STEM CELL TRANSPLANTATION�

MEDICAL STUDENTS LECTURE

Introduction

• Stem cells are those cells which have the capacity for self-renewal and multipotentially ie the capacity to generate cells of all the lymphohaemopoietic and other tissue lineages

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• In stem cell transplant, the aim is to provide the recipient with a normal haemopoietic and/or immune system

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• The first successful SCT was done in the late 1960s and this begun the modern era of SCT
• Prior to this period many SCT were attempted in terminally ill patients with leukaemias and Aplastic anaemia without success
• Successful SCT that was done in the late 1960s followed the development of the knowledge of HLA system and tissue typing

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• Currently it is estimated that about 30,000 patients undergo SCT each year for a wide range of disease conditions

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• Stem cell transplantation is the transfer of stem cells from one individual (donor) to the other recipient or within the same individual for the purpose of providing the recipient with a normal haemopoietic and /or immune system

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Types of SCT

• Autologous – involves use of patients own stem cells from bone marrow or peripheral blood to reconstitute haemopoiesis after conditioning of the patient
• Most patients not having a compatible sibling donor undergoes autologous SCT

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• Allogeneic - involves the use of a matched or compatible non-identical siblings’ stem cells for SCT

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• Risk of graft versus host disease (GvHD) is high when mis-matched donors are used

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• Syngeneic – this is the use of identical twins stem cells to reconstitute the recipient’s haemopoietic or immune system

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• Risk of relapse in malignant disease is a major complication associated with this type

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Sources of stem cells

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• Bone marrow
• Peripheral blood
• Placental (cord) blood

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Advantages of peripheral blood stem cells over bone marrow stem cells

• Easily collected
• No general anaesthesia required
• Higher yield of CD34+ cells is achieved especially after administration of haemopoietic growth factors eg G-CSF
• Easily engrafted with faster platelets and myeloid recovery after transplantation of autologous and probably allogeneic peripheral blood stem cells

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• Cord blood stem cells has the advantage of less risks of occurrence of GvHD ie reduction in the immunological complications of SCT due to the immunological naivety of cord stem cells

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Indications for SCT

Allogeneic SCT

i. Most common indications

• Acute myeloid leukaemia – first remission
• Chronic myeloid leukaemia – chronic phase
• Adult Acute lymphoblastic leukaemia – first remission
• Childhood Acute lymphoblastic leukaemia – second remission
• Severe Aplastic anaemia

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ii. Less common indications

• Severe combined immunodeficiency
• Wiskott-Aldrich’s syndrome
• Fanconi’s anaemia
• Juvenile CML
• Myelodysplastic syndrome(MDS)
• Homozygous β- thalassaemia
• Haemoglobinopathies like sickle cell anaemia

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iii. Less well defined indications

• Chronic granulomatous disease
• Gaucher’s disease
• Osteoporosis
• Hurler’s syndrome
• Paroxysmal nocturnal haemoglobinuria

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Autologous SCT

• Acute leukaemia – if no fully matched sibling
• Hodgkin’s disease – refractory or relapsed disease
• Non-Hodgkin’s lymphoma – intermediate and high grade type
• Paediatric solid tumours
• Multiple myeloma
• Breast cancer
• Autoimmune disease

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Technique (procedure)

The donor

• Stem cell harvest is performed under general anaesthesia if sourced from the bone marrow
• There is minimal risk to the donor
• Marrow is aspirated from both posterior iliac crests, anticoagulated, and filtered to provide a uniform cell suspension

• About 500 – 1000ml of marrow content is required for allogeneic transplant
• This contains approximately 3 x 10⁸ nucleated cells/kg recipient body weight
• Fewer cells are required for autologous transplant

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• If there is ABO blood group incompatibility between donor and recipient, donor red cells or plasma are removed by apheresis
• For autologous SCT, the patient’s stem cells is usually processed to remove red cells and plasma, and to reduce bulk before cryopreservation in liquid nitrogen until it is required

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The recipient

• is admitted to a single room with reverse barrier nursing or a laminar airflow facility with a clean or sterile environment
• Harvested and processed stem cell suspension (fresh or recently thawed) is simply infused intravenously

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• Conditioning: All recipients of SCT receive intensive immuno-suppression or cytoreduction a few days before stem cell infusion
• Note: Semen of patients who have not already had heavy chemotherapy may be stored prior to procedure

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• Most widely used conditioning regimen is cyclophoshamide given over 2 days at 120mg/kg body weight
• This is followed by total body irradiation
• Other conditioning regimen may include melphalan, busulphan, etoposide or high dose cytosine arabinoside
• Supportive management include anti emetic and fluid therapy

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• Conditioning results in profound pancytopaenia lasting several weeks

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• Infection prevention and control is very important during this period

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• This may include reverse barrier isolation, prophylactic antimicrobial agents (antibiotics, antiviral and antifungal), gut sterilization and clean or sterile food

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• Frequent red cell and platelet transfusions (irradiated to prevent third-party GVHD) are necessary
• Prompt treatment of any sign of infection eg fever is very important

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Haemopoietic regeneration

• Influenced by the following factors:
• Age
• Diagnosis
• Previous therapy
• Type of graft
• Degree of histocompatibility
• Therapy given after SCT
• Complicating infections or GVHD

Generally, in uncomplicated allogeneic SCT, neutrophils recover within 3-4 weeks; platelets are the last component to recover, usually within 5 weeks

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Complications of SCT

• Early or late
• Early complications
• Infections
• Graft rejection
• Acute graft verse host disease (GVHD)
• Idiopathic pneumonitis
• Veno-occlusive disease of the liver
• Haemorrhagic cystitis

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• Late complications

Occurs 100 days post transplant

• Chronic GVHD
• Complications of chemotherapy and irradiation:
• eg pulmonary
• neurological (myelitis, leuco-encephalopathy, blindness)
• endocrine dysfunction,
• gonadal hypofunction and infertility

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• Growth and developmental complications
• Cataract
• Secondary malignancies
• Disease relapse or recurrence

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Prevention /reducing complications of SCT

• Suitable donor selection
• Adequate conditioning of recipient
• Use of haemopoietic growth factors and other haemopoietic cytokines to enhance immune recovery and shorten period of marrow aplasia
• T- cell depletion of stem cell source for SCT
• Deliberate induction of GVHD

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Application of SCT in haematology practice

• Treatment of both malignant and non-malignant haematological diseases and inherited immune disorders
• As a tool for gene transfer and gene therapy
• As a vehicle for gene marker studies

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Conclusion

• SCT is a valuable procedure for life threatening failure of the haemopoietic or immune systems
• Promises a cure for many life threatening conditions however, the attendant complications and cost especially in resource poor settings poses a challenge to its application and acceptability

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