Jeffrey Schriber, M.D. FRCP (c) Medical Director Cancer Transplant Institute Virginia G. Piper Cancer Center Everything You Ever Wanted to Know About Transplant But Were Afraid to Ask

Suddenly, Dr. Schriber realized he had left his brain in Toronto

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

Stem Cell Transplant Principles  Dose Intensity  Stem Cell Rescue  Immune System

Dose Intensity  Active Agents at Conventional Doses  Avoid Overlapping Nonhematologic Toxicity  Non Cross Resistant Agents  Immunosuppressive* *Allo only

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

Dose Limiting Toxicities  BCNU  Busulfan  Carboplatinum  Cyclophosphamide  Etoposide  Thiotepa  Pulmonary  Gastrointestinal  Renal  Cardiac  Mucosal  CNS

Stem Cell Properties  Capable of Producing all Blood cell lines  Capable of Self Renewal  Rare in Resting Peripheral Blood  Has Marker called CD 34

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

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

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

HSCT: Choice of Stem Cells: Autologous  Disadvantages Contamination with tumor Stem cell damage from prior cytotoxic therapy No graft vs. tumor reaction

Changes in Autologous Transplant: Myeloma Stem Cell SourceBone MarrowPBPC TypeInpatientOutpatient Median Age5770 ANC Recovery18 Days11 Days Plt Recovery22 Days14 Days Length of Stay3-4 weeks6 days Mortality2-5 %< 1%

Multiple Myeloma Outcomes NAdmitted > 1 Day %TX Solely Outpatient LOS (Median Range) All Myeloma Patients 24867%7.5 Days (4-24) Myeloma < 70 Years of Age 15473%5 Days (4-7) Myeloma >70 Years of Age 9456%9 Days (8-24)

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

HSCT: Choice of Stem Cells: Allogeneic  Advantages No contamination with tumor Graft vs. tumor reaction No exposure to prior therapy

HSCT: Choice of Stem Cells: Allogeneic  Disadvantages Lack of compatible donors Graft vs. Host Disease Prolonged immunosuppression necessary Higher morbidity & mortality

HSCT: Complications  Toxicity of Preparative Regimen Mucosal, Liver, Lung, (Heart)  Myelosuppression, Immunosuppression Infection, Hemorrhage  Graft vs. Host Disease (allo only) Acute80% (20-40% severe) Chronic30%  Overall Mortality Allogeneic:10-40% Autologous: 1-5%

Acute GVHD  Typically first 100 days  Skin Rash (from minimal to desquamation)  Liver Hyperbilirunemia, Elevated ALP  Gut Diarrhea Persistent Nausea

GVHD of the Skin Recurrence of GVHD

Chronic GVHD  Later appearing  More like autoimmune disease  Skin  Mucous membranes Mouth Eyes Vagina  Lung, Liver, Joint Involvement Bronchilitis

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

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

Prevention of GVHD  Prednisone  ATG  Rituxan  Methotrexate  Cyclophosphamide post Transplant  Antibodies to IL2, TNF

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

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

Nonmyeloablative Transplant  Less intense chemotherapy  Older patients now feasible  Decreased mucositis  Shift to outpatient therapy  Less transfusion requirements  No change in Chronic GVHD/GVL

Nonmyeloablative Transplant  Increase Patient Eligibility Age to 70 Allows for Cardiac Pulmonary function Hepatic Renal  Infection not absolute contraindication

Changes in Allogeneic Transplant: Stem Cell SourceBone MarrowPBPC TypeInpatientInpatient/ Mix Median Age40 (20-55)60 (20-75) ANC Recovery25 Days14 Days Plt Recovery35 Days30 Days Length of Stay8-12 weeks6 -8 weeks Mortality30-40 %20-30 %