Background:
Since their initial introduction in the ’80s, peripheral blood stem cells (PBSCs) have gained momentum as a source of stem cells. Over a period, PBSCs mobilized from the bone marrow through cytokine treatment and collected by apheresis have come to account for the majority of hematopoietic stem cell transplants (HSCTs). Compared to bone marrow stem cell transplantation, PBSC transplantation (PBSCT) has the following advantages:
✓ a nonsurgical method of stem cell collection
✓ a larger number of stem cells that can be collected by apheresis
✓ higher graft-versus-tumor effect due to the presence of higher numbers of T cells in the peripheral blood
✓ decreased relapse rates
✓ rapid engraftment with a higher number of committed progenitor cells
✓ decreased mortality
✓ early hospital discharges
There are three types of PBSCTs:
- Autologous transplants: patients receive their stem cells
- Syngeneic transplants: patients receive stem cells from their identical twin
- Allogeneic transplants: patients receive stem cells from their siblings, parents, or unrelated donors
All identical twins have the same genes and thus have the same set of HLA antigens, which results in better acceptance of the syngeneic transplant. Unfortunately, identical twins represent a small number of all births, making syngeneic transplants less common. On the other hand, in allogeneic transplants, although siblings are more likely to be HLA-matched than an unrelated donor, only 25–35 percent of patients have an HLA-matched sibling, whereas the chances of obtaining HLA-matched stem cells from an unrelated donor are slightly better, around 50 percent. HLA-matching is greatly improved when donors and recipients have the same ethnic and racial backgrounds.
Hematopoietic stem cells (HSCs), also called blood stem cells are immature cells found mainly in the bone marrow; however, some stem cells, PBSCs, are found in the bloodstream as well. These HSCs mature into more blood-forming stem cells and eventually into one of the following three types of blood cells:
a) white blood cells, which fight infection;
b) red blood cells, which carry oxygen; and
c) platelets, which help to stop bleeding by forming a blood clot.
PBSCT is the procedure that restores stem cells in cases of destruction via high doses of chemotherapy and/or radiotherapy or bone marrow failure where hematopoietic cells cannot mature into one or more of the three types of blood cells.
The list of diseases for which PBSCT is being used is rapidly increasing, with possible use in more than 70 diseases. Thus, allogeneic transplants are being performed in the case of not only malignancies (hematologic and lymphoid cancers) but also nonmalignant disorders. Further discussion in this article will be focused on allogeneic PBSCT.
Indications:
Allogeneic PBSCT is often performed as a part of therapy to eliminate a bone marrow infiltrative process such as leukemia or to correct congenital immunodeficiency disorders. In addition, the transplant is used to allow patients with cancer to receive higher doses of chemotherapy than bone marrow can usually tolerate; the bone marrow function is then salvaged by replacing the marrow with previously harvested stem cells. Examples of emerging indications for allogeneic PBSCT include the replacement of marrow progenitors to make normal red cells (e.g., in cases with abnormal hemoglobin), making corrective enzymes (e.g., in storage disorders), and mediating tissue repair (e.g., in patients with very fragile skin, epidermolysis bullosa). Specifically, allogeneic PBSCT has been successfully used in patients with severe aplastic anemia, thalassemia major, Fanconi anemia, immunodeficiency diseases, and inherited metabolic disorders.
Matching:
The donor stem cells should match the patient’s stem cells as closely as possible to reduce the potential adverse effects of transplantation. Such matching is achieved with a special blood test that identifies human leukocyte-associated (HLA) antigens, which are specific proteins on the surface of the cells.
In most cases, the success of allogeneic transplantation depends at least partly on the success of HLA matching of the donor’s and the recipient’s stem cells. The higher the number of matching HLA antigens, the greater the chance that the patient’s body will accept the donor’s stem cells. The likelihood of developing a known complication of graft-versus-host disease (GVHD) is also minimized if the stem cells of the donor and the patient are well matched. Moreover, because of the graft-versus-tumor effect that appears after allogeneic HSCT, as this graft contains the donor T cells that can eliminate the patient’s residual malignant cells by recognizing tumor-specific or recipient-specific alloantigens. This graft-versus-tumor effect seen after allogeneic HSCT can lead to lower relapse rates than with autologous transplants.
Preparation and procedure for collecting stem cells from the donor:
HSCs circulate in the blood as PBSCs, albeit in very low concentrations. However, these stem cells can be successfully mobilized from the bone marrow by administering cytokines to the donor, which has led to the widespread adoption of peripheral blood as a cell source for HSCT. Cytokines such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) cause the release of cytokine stem cells into the peripheral blood. The cells can then be collected by apheresis and identified and quantified using flow cytometry (HSCs express the CD34 antigen). Next, the donor undergoes apheresis wherein the blood extracted through a flexible tube placed in a large vein (in the neck, arm, or groin) is passed through a machine that removes the stem cells. The blood is then returned to the donor. Apheresis typically takes 4 to 6 hours, and the collected stem cells are frozen until they are given to the recipient.
Cytokine treatment for stem cell mobilization is initiated at least 4 days before apheresis, and the dose of G-CSF used for mobilization is 10 mcg/kg/day. Clinical trials have shown that mobilization with G-CSF (Filgrastim) is better than with GM-CSF.
Common adverse effects of G-CSF include bone pain, malaise, headaches, chills, and (sometimes) fever. These side effects generally stop within 2 to 3 days of the last dose of the medication.
PBSCT procedure for the patient:
The allogeneic PBSCT process is generally divided into the following 5 phases:
• Conditioning
• Stem cell infusion
• Neutropenic phase
• Engraftment phase
• Post-engraftment phase
➢ The conditioning phase typically lasts for 7-14 days and involves undergoing chemotherapy, immunotherapy, and/or radiotherapy to eliminate malignancy, prevent rejection of new stem cells, and create space for the new cells.
➢ The stem cell infusion phase is a relatively simple process that is performed at the bedside with minimal toxicity observed in most cases.
➢ The neutropenic phase is about 2-4 weeks long when the patient essentially has no effective immune system with high susceptibility to infection and poor healing. Supportive care and empiric antibiotic therapy are the mainstays of successful management in this phase.
➢ The engraftment phase lasts several weeks. The healing process begins with the resolution of mucositis and other acquired lesions. The fever begins to subside and infections often begin to clear. The greatest challenges at this time include management of GVHD and prevention of viral infections.
➢ The post-engraftment phase lasts for months to years, with the gradual recovery of immune function and management of chronic GVHD.
Side effects:
Patients who undergo allogeneic PBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hair loss, and skin reactions. With allogeneic transplants, GVHD sometimes develops when white blood cells from the donor (the graft) identify cells in the patient’s body (the host) as foreign and attack them.
Conclusion:
Allogeneic PBSCT is a potentially curative modality not only for malignant diseases but also for a variety of nonmalignant disorders. The majority of adult transplants in the present era are performed using mobilized stem cells that are harvested from the peripheral blood by apheresis. PBSC collections are designed to target a dose of stem cells that will result in safe engraftment and hematopoietic recovery. A better understanding of the impact of the quantity and quality of various cell types in PBSC grafts may lead to the development of novel collection methods or an improved donor selection process and thus provide a better disease-free survival for many life-threatening disorders with minimal adverse effects.
Our services:
Bioviser has an excellent team specializing in medical writing and editing. We are currently providing medical writing services for a phase 2 study evaluating the role of pegfilgrastim in allogeneic PBSCT. Pegfilgrastim (pegylated filgrastim) is a sustained-duration formulation of filgrastim (a recombinant form of human granulocyte colony-stimulating factor). It has been used in several studies involving lymphoma and multiple myeloma patients. It is known to prolong the half-life of filgrastim by tenfold and reduce the number of injections.
