Rationale for High-Dose Therapy With Stem Cell Transplantation

HSCT involves replacing diseased, destroyed, or nonfunctioning hematopoietic cells with healthy hematopoietic progenitor cells, also called stem cells. Stem cells are primitive hematopoietic cells capable of self-renewal, and they are pluripotent, meaning that they are capable of maturating into a red blood cell (RBC), a white blood cell (WBC), or a platelet. These stem cells may be collected directly from the bone marrow spaces by a bone marrow harvest procedure or from the peripheral blood by apheresis. Stem cells can also be harvested from the placenta immediately after delivery.

In both autologous and allogeneic HSCT, peripheral blood stem cells have become the preferred source of hematopoietic stem cells for grafting. Collection of cells through apheresis is easier and less costly and may also result in a more rapid recovery of neutrophil and platelet counts. In unrelated allogeneic transplantation, the source of stem cells may be either a bone marrow harvest procedure or a peripheral blood stem cell collection.

Types of Hematopoietic Stem Cell Transplantation

The various types of HSCTs can be differentiated in terms of the hematopoietic stem cell donor, the method used to collect the cells, and the intensity of the conditioning regimen. Each type of HSCT has relative advantages and disadvantages, as summarized in the table below. In an autologous stem cell transplant, the patient serves as his or her own donor of stem cells, whereas for an allogeneic transplant the donor is either related (typically a sibling) or unrelated. If an identical twin donor is available, the transplant is termed a syngeneic transplant. The source of the stem cells may be the peripheral blood stream (peripheral blood stem cell transplant), or the cells may be collected directly from the bone marrow spaces (bone marrow transplant) or from a placenta (cord blood transplant). Transplants can also be differentiated on the basis of the intensity of the conditioning regimen. A myeloablative transplant provides high doses of radiation or chemotherapy to treat the underlying malignancy and ablate the bone marrow, thereby causing myelosuppression that would be irreversible without stem cell support. A reduced-intensity transplant delivers lower doses of radiation or chemotherapy, typically causing less severe myelosuppression and less nonhematologic toxicity.

Comparison of Techniques for Harvesting Hematopoietic Stem Cells

Indications for and Outcomes of Hematopoietic Stem Cell Transplantation

HSCT represents an important advance in restoring hematopoietic function in patients whose bone marrow has been destroyed by radiation or high-dose chemotherapy to treat an underlying malignancy. Many factors influence the indications for and patient eligibility for transplantation. HSCT is used when bone marrow is defective or destroyed by a disease process or as a result of treating an underlying disease. The box below lists the diseases for which adults are currently treated with autologous or allogeneic HSCT.

Factors that may affect the outcomes of HSCT include the type and stage of disease at the time of transplantation, the type of transplant (allogeneic versus autologous), the degree of human leukocyte antigen (HLA) matching in allogeneic transplants, the intensity of the conditioning regimen, the ages of both the donor and the recipient, and the experience of the transplantation center. In general, the transplant-related mortality risk in allogeneic HSCT is about 20% to 30% higher than in autologous HSCT. At most transplant centers, the transplant-related mortality rate in autologous HSCT is less than 5%.

Disease-free survival at 5 years after HSCT varies substantially, depending on the age of the recipient, the underlying disease, disease status at the time of transplantation, the type of HSCT procedure, and the extent of prior treatment. Depending on these factors, disease-free survival can range from 10% to 75% (Baron & Storb, 2007; Brunstein, Baker, & Wagner, 2007; Chantry et al., 2006; Koreth et al., 2007; Nademanee & Forman, 2006; Tabbara et al., 2002; Yakoub-Agha et al., 2006).

Pretransplant Evaluation of the Recipient and Donor

The pretransplant evaluation of the recipient includes physical and psychosocial evaluation, an evaluation of the adequacy of insurance coverage, and family support and education about the transplant process to permit informed consent for the procedure. Evaluation before final selection of a donor includes confirmatory high-resolution tissue typing, an assessment of viral serology, and an evaluation of overall health. The components of the evaluation of recipient and donor are summarized in the box on page 144.

In selecting an individual to serve as an allogeneic HSCT donor, histocompatibility testing (tissue typing) is performed to evaluate the human leukocyte antigen (HLA) match between antigens of the donor and that of the recipient. A person’s tissue type is coded by genes of the major histocompatibility complex. These genes contain information for cell surface antigens that differentiate self from nonself. The major histocompatibility complex involved in the immune response include class I antigens (A, B) and class II, the DR antigens. Each person has two A-, B-, and DR-locus antigens that are inherited as a haplotype (i.e., a single unit) from each parent. Many possible antigens may occur at each locus, resulting in a large number of HLA combinations. The higher the number of antigens that match, the higher the likelihood of compatibility, and the lower the risk of acute and chronic GVHD and graft rejection.

Selection of a donor for HSCT is based on the type and stage of the underlying disease, donor and recipient age, and comorbidities, together with HLA- and mixed leukocyte culture (MLC)-matched donor. MLC is performed to observe for interaction between the potential donor’s cells and recipient cells. Low reactivity indicates greater compatibility. A related donor is usually a sibling (siblings have the greatest chance of matching on both HLA and on other minor and as yet unrecognized antigens). If more than one donor is HLA identical to the patient, donor selection is based on sex, ABO compatibility, negative viral titers, younger donor age, and donor nulliparity because all these factors are associated with an improved outcome of HSCT (Confer & Miller, 2007). Into the future, there is a potential role for non-HLA genetics in donor selection, based on the insights into the immunobiology of HSCT complications provided by genotyping for non-HLA genes (Dickinson, 2007).

If the patient does not have a suitable family donor, a search for an unrelated donor may be undertaken. The National Marrow Donor Program, a donor registry developed in 1986, allows patients without a related donor to find an HLA-matched unrelated donor. Umbilical cord blood is another potential stem cell source, particularly in pediatric allogeneic transplantation.

Mismatch in ABO blood group between patient and donor does not preclude successful HSCT. Depending on the direction of the incompatibility (major versus minor incompatibility), the hematopoietic stem cell product may have to be depleted of RBCs to prevent a hemolytic reaction caused by ABO antibodies still circulating in the patient’s bloodstream. After engraftment and approximately 100 days after transplantation, the recipient of an ABO-mismatched transplant will seroconvert to the ABO type of the donor.

Stem Cell Harvesting, Mobilization, and Collection

Stem cells are most numerous in the bone marrow spaces, and some circulate in the peripheral blood. The process of harvesting and collecting hematopoietic stem cells differs depending on the type of transplant. Progenitor cells may be obtained through a bone marrow harvest or collected through the peripheral blood. Immediately after delivery, hematopoietic stem cells may also be collected from the placental cord and cryopreserved for subsequent use.

When stem cells are obtained from the donor’s bone marrow, the harvesting procedure is performed in the operating room under spinal or general anesthesia. Multiple aspirations are obtained from each posterior iliac crest with large-bore needles until a total of 2 to 3 × 10⁸ nucleated cells per kilogram of recipient’s body weight is obtained. The total volume of aspirate is 1 to 2 L. The marrow is placed in a heparinized tissue culture medium and filtered for the removal of fat and bone particles, and the cells are taken directly to the recipient’s room for infusion or cryopreserved for subsequent infusion. The bone marrow harvest procedure usually takes 1 to 2 hours, and the donor is often hospitalized overnight for observation. The harvest sites may be mildly uncomfortable for 2 to 7 days after the procedure.

Hematopoietic stem cells may also be collected from the peripheral blood. However, because stem cells are not abundant in the peripheral blood, chemotherapy (for autologous transplant recipients who are providing their own stem cells for subsequent administration) or colony-stimulating factors (for healthy donors providing an allogeneic stem cell transplant product) (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) must be given before collection to drive progenitor cells into the peripheral circulation. This process is termed mobilization or priming. The chemotherapy that patients undergoing an autologous stem cell transplant receive for stem cell mobilization is also useful for tumor reduction. For both related and unrelated donors, colony-stimulating factors (CSF) alone are used to increase the number of stem cells in the peripheral blood. Protocols vary, but G-CSF or GM-CSF is given by a subcutaneous injection daily. Stem cell collections begin after 4 or 5 days of CSF injections.

Hematopoietic progenitor cells are collected from the peripheral blood by a method called leukapheresis. A commercial cell separator machine collects the progenitor cells and returns the remainder of the plasma and cellular components to the bloodstream. This is performed either through wide-bore double-lumen central catheters or large-bore antecubital angiocath intravenous catheters. The procedure takes approximately 3 to 4 hours, and the number of leukapheresis procedures required is determined by the number of stem cells harvested at each session. The goal is to collect 5 × 10⁶ CD34-positive cells per kilogram of recipient body weight. The CD34-positive antigen is an antigen expressed on the surface of early progenitor cells.

During and immediately after apheresis and stem cell collection, the donor may have a transient hypocalcemia reaction with chills, fatigue, tingling in the lips and extremities, and vertigo resulting from the citrate infusion, which is used to prevent clotting of the blood during the procedure. The symptoms can be prevented or treated by taking an oral calcium carbonate supplement, such as Tums.

Conditioning Therapy/Preparative Regimen

A conditioning therapy or preparative regimen including total body irradiation or chemotherapy is administered for several days before stem cell infusion; it is designed to prepare the recipient to receive the transplanted stem cells. The goals of the conditioning regimen depends in part on whether the transplant is autologous or allogeneic and on the nature of the patient’s underlying disease. In allogeneic transplantation, the purpose of conditioning is to eradicate any malignant disease, eliminate the bone marrow to create a space for the new donor stem cells, and provide sufficient immunosuppression to allow engraftment of the transplanted stem cells. In autologous transplantation, immunosuppression is not required because the patient is the source of the hematopoietic stem cells. However, intensive therapy is still needed to eradicate the underlying malignant disease.

The rationale for selecting the agents that are included in the preparative regimen is based on the hypothesis that increasing the total dose or dose rate will kill more tumor cells, resulting in improved response and survival rates. Typically, drugs with different (i.e., nonoverlapping) nonhematologic dose-limiting toxicities are combined in maximal doses. Alkylating agents (cyclophosphamide, carboplatin, busulfan, thiotepa, cisplatin, melphalan, carmustine), etoposide, cytarabine, and sometimes total-body irradiation are used to destroy the bone marrow and eradicate disease. The regimen is administered over 2 to 8 days. The individual drugs that may be used in combination as part of the transplant conditioning regimen may have several adverse effects (see table on page 146). The patient is then allowed 1 or 2 rest days to clear the chemotherapy from the system before the infusion of stem cells. Bone marrow aplasia occurs within days after the conditioning regimen is completed.

A reduced intensity conditioning regimen followed by allogeneic HSCT is a newer approach that may provide a treatment option for older patients and those who have undergone a prior autologous transplant or have comorbidities, such as lung, kidney, or liver disease and cannot tolerate the toxicities of a high-dose conditioning regimen. The rationale for reduced intensity conditioning regimens is that the immune-mediated graft-versus-tumor effect provided by the new immune system, rather than primarily the conditioning regimen itself, is responsible for control of the disease. Reduced intensity regimens under investigation include fludarabine, single-dose total-body irradiation (≤500 cGy), cyclophosphamide, melphalan, busulfan, and a combination of potent immunosuppressive medications. Data to support the potential efficacy of a reduced intensity regimen exist for patients with Hodgkin disease, multiple myeloma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute leukemia and myelodysplastic syndrome (Giralt, 2005). These reduced intensity regimens are not without risk, and patients undergoing transplant after a reduced intensity conditioning regimen still experience many of the expected complications of a conventional, fully myeloablative allogeneic transplantation. The problems encountered in the early posttransplantation period, such as infection, bleeding, and regimen-related toxicities, may be reduced after nonmyeloablative transplantation, but the risk of GVHD and the long-term risks of infection continue to be important. The role of strategies such as posttransplant immunotherapy and posttransplant maintenance therapy with agents such as rituximab or imatinib in improving the outcomes for patients who have received a reduced intensity allogeneic HSCT are the subject of continuing study.

Stem Cell Infusion

The infusion of stem cells is a relatively simple procedure, much like a blood transfusion. The cells are infused through a central venous catheter over 30 to 90 minutes, depending on the total volume of the product. In allogeneic HSCT, the stem cells are usually infused immediately after they are collected. Autologous stem cells are cryopreserved with dimethylsulfoxide (DMSO) and must be thawed in a warm normal saline solution bath at the bedside immediately before reinfusion. Premedication with acetaminophen, hydrocortisone, and diphenhydramine is usually recommended, and patients may also receive prehydration to maintain renal perfusion. Vital signs and pulse oximetry are monitored closely before, during, and at intervals after stem cell infusion. An infusion pump should not be used to administer stem cells; normal saline solution is used to prime and flush the tubing.

Nonhematologic Side Effects of Agents Used in Preparative Regimen/Conditioning Therapy

Data from Chan, 2000; Gupta-Burt & Okunieff, 1998; McAdams & Burgunder, 2004; Petros & Gilbert, 1998; Rees, Beale, & Judson, 1998; and Solimando, 1998.

Complications of stem cell infusion are rare but may include pulmonary edema, hemolysis, infection, and anaphylaxis. Infrequently, DMSO can cause an infusion reaction that may include bradycardia (rarely heart block) or hypertension, and an acute hypersensitivity reaction may occur; this is caused by excretion of DMSO. The excretion of DMSO used in cryopreserving autologous stem cells typically causes a characteristic odor or taste that may be described as “garlicky.” DMSO-associated RBC hemolysis may also occur and may require vigorous hydration to prevent renal toxicity. During infusion, patients are also monitored for volume overload and for complaints suggestive of pulmonary embolism such as chest pain, dyspnea, and cough.

Early Complications of Stem Cell Transplantation

After stem cell infusion, the hematopoietic stem cells migrate to the bone marrow spaces, where they are attracted by chemotactic factors. Engraftment occurs when the transplanted progenitor cells begin to grow and manufacture new hematopoietic cells in the bone marrow. After the stem cell infusion but before complete hematopoietic cell engraftment, patients have severe pancytopenia, and the resulting complications may include infection and bleeding. Patients are also at risk for mucositis, skin toxicities, and veno-occlusive disease of the liver. Examples of early and late complications arising from autologous and allogenic stem cell transplantation can be found in the box on page 147. Nonhematologic adverse effects vary depending on the agents used for the conditioning regimen. The nonhematologic adverse effects that are associated with the agents that typically comprise stem cell transplant conditioning regimens are outlined in the table on left.

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