Richard W. Childs‡
*Section of Hematology/Oncology, Department of Medicine, West Virginia University, Morgantown, West Virginia
†Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
‡National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
Hematopoietic stem cell transplantation (HSCT) remains an effective treatment option for many patients with a wide range of malignant and nonmalignant conditions. In addition to autologous and matched related donor allogeneic transplantations, many patients may be offered unrelated donor, nonmyeloablative, or cord blood transplantation. An estimated 40,000 to 50,000 transplantations were performed worldwide in 2002. Although transplantation may be associated with significant morbidity and mortality, recent advances in supportive care, human leukocyte antigen (HLA) typing, and treatments for graft versus host disease (GVHD) have led to improved outcomes for patients undergoing the procedure. An overview of autologous and allogeneic transplantation is provided in this chapter, along with a discussion of the complications and their management.
HEMATOPOIETIC STEM CELLS
Hematopoietic stem cells (HSCs) are immature precursor cells residing within the marrow space that are capable of giving rise to most of the cellular elements within the blood, including lymphoid, erythroid, and myeloid lines. These cells are defined by their ability to rescue lethally irradiated animals from marrow aplasia. In humans, most HSCs express the CD34 antigen and lack lineage-specific markers, although a population of CD34- stem cells has also been described. The number of CD34+ cells that are present in the graft has an impact on transplant outcome; in the allogeneic setting, fewer CD34+ cells are associated with a higher risk of transplant-related mortality and delays in the time to hematopoietic recovery in contrast to more CD34+ cells where transplant-related mortality and the risk of disease relapse is decreased. HSCs can be obtained from peripheral blood, bone marrow, or umbilical cord blood (discussed in subsequent text).
Peripheral Blood Stem Cell Collection
Bone Marrow Harvest
CURRENT INDICATIONS FOR TRANSPLANTATION
Many malignant and nonmalignant disorders have been treated successfully with HSCT [the National Marrow Donor Program (NMDP) currently lists more than 70 diseases]. Most transplantations are performed for malignant conditions, including acute myeloid and lymphocytic leukemias, chronic myelogenous leukemia (CML), multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Stem cell disorders (e.g., aplastic anemia and paroxysmal nocturnal hemoglobinuria), inherited immune-system defects (e.g., severe combined immunodeficiency and Wiskott-Aldrich syndrome), erythrocyte disorders (e.g., sickle cell anemia and β-thalassemia), and congenital metabolic diseases have been cured by allogeneic HSCT.
Prior to treatment, a thorough discussion highlighting the transplantation procedure itself as well as risks and benefits associated with the procedure should take place between the physician and the patient.
AUTOLOGOUS STEM CELL TRANSPLANTATION
High-dose chemotherapy (HDCT) without stem cell rescue may result in prolonged cytopenias. Autologous stem cells are collected and are reinfused into the patient after the completion of HDCT to reconstitute the hematopoietic system.
ALLOGENEIC STEM CELL TRANSPLANTATION
Allogeneic stem cell transplantation has progressed from a treatment of last resort to first-line therapy for some patients. Extensive planning and coordination of care is required for all transplantation candidates, usually involving a network of physicians and support staff. The NMDP is an invaluable resource for physicians and their patients for the purpose of transplantation. The NMDP Web site ishttp://www.marrow.org. All physicians may perform a free initial search for an HLA-matched unrelated donor in the NMDP, which maintains a registry of more than 5 million potential donors.
Graft versus Malignancy
The main therapeutic benefit of allogeneic transplant depends on the potential of the donor's immune system to recognize and eradicate the malignant or abnormal stem cell clone [the so called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect]. This immune effect is evidenced by the lower relapse rate of hematologic malignancies in patients who
undergo allogeneic transplantation than in those who undergo autologous transplantation, as well as by an increased relapse rate in patients receiving a transplant from a syngeneic (identical twin) donor or an allograft that has undergone T-cell depletion. In addition, patients who develop GVHD have a lower risk of relapse than those who do not, and those who relapse after transplantation may be induced into a second remission with a donor lymphocyte infusion (DLI). CML, low-grade lymphoma, and acute myelogenous leukemia (AML) are most susceptible to the GVT effect, whereas acute lymphoblastic leukemia and high-grade lymphomas are relatively resistant to GVT. GVL is predominantly mediated by donor-derived T cells, although new evidence supports a potential contribution from nonspecific cytokines (both host and/or donor derived) and donor-derived natural killer (NK) cells in some settings.
Sources of Donor Hematopoietic Progenitor Cells
Matched Related Donor
Matched Unrelated Donor
Umbilical Cord Transplantation
Careful donor selection and evaluation is an integral part of the pretransplantation workup. The donor must be healthy and able to withstand the apheresis procedure or a bone marrow harvest.
Human Leukocyte Antigen Typing
The HLA system is a series of cell surface proteins, which play an important role in immune function. The system is intimately involved in cell-to-cell interactions and recognition. The genes encoding the HLA system are located on chromosome 6 and are codominantly expressed. A striking feature of the HLA system is its enormous diversity. HLA class I molecules include HLA-A, HLA-B, and HLA-C loci. HLA class II molecules are made up of more than 15 antigens, with HLA-DR having the greatest impact on transplantation outcome. Further complexity of the HLA system was revealed with the advent of molecular-based HLA typing, showing that HLA antigens previously identified by serologic testing were actually diverse when classified by DNA analysis. Current recommendations include matching of the donor and recipient at the allele level for HLA-A, HLA-B, and HLA-DRB1 loci.
Stages of Transplant
Conditioning (“The Preparative Regimen”)
Supportive Care Phase
Infection remains a major cause of morbidity for patients undergoing HSC transplantation. Figure 30.1 displays an overview of potential pathogens. Indwelling catheters are a common source of infections, and sepsis may occur during the neutropenia phase of the transplantation. Current approaches to minimize the risk of life-threatening infections include the use of prophylactic antimicrobial, antifungal, and antiviral agents, as well as aggressive screening for common transplantation-associated infections.
FIG. 30.1. Phases of opportunistic infections among allogenic HSCT recipients. *without standard prophylaxis; Δprimarily among persons who are seropositive before transplant. (From Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal Wkly Rep 200;49(No. RR-10):[1–60], with permission.)
See Chapter 36 for overview of management of neutropenic fever.
Invasive Fungal Infection
Hepatic venoocclusive disease (VOD) is characterized by jaundice, tender hepatomegaly, and unexplained weight gain or ascites. VOD remains extremely difficult to treat, with the risk for this complication increasing with the use of busulfan-containing preparative regimens. Treatment typically involves supportive care measures focused on maintaining renal function, the coagulation system, and fluid balance. Monitoring busulfan drug levels with appropriate dose adjusting appears to decrease the incidence of this complication. Defibrotide, an investigational agent, has recently been used with success to treat severe VOD.
Graft Versus Host Disease
GVHD remains a main toxic effect associated with allogeneic transplantation. This clinical condition results when donor-derived T cells recognize and react against normal recipient tissues. Acute GVHD occurs most commonly within the first 100 days of the transplantation, whereas chronic GVHD occurs most commonly more than 100 days after transplantation. Up to 50% of matched sibling allogeneic transplants are complicated by acute GVHD. Current approaches to lessen the risk include the use of prophylactic pharmacologic agents and T-cell depletion of the graft. The clinical presentation of GVHD may be variable but the most commonly affected organs are skin, liver, and the gastrointestinal system. The staging system for GVHD is presented in Table 30.1. Risk factors for acute GVHD are shown in Table 30.2.
TABLE 30.1. Staging System for Graft versus Host Disease (GVHD)
TABLE 30.2. Risk factors for Acute Graft versus Host Disease (GVHD)
Prevention of Acute Graft Versus Host Disease
Treatment of Acute Graft versus Host Disease
TABLE 30.3. Treatments that May be Useful for Acute Graft versus Host Disease (GVHD) Treatment
Chronic Graft versus Host Disease
Relapse after Transplant
Relapse of malignant disease after allogeneic transplant is an ominous event. Most relapses occur within 2 years of transplantation. Immunosuppression is typically withdrawn to enhance a GVT effect, and in some cases, a DLI is given (lymphocytes from the original stem cell donor). This frequently results in GVHD, which may also be associated with a GVT response. The most favorable responses to DLI have been seen in patients with CML, especially those in the molecular or chronic phase of relapse.
Nonmyeloablative transplantation (NST) relies principally on the graft versus malignancy effect. Instead of intense myeloablative preparative regimens, this technique incorporates immunosuppression to allow for engraftment of donor cells. The most common preparative regimen consists of fludarabine combined with an alkylating agent or low-dose TBI. Nonmyeloablative transplants may be performed in older adults (i.e., older than 60 years) because regimen-related toxicities are less in this case. A mixture of donor and recipient hematopoietic cells is present just after transplant (called mixed chimerism). As immune suppression is removed, the surviving recipient cells are gradually eradicated by the donor immune system, ultimately resulting in full donor engraftment. GVT effects have been observed to occur in CML, AML, chronic lymphocytic leukemia (CLL), lymphoma, multiple myeloma, as well as in select metastatic solid tumors.
A number of small studies have recently reported that GVT effects may be observed in patients with cytokine-refractory metastatic renal cell carcinoma. Disease regression is usually delayed, occurring 4 to 6 months after transplantation following the withdrawal of immunosuppression and occurring frequently in association with either acute or chronic GVHD. Clinical trials investigating GVT effects in renal cell carcinoma and a variety of other metastatic solid tumors are ongoing.
HSC transplantation has dramatically improved over the last several decades into an effective therapeutic treatment for a variety of malignant and nonmalignant conditions. The number of patients who benefit from this procedure will likely increase as future transplantation strategies continue to evolve that limit complications while maximizing beneficial donor immune-mediated graft-versus-malignancy effects.
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