Myeloablative therapy with haemopoietic progenitor cell support (HPCS)

Overview:

• High-doses of chemotherapy and radiotherapy kill dividing cells indiscriminately, so that both normal and malignant cells are killed
• Since the bone marrow is a highly dividing tissue, myelosuppression is the main dose-limiting toxicity
• Thus, without a ‘transplant’ as a source of haemopoietic progenitor cells, the person would die of bone marrow failure
• High-dose treatment may be given using one of the following as a source of haemopoietic progenitor cells:
• Allogeneic bone marrow transplantation (BMT)/peripheral blood progenitor cells (PBPCs)
• Autologous BMT/PBPCs

High-dose treatment with allogeneic BMT/PBPCs:

• The recipient patient first undergoes a ‘conditioning’ regimen of myeloablative therapy over several days, comprising:
• Drugs
• Drugs + total body irradiation (TBI)
• The donor (usually an HLA-identical sibling) has ~1L of bone marrow aspirated from the posterior iliac crests
• The BM is given IV to the recipient on completion of the myeloablative therapy
• Immunosuppressive drugs (usually methotrexate and cyclosporine A) are used to prevent both:
• Rejection
• Graft-versus-host disease (GVHD)

• The patient’ s blood count usually recovers within 3-4 weeks
• Can be very effective but has a 20-30% mortality
• The main causes of death are:
• Infection (bacterial, viral and fungal)
• GVHD

Graft-versus-host disease (GVHD):

• Is a syndrome in which mature T-cells in the donor BM infiltrate the skin, gut and liver
• Acute GVHD occurs in the first 3 months, but it may also run a chronic course
• When fatal, patients usually die of liver failure
• Patients who develop GVHD have a lower incidence of recurrent leukaemia than those who do not
• Thus, not only does the myeloablative chemoradiotherapy have an anti-leukaemic effect, but the T-cells within the donor BM appear to exert an immunologically-mediated ‘graft-versus-leukaemia’ effect
• The use of allogeneic BMT is primarily limited by donor availability
• Allogeneic PBPCs are currently being evaluated:
• Granulocyte-colony stimulating factor (G-CSF) is given to the donor and haemopoietic progenitor cells are collected from a vein
• Large volumes of blood are phoresed (centrifuged)
• The PBPCs are separated and collected and the RBCs, granulocytes, platelets and plasma are then returned to the donor through another vein

• Advantages include:
• Donor does not require a GA
• Donor does not have the discomfort associated with collecting BM from the pelvic bones
• Incidence and severity of GVHD seems to be lower

High-dose treatment with Autologous BMT:

• Remission is first induced with chemotherapy
• 1L of BM is then aspirated from the patient’s posterior iliac crests under GA and cryopreserved in liquid nitrogen
• The myeloablative therapy is then given and then thawed BM is reinfused IV
• Advantages:
• Mortality is less than for allografts (5-10% compared with 20-30%)
• Disadvantages:
• The time to blood count recovery after an autograft is usually longer than after an allograft
• Risk of reinfusing malignant cells (risk can be reduced using in vitro techniques)

High-does treatment with autologous PBPCs:

• PBPCs have virtually replaced autologous BMT as support for myeloablative therapy
• Chemotherapy followed by the growth factor G-CSF alone are administered to stimulate haemopoietic progenitor cells in the BM to proliferate, so that they can be collected from the peripheral blood
• Because PBPCs are more differentiated than those collected directly form the BM, the time to blood count recovery is faster (only 2-3 weeks)
• As the duration of neutropenia is shorter, the treatment is also safer