jeffrey schriber, m.d. frcp (c) medical director cancer transplant institute virginia g. piper...
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Jeffrey Schriber, M.D. FRCP (c)Medical Director
Cancer Transplant InstituteVirginia G. Piper Cancer Center
Everything You Ever Wanted to Know About Transplant But
Were Afraid to Ask
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Suddenly, Dr. Schriber realized he had left his brain in Toronto
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Objectives
Understand Basic Principles of Transplantation
Understand Differences between Autologous and
Allogeneic Transplants
Understand which Diseases are best treated by each type
of Transplant
Understand Major Complications of each type of
Transplant
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Stem Cell Transplant Principles
Dose Intensity
Stem Cell Rescue
Immune System
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Dose Intensity
Active Agents at Conventional Doses
Avoid Overlapping Nonhematologic Toxicity
Non Cross Resistant Agents
Immunosuppressive*
*Allo only
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Dose Intensity
Increase dose intensity of Cytotoxic Chemotherapy
Up to 10-fold over conventional therapy
Up to 2.5 times MTD without stem cell support
TBI
Busulfan
ThioTEPA
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Dose Limiting Toxicities
BCNU
Busulfan
Carboplatinum
Cyclophosphamide
Etoposide
Thiotepa
Pulmonary
Gastrointestinal
Renal
Cardiac
Mucosal
CNS
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Stem Cell Properties
Capable of Producing all Blood cell lines
Capable of Self Renewal
Rare in Resting Peripheral Blood
Has Marker called CD 34
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Steps in Stem Cell Transplant Prior therapy to decrease tumor burden
Disease and Functional Testing
Choose Donor (auto vs. allo)
Transplant Regimen
Cytoreductive
Immunosuppressive
Period of Neutropenia
Count Recovery
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Autologous Stem Cell Transplant
“Trick” to give high doses of chemotherapy
Use Stem Cells to Recover
Cytopenic Phase (Need for transfusions, antibiotics,
pain control)
Late Complications Rare
Most Common Cancer Treated is Myeloma
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HSCT: Choice of Stem Cells: Autologous
Advantages
• Available for most patients
• No graft vs. host disease
• Regimen can be optimized for antitumor activity
• Low morbidity & mortality
• Few long-term complications
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HSCT: Choice of Stem Cells: Autologous
Disadvantages
• Contamination with tumor
• Stem cell damage from prior cytotoxic therapy
• No graft vs. tumor reaction
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Changes in Autologous Transplant: Myeloma
1996 2014
Stem Cell Source Bone Marrow PBPC
Type Inpatient Outpatient
Median Age 57 70
ANC Recovery 18 Days 11 Days
Plt Recovery 22 Days 14 Days
Length of Stay 3-4 weeks 6 days
Mortality 2-5 % < 1%
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Multiple Myeloma Outcomes
N Admitted> 1 Day
%TX Solely
Outpatient
LOS (Median Range)
All Myeloma Patients
24 8 67% 7.5 Days(4-24)
Myeloma < 70 Years of Age
15 4 73% 5 Days(4-7)
Myeloma >70 Years of Age
9 4 56% 9 Days(8-24)
0 % Mortality
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Allogeneic Stem Cell Transplant
True Transplant of the Immune System
Need to Find a Donor
• Sibling
• Unrelated
• Cord Blood
Cytopenic Phase
Immunosuppressive therapy early and late
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HSCT: Choice of Stem Cells: Allogeneic
Advantages
• No contamination with tumor
• Graft vs. tumor reaction
• No exposure to prior therapy
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HSCT: Choice of Stem Cells: Allogeneic
Disadvantages
• Lack of compatible donors
• Graft vs. Host Disease
• Prolonged immunosuppression necessary
• Higher morbidity & mortality
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HSCT: Complications Toxicity of Preparative Regimen
• Mucosal, Liver, Lung, (Heart)
Myelosuppression, Immunosuppression• Infection, Hemorrhage
Graft vs. Host Disease (allo only)• Acute 80% (20-40% severe)• Chronic 30%
Overall Mortality• Allogeneic: 10-40%• Autologous: 1-5%
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Acute GVHD
Typically first 100 days
Skin
• Rash (from minimal to desquamation)
Liver
• Hyperbilirunemia, Elevated ALP
Gut
• Diarrhea
• Persistent Nausea
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GVHD of the SkinRecurrence of GVHD
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Chronic GVHD
Later appearing
More like autoimmune disease
Skin
Mucous membranes
• Mouth
• Eyes
• Vagina
Lung, Liver, Joint Involvement
• Bronchilitis
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Prevention of GVHD
Remove T Cells• Eliminates GVHD• High Relapse Rate with lose of GVL• Add Backs at later date
Selective Removal of T subsets• Remains under investigation
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Prevention of GVHD
Calcineurin inhibitors (Cyclosporine and Prograf)• Inhibit Ca+ dependent signaling protein for IL 2
transcription (via TCR) Rapamycin
• Inhibits protein kinase required for protein synthesis and cell cycle progression (cytokines and growth factors)
MMF• Inhibits enzyme responsible fro Nucleotide synthesizes in
B and T lymphocytes
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Prevention of GVHD
Prednisone
ATG
Rituxan
Methotrexate
Cyclophosphamide post Transplant
Antibodies to IL2, TNF
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Autologous vs. Allogeneic Transplant Donors Easily
Available Regimen Tailored Potential Tumor
Contamination Low Morbidity /
Mortality No GVHD/GVT Few Long Term
Complications Major Risk Relapse
Must Find Donor Regimen must be
Immunosuppressive Higher Morbidity/
Mortality GVHD both Acute
and Chronic as Major Complication
GVT Effect Lower Risk of
Relapse
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Diseases Commonly Treated with Transplant
Acute Myeloid Leukemia
Acute Lymphoid Leukemia
Chronic Leukemia (CML, CLL)
Myelodysplastic Disorders
Congenital Disorders
Non Hodgkin’s Lymphoma (low or high grade)
Hodgkin’s Disease
Myeloma
Germ Cell
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Nonmyeloablative Transplant
Less intense chemotherapy
Older patients now feasible
Decreased mucositis
Shift to outpatient therapy
Less transfusion requirements
No change in Chronic GVHD/GVL
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Nonmyeloablative Transplant
Increase Patient Eligibility• Age to 70• Allows for
Cardiac
Pulmonary function
Hepatic
Renal
Infection not absolute contraindication
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Changes in Allogeneic Transplant:
1996 2011
Stem Cell Source Bone Marrow PBPC
Type Inpatient Inpatient/ Mix
Median Age 40 (20-55) 60 (20-75)
ANC Recovery 25 Days 14 Days
Plt Recovery 35 Days 30 Days
Length of Stay 8-12 weeks 6 -8 weeks
Mortality 30-40 % 20-30 %
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