Newest Modalities in Bone Marrow Transplantation
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New Modalities in Stem Cell Transplantation
Richard Champlin, M.D.
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Major Innovations SCT-CT
• Nonmyeloablative Conditioning• Alternative Donors
– Cord Blood– Haploidentical Transplants
• Cell Therapy– T-cells– Chimeric Antigen Receptors– NK Cells
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HSCT
DRL
RRL
RR D
DD
D
D
D
DD
Hematopoietic Stem Cell TransplantationPreparativeRegimen
Allogeneic hematopoietic is an effective, but toxic treatment for hematologic malignancies, associated with a high risk of morbidity and mortality (10->50%), restricting its use to young patients withoutcomorbidities
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Goal of Conditioning Regimen
• Provide immune suppression to prevent rejection and create “space” for engraftment
• Eradicate the malignancy– Most effective drugs/radiation treatments
for hematologic malignancies also kill normal myeloid and lymphoid cells
– Kill malignant stem cells
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BMT
Remission
Limit of Detection
High DoseChemoradiotherapy
Unmodified
T-cell depletionIdentical twin
Donor Lymphocyte Infusion
Time
Allogeneic BMT for CMLImportance of GVL
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Graft-vs-Malignancy Allogeneic SCT
• High dose therapy and allogeneic SCT is an effective treatment for hematologic malignancies
• Much of the benefit of alloSCT is due to immune GVL effect; therefore maximally ablative therapy may not be needed.
• Lower dose nonmyeloablative preparative regimens are sufficient to prevent rejection.
• We hypothesized that a reduced intensity, nonmyeloablative allogeneic transplant could reduce toxicity and allow successful treatment of older patients and those with major comorbidities.
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Nonablative and Reduced Intensity Regimens
Myelosuppression
FCRMF
BuCy
TBI/CyT
BuFF-TBI2Gy
Nonablative Reduced Intensity Ablative
Champlin et al 2000
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HSCT +DLI
DTDNK
DRLRL
RRL R
R DBDsc
DT
DNK
DT
DTDT
Dsc
D
DT
DT
DscD
Complete ChimeraRecipient Donor Mixed Chimera
Nonmyeloablative TransplantPreparativeRegimen
R
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AUC
Prob
abilit
y
800 1000 1200 1400 1600 1800
0.0
0.2
0.4
0.6
0.8
AUC
Prob
abilit
y
800 1000 1200 1400 1600 1800
0.0
0.2
0.4
0.6
0.8
AUC
Prob
abilit
y
800 1000 1200 1400 1600 1800
0.0
0.2
0.4
0.6
0.8
AUC
Prob
abilit
y
800 1000 1200 1400 1600 1800
0.0
0.2
0.4
0.6
0.8
1.0
Probability of Mucositis ≥ 3 Probability of GI Toxicity ≥ 3
Probability of Hepatic Toxicity ≥ 2 Probability of GVHD ≥ 2
Busulfan AUC Relative to Toxicity and aGVHD
Andersson et al 2002
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Pathophysiology of Acute GVHD
APC=antigen-presenting cell; CTL=cytotoxic T lymphocyte; IFN=interferon; IL=interleukin; LPS=lipopolysaccharide; Mac=macrophage; NK=natural killer cell; TH=T-helper cell; TNF-α=tumor necrosis factor-alpha.
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Days0 50 100
0.00
0.25
0.50
0.75
1.00
NMA
BUCY/FM
ACUTE
GVHD
HR 3.1 (CI= 1.3-7.2)
Grade 2-4 Acute GVHD
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Nonablative BMT• Reduced toxicity• Reduced GVHD• Similar infections occur, but generally
respond to therapy
• Lower treatment related mortality• Can extend the use of HSCT to patients
up to 75 years of age
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Comparisons Albative vs. RIC SCT• Lack of randomized controlled trials• Non-randomized comparisons always
confounded by different patient populations– Ablative- young, fit patients– RIC- Older patients with comorbidities
• Conclusions– RIC higher relapse, lower NRM, survival not
significantly different. • Can one develop effective anti-tumor
preparative regimens, with acceptable (less) toxicity?
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Time(weeks)
Surv
ival P
robabili
ty
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
In remission, PB.blast=0Active Disease, PB.blast=0Active Disease, PB.blast>0
p<0.0001
Time(weeks)
Eve
nt-
free p
robabili
ty
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
In remission, PB.blast=0Active Disease, PB.blast=0Active Disease, PB.blast>0
p<0.0001
IV Bu-Flu Overall Survivaland Event Free Survival
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Nonablative AlloSCT vs Chemo for Elderly AML
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Opportunities for Cure in CML
Preparative Regimen
Imatinib Donor Lymphocyte Infusion
CM
L C
ell M
ass
Time
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Survival
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Ablative Allo-BMT in Indolent Lymphoma
van Besien et al. Blood. 1998;92:1832-1836. Years
Prob
abili
ty, %
5432100
20
40
60
80
100
6
SurvivalDFSTreatment-related mortalityRelapse
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Rituximab Fludarabine 30 mg/m2 Rituximab375 mg/m2 Cyclophosphamide 750 mg/m2 1000
mg/m2
-13 -6 -5 -4 -3 0 +1 +8
ASCT
Days
NON-MYELOABLATIVE ALLOGENEIC SCT
Conditioning Regimen
•ATG 15 mg/kg daily, was given days –5 to –3 for mismatched or unrelated SCT•Tacrolimus and methotrexate were used for GVHD prophylaxis
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FCR allo SCT for Low Grade Lymphoma
Khouri et al Blood 2008
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Rituximab: Mechanism of Action
Anderson DR, et al. Biochem Soc Trans. 1997;25:705-708, Clynes RA, et al. Nat Med. 2000;6:443-446.
CD20
CELLLYSIS
FcγRI, FcγRII, or FcγRIII
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Macrophage,Monocyte,
or Natural Killer Cell
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Dendritic Cell
T Cells
Tumor Antigen
RituximabAntigen Presentation and Cross-Priming
Tumor Cell
FcR
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Efficacy of Nonablative HSCT
Highly Effective(better than ablative)
Dose Intensity Important
LGL, CLL CML
Mantle cell lymphoma AML /MDS
Myeloma (tandem)? LCL, Hodgkin’s disease
Renal Cell, OvarianBreast CA-Promising
ALL
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ATG with RIC SCTCIBMTR-Soiffer Blood 2011
• Compare T-replete transplants with no ATG, ATG, Alemtuzumab
• ATG- assoc with decreased cGVHD, increased relapse, worse PFS and survival
• Alemtuzumab- assoc with decreased acute and cGVHD, increased relapse, no change in survival
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Best Available Donor
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MD Anderson Cord Blood BankElizabeth J. Shpall MD
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Cord Blood Transplantation• Rich source of stem cells• ~50,000 units banked, immediately available
for transplantation• Immunologically immature- less prone to
produce GVHD• Less risk of transmitting infection• Can successfully transplant across HLA
mismatch• Major concern- low stem cell dose, longer
time to engraftment- may be overcome by ex vivo expansion
• Results comparable to MUD BMTs
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Mesenchymal Stem Cells (MSC)
• MSC are a stromal componentof the hematopoietic microenvironment.
• They provide cellular and extracellular components of the stem cell “niche”.
• When isolated and used in vitroin combination with cytokines, MSC markedly increase the expansion of CB hematopoietic progenitors.
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Day 14 hematopoietic output from liquid culture of CD133+ (solid bar) vs.co-culture of non-selected CB cells with MSC (striped bar)
x13 x25 x7 x14 x200 x44
Co-culture with MSC significantly enhancesex vivo expansion of CB cells
Robinson et al. Bone Marrow Transplantati
Fold increase
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Median time to engraftment (range)
Neutrophil (>500/µl) 15 days (range 9-42)Platelet (>20,000/µl) 40 days (range 13-62)
Cumulative Incidence of Engraftment
Neutrophil (>500/µl) 97% (n=31)Platelet (>20,000/µl) 81% (n=26)
- One patient died before engraftment
MSC-CB Expansion Trial Engraftment Data
de Lima et al. Blood (ASH Annual Meeting Abstracts), 2010; 116: 362
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Post Transplant Cyclophosphamide for Haploidentical Transplantation
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NST for Haploidentical Transplantation
Luznick et al 2008
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Cell Therapy +/- HSCT
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36
T-cell Immune Response
T-Cell Activation and Proliferation
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Chimeric antigen receptors (CARs)
vL
vH
CH1
CL
Antibody
Fab
vH vL
Chimeric antigen receptor
α βTCR-complex
γ ε ε δ ζ ζ
(Eshhar et al; PNAS 1993)
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Chimeric Antigen Receptors
Cooper et al
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Lysis
Lysisleukemia
DC
NK
DC
DC
NK
NK
Donor alloreactiveNK cells
Lysis
T T T
Kill recipient APCs =protection from GvHD
Kill recipient T cells =improved engraftment
Kill leukemia =GvL effect
Ruggeri et al. Science 2002
Allo NK-based conditioning:Ablation of recipient targets
T T
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Busulfan Fludarabine
HaploidenticalAllo reactive NK Cells
ATG
Allo matchPBPC
Addition of NK cells to HSCT
Phase I/II study to determine toxicity and efficacy of addition of alloreactive NK cells to high dose chemotherapy and allogeneicstem cell transplantation for myeloid leukemias
Champlin et al
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Hematopoiesis
Stem Cells
Granulocytes
Monocytes
Eosinophils
Basophils
Erythrocytes
Megakaryocytes
Platelets
T-lymphocytes
B-lymphocytes
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Immune System
BloodStem Cell
Nervous System
Liver and other organs
MesenchymalBlood vesselsFibrous tissue
GlandsGI tract, islet cells
Heart
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Approach to Abrogate GVHD
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Suicide Switch- Prevention of GVHD
45
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Modified Caspace 9- Self Destruct Switch
46
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If We Can Prevent GVHD • Dramatically expand use of allogeneic
SCT• Bone marrow failure/immune deficiency/metabolic
diseases of hematopoietic cells• Non malignant hematologic/metabolic/immune
mediated diseases– Thalassemia, Hemoglobinapathies– Autoimmune diseases
» Arthritis, Diabetes, Rheumatologic diseases, ……• Tolerance for Organ Transplants• Malignant Diseases
– Eliminates major toxicity of highly effective treatment
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HSCT
Vaccine or ImmuneEffector cells
DD
DRLRLR
RR
R
RLR
R DD
D
D
D DD
D
D
D
D
DD
Complete ChimeraRecipient Donor TolerantMixed Chimera
Ideal Nonablative Hematopoietic Transplant
PreparativeRegimen
No GVHD, Immune Reconstitution, GVL for malignancy