBI Dose (cgy) No. of Dogs Studied % with Sustained Engraftment % with Autologous Recovery 920-immunosuppressive myeloablative and supralethal Sandmaier B, Storb R. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas Hematopoietic Cell Transplantation. 3 nd ed. Malden, MA: Blackwell Science; 2004:

124 Nonmyeloablative Allogeneic Therapy Enhancing Engraftment: Modulating Immunosuppressive Treatment TBI Dose (cgy) 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:

125 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 Tab Mycophenolate 30mg/kg D0 to +27 Donor s PBSC 5x10 6 /kg CD34

126 Nonmyeloablative Allogeneic Therapy 1. Drive Thru Transplant 2. Mixed-Chimerism Transplant 3. Mini-Transplant 4. Reduced Intensity Conditioning Transplant 5. Transplant-Lite

127 Frequent and commonly transient state of mixed hematopoietic chimerism is a hallmark of RIC

128 Weeks post-transplant

129 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.

130 Comparison between Myelobalative vs Nonmyeloablative Regimen Hematopoetic Toxicity % 96% % Standard Platelets 23% Standard RBC Nonmyeloablative Nonmyeloablative Platelet and RBC Transfusion Requirement Weissinger F, et al. Blood 2001;97:

131 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:

132 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:

133 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,

134 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:

135 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:

136 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:

137 Comparison between Myelobalative vs Nonmyeloablative Regimen Non Related Mortality NRM Day 100: 3% vs 23% P= Year 16% vs 30% P=0.04 Diaconescu R, et al. Blood 2004;104:

138 Nonmyeloablative Allogeneic Transplantation 1 year O.S. Patients with more Indolent Diseases do better Maris MB et al. Blood 2003; 102:

139 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

140 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

141 Our Experience with NMSCT

142 67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation yr OS 43% 5 yr C-PFS 36% 5 yr PFS 28% Koh et al. Biol Blood Marrow Transplant 2007; 13:

143 67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation OS PFS Patients given MTX/MMF/CsP as GvHD Prophylaxis had superior OS and PFS Koh et al. Biol Blood Marrow Transplant 2007; 13:

144 67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 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:

145 67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation 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:

146 67 patients (SGH N= 54; NUH N= 13) undergoing nonmyeloablative allogeneic transplantation % 85% Subgroup of 21 standard risk patients given MMF/CsP/MTX as GvHD prophylaxis Koh et al. Biol Blood Marrow Transplant 2007; 13:

147 27 NUH patients undergoing nonmyeloablative allogeneic transplantation Overall survival Progression free survival Poon LM et al BMT Tandem Meeting. American Society of Bone Marrow Transplant February, 11-15, Tampa, Florida

148 Infections in SCT Recipients

149 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

150 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

151 Invasive Fungal Infections in HCT Recipients

152 Fungal Infections in HSCT Recipients Marr KA et al. Clin Infect Disease 2002;34: Wingard J. Sem Oncol 1993;20:80-7 Schimpff. In Principles and Practice of Infectious Disease. 1995;

153 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 Marr KA et al. Blood 2000 Marr KA. Curr Opin in Inf Dis 2001

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155 Complications of Allogeneic Transplantation Aspergillus Infections in HSCT Recipients

156 Incidence of Invasive Aspergillosis at FHCRC, Allograft Recipients Autograft Recipients Marr KA et al. Clin Infect Dis. 2002;34:

157 Invasive Aspergillosis in HSCT 1682 receiving HSCT from FHCRC 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:

158 FHCRC Study year survival after Dx : 30% Upton A et al. Clin Infect Dis 2007;44:531-40

159 Posaconazole or Fluconazole for Prophylaxis in Severe Graft-versus-Host Disease Ullmann AJ, et al. NEJM 2007; 356:

160 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:

161 What do you do if patients do not have matched sibling or URD?

162 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 / /61 Sister /18/ 21/29/32 What would you do next? 1104/44

163 Unrelated Donor Registry Search BMDP, Singapore: No compatible donor NMDP, Taiwan Tze Chi Registry: No potential matched donor What would you do next?

164 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

165 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

166 Haploidentical HSCT using T-Cell Replete (unmanipulated) graft

167 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

168 Early studies using T- cell replete marrow grafts 1. Early 1990s 2. Largely disappointing 3. High incidence of mortality from GVHD and Graft Rejection

169 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: Anasetti C, et al. N Engl J Med. 1989;320:

170 T Cell Depletion

171 T Cell Depletion Ex Vivo TCD In Vivo TCD Positive Selection Negative Selection ATG Alemtuzumab

172 Allogeneic Peripheral Blood Stem Cell Transplantation Positive selection

173 Allogeneic Peripheral Blood Stem Cell Transplantation Negative Selection

174 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

175 T cell Depletions Ex vivo TCD Positive Selection CD34+ immunoadsorption column (eg: CliniMACS)

176 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

177 Haploidentical HSCT using TCD graft

178 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.

179 Haploidentical HSCT using TCD graft The Perugia Experience

180 Haploidentical Transplant for Acute Leukemia Aversa F et al. N Engl J Med 1998;339:

181 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:

182 Haploidentical Transplant for Acute Leukemia All engrafted TRM 40% Aversa F et al. N Engl J Med 1998;339:

183 Haploidentical Blood Stem Cell Transplantation Aversa et al. J Clin Oncol 2005;23:3447

184 Nonmyeloablative Haploidentical HSCT

185 Nonmyeloablative Haploidentical Transplant Koh LP, Rizzieri DA et al. American Society of Hematology 2002 Blood 2002; 100: 638a (Abstract 2512)

186 Nonmyeloablative Haploidentical Transplant Rizzieri DA et al. J Clin Oncol 2006; 25:690-7

187 Nonmyeloablative Haploidentical Transplant N=29 (59%) are 3/6 matched Rizzieri DA et al. J Clin Oncol 2006; 25:690-7

188 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

189 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

190 Umbilical Cord Blood Transplant

191 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 )

192 Disadvantages of Umbilical Cord Blood (UCB) One time donation with finite small volume Prolonged kinetics hematopoietic engraftment Limited graft cell dose in adult recipients

193 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 (72-85) 2 82 (76-88) 3 69 (52-86) HLA mismatch RR Mortality ( ) >2 2.5 ( ) Rubinstein P et al. New Engl J Med 1998; 339:

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195 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:

196 Eapen et al. Lancet 2007; 369:

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199 Comparison of UCBT and Unrelated BMT for Adult Leukemia NEJM : November Takahashi S et al. Blood 2004; 104:

200 Comparison of UCBT and Unrelated BMT for Adult Leukemia 33% 23% 19% Laughlin MJ et al. NEJM 2004; 351: Rocha V et al. NEJM 2004; 351: Takahashi S et al. Blood 2004; 104:

201 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

202 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

203 N= 110 Adults Brunstein C, et al. Blood 2007; ;110:

204 Courtesy of John Wagner, University of Minnesota

205 Courtesy of John Wagner, University of Minnesota

206 N= 32 ; median age 36 (18-66) Median infused cell dose was 2 6 ~10 7 /kg (range ) 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:

207 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:

208 Conclusions

209 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.

210 Thank You