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

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

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%

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

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)• Acute 80% (20-40% severe)• Chronic 30%

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 SkinRecurrence 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:

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 %