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Features Departments Information |
 Reggie E. Duerst, MD
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Hematopoietic Stem Cell Transplantation: Reggie E. Duerst, MD Odyssey: a long wandering or voyage usually marked by many changes of fortune. INTRODUCTION AND HISTORICAL PERSPECTIVES Hematopoietic stem cell transplantation (HSCT) is a descriptive term for a variety of evolving techniques that provide blood precursor cells and are refinements of bone marrow transplantation. In 1957, Thomas reported the safe infusion of blood precursor cells from adult or fetal marrow, indicating the potential to treat marrow failure or rescue cancer patients following high-dose therapy. Bone marrow transplantation (BMT) has become the established treatment for many patients because of its potential for long-term, disease-free survival from immunodeficiencies, defects of the marrow or hematopoietic stem cells, and high-risk malignancies. Since the late 1980s, peripheral blood progenitor (precursor) cells obtained by apheresis and from the umbilical cord have supplanted much of the reliance on bone marrow as the source of these cells. The goals of HSCT are either (1) to replace a defective blood or immune cell-producing "organ" with a healthy system, or (2) to "rescue" the destroyed marrow of a patient treated for resistant malignancies with high-dose therapy. The blood-producing "organ" can be transplanted as a suspension of cells that are capable of "homing" to the bone marrow space. There, a nurturing microenvironment is in place to facilitate reestablishment of the blood-producing organ from the donated precursor or progenitor cells. The differentiation of precursor cells to mature blood or immune cells and their journey (Odyssey) to the blood and subsequently to all tissues of the body are regulated by influences of both donor and host tissues. As will be discussed below, potential sites for the hematopoietic stem cell Odyssey include air travel, passage through magnetic fields, and freezing experiences. Autologous (self) cells may be used after collection and cryopreservation in advance of the high-dose treatment. Syngeneic cells (from an identical twin) would be the ideal source of hematopoietic stem cells for most applications. Allogeneic (from a different individual of the same species) cells can be obtained from a sibling, other relative, or an unrelated volunteer donor. Allogeneic cells will not be genetically identical to those of the recipient and have the potential for immunologic disparity that will challenge mutual "tolerance." When donor/host tolerance is achieved, blood and immune cell production is a smooth, coordinated effort. Without tolerance, donor and host cells do not cooperate. The donated hematopoietic cells may be rejected (graft failure). On the other hand, the immune cells from the donor may attempt to "reject" the normal, healthy tissues/cells of the recipient. The resulting "graft-versus-host disease" (GVHD) is associated with significant risk for morbidity and mortality, primarily from infection. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION When allogeneic sources of hematopoietic stem cells are used, factors that promote mutual tolerance and a favorable result of the treatment include the degree of tissue antigen matching and younger ages of donor and recipient (indirect measures of the "plasticity" of the two immune systems). The tissue antigen, or human leukocyte antigen (HLA), system is coded by genes on chromosome 6. The antigens are inherited as sets from each parent and are divided into class I (e.g., A, B, or C) and II (DP, DQ, or DR) systems. Although each of the antigen families (A, B, C, DR, etc.) may affect the clinical course of HSCT, the A, B, and DR antigens have been the most consistently defined and correlated with outcome. The Figure demonstrates the potential inheritance pattern—one haplotype or set of antigens from each parent, thus four possible "sets" of antigens amongst siblings. Each sibling has a 1 in 4 chance of matching the patient, and the probability of finding a match in any one sibling is calculated as p = [1 – (3/4)n-1] where n = the total number of full siblings in the patient's family (including the patient). If a patient is one of a family of 4 children, the likelihood of any 1 of the 3 sibs matching the patient is [1 – (3/4)3] = ~58%.  Figure. Each parent has a pair of chromosome 6 with respective A, B, and DR HLA antigens. The original typing systems relied on serologic (antibody) reactions with the HLA antigens for identification and matching. Molecular typing of the DNA sequence of the HLA antigens has defined the multiple variations of these proteins and can identify clinically significant disparity between the donor and the recipient. The improved specificity of this typing should allow better selection when unrelated donors must be considered. Regardless of the source of hematopoietic stem cells, recipients who are in good general health can withstand the side effects of the high-dose therapy better and have fewer infectious complications. The primary disease for which HSCT is warranted should be under optimal control. The donor immune cells that mediate graft vs. host disease also can have a graft-versus-tumor/leukemia (GVL) effect that ultimately enhances the outcome of the HSCT. This effect was suggested by the decrease in leukemia recurrence rates among patients who develop clinically significant GVHD. The GVL effect is most clearly documented by the remissions obtained when an HSCT recipient has developed a recurrence of leukemia following the transplant but returns to remission following infusion of "fresh" leukocytes from the donor. Often a response will be associated with development of GVHD, but repeated infusions of graded amounts of donor leukocytes can result in a remission without the toxicity of GVHD. The goal of many HSCT clinicians is to "harness" the GVL while still preventing GVHD. In earlier years, complete ablation of malignant cells was attempted with high-dose chemotherapy, sometimes combined with total body irradiation. These treatments also destroy the patient's bone marrow. Now the cancer therapy can be less intense, relying on the GVL effect to kill remaining tumor cells. These treatments can focus on immune suppression of the recipient as opposed to immune destruction (myeloablative therapy). Inflammation of the gastrointestinal, pulmonary,and other organ systems should be reduced with less intense cancer therapy. The decrease in inflammation is expected to decrease stimulation of the donor immune cells toward the normal tissues of the recipient, thereby reducing the morbidity of GVHD. The goal following immunoablative therapy remains to ensure that donor hematopoietic cells will fully (if over a longer period of time) take over all aspects of blood and immune cell production. "Engraftment" of the donor's hematopoietic cells in the recipient generally is established within 3 to 5 weeks after infusion of donor hematopoietic stem cells. Full engraftment constitutes complete "takeover" of bone marrow "organ" function by the donated cells. Thus, neutrophils, platelets, and erythrocytes are produced in normal quantities but are all derived from the donor's hematopoietic stem cells. The process of immune system regeneration entails establishment of multiple clones of lymphocytes (e.g., T-, B-, natural killer, and antigen- presenting cells) with specific assignments. Clones of these lymphocytes may attack recipient tissues if tolerance has not been achieved and GVHD results. Generalized inflammatory stimuli result from infections and tissue damage following the high-dose tumor therapy. Mediators of inflammation are part of the cytokine system for cell-cell signaling and stimulate lymphocyte activity. A surge in production of cytokine mediators, a cytokine storm, enhances the risk for developing GVHD. The stimulated donor lymphocytes become the "effectors" of GVHD and must be brought back under control or eliminated to control GVHD. The immune suppression administered to prevent GVHD delays return of normal immune function. GVHD itself is a potent inhibitor of coordinated immune responses. Unless GVHD develops, the recipients of HSCT will eventually be tapered off of their immunosuppressive medications. Thus, some T-lymphocyte functions may return within 4 to 6 weeks of the HSCT, while specific antibody production may be delayed for 12 months or more. Patients are continually reassessed for immune function throughout the first year after HSCT, assuming that protective immunity is lost following HSCT. Resuming immunizations is considered beginning at about one year from HSCT. Ongoing GVHD would be a relative contraindication to immunizations AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION As the efficacy of HSCT from matched siblings was borne out in the 1970s, opportunities were sought to expand the pool of potential donors for more patients who might be offered curative treatment. Allogeneic cell donation was limited by the difficulty of controlling GVHD. The development of monoclonal antibody technology permitted "magic-bullet" targeted treatments that could destroy selective tumor cells from a cancer patient's own bone marrow. Patients could donate their own cells for an autologous HSCT if cancer cells could be eliminated. Most of the procedures that were developed to purge tumor cells from the marrow have since been abandoned for lack of efficacy. However, the concept remains appealing and an immunomagnetic bead technique remains under evaluation for children with neuroblastoma. The child's marrow cells are sequentially incubated with (1) murine monoclonal antibodies to neuroblastoma, and then (2) plastic beads incorporated with magnetic material and coated with goat antimouse antibody. Tumor cells become attached to the beads by the combined antibody links, and the tumor cells are then separated from marrow cells pumping the mixture through a strong magnetic field. Nonspecific removal of hematopoietic precursor cells and incomplete removal of tumor cells have limited the efficacy of this and similar procedures. Many patients, particularly those who had received radiation to the hip region, were unable to generate sufficient hematopoietic stem cells following bone marrow harvest from the iliac crests to assure rescue of hematopoiesis. Today, sufficient precursor cells can be collected from the peripheral blood of most patients by apheresis after prior administration of growth factors, and this option is now preferred over marrow collection in most situations. The apheresis procedure entails temporarily removing whole blood from the patient or donor, separating the mononuclear cells by centrifugation (to enrich collection of hematopoietic progenitor cells), and returning the remaining white cells, red cells, and plasma back to the patient/donor. Hematopoietic growth factors are the proteins produced within the marrow microenvironment that stimulate blood cell production. When administered in pharmacologic amounts, these proteins also stimulate mobilization of the precursor cells into the peripheral blood. The apheresis procedure can secure sufficient precursor cells for marrow rescue following subsequent high-dose therapy. Dr. Morris Kletzel, Director of the Children's Memorial Hospital Stem Cell Transplant Program, pioneered the application of peripheral blood stem cell collection in pediatric patients. This now-standard approach for collecting autologous hematopoietic stem cells from patients with solid tumors (e.g., neuroblastoma) is coordinated with the recovery of blood counts following chemotherapy treatment cycles. Repeated collections can be harvested to collect sufficient cells for rescue from single or multiple cycles of high-dose treatments. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FROM "ALTERNATIVE DONORS" Two improvements in the prevention and treatment of GVHD supported the feasibility of expanding allogeneic HSCT to nonsibling and volunteer unrelated donors. Monoclonal antibodies can be targeted to selectively remove or deplete the GVHD-causing T-lymphocytes from the hematopoietic stem cell product (techniques similar to those for removing tumor cells as discussed above). Another boost was the introduction of cyclosporine A, a very effective immunosuppressant. he National Marrow Donor Program in the United States and many other national marrow donor registries have been established to facilitate coordination of the search for the best-matched donor for a patient in need of HSCT. When no suitable family member can be identified and autologous cells are deemed inappropriate (as for most leukemia patients and all patients with a disease resulting from inherent defects of the hematopoietic stem cells), an unrelated donor search can be initiated. The patient's HLA typing is matched to potential donors in the respective registries. Typing results are confirmed and a best match is chosen. If no contraindications to the donation are present and the donor gives informed consent, arrangements are coordinated for the patient to receive high-dose therapy and the donor to undergo hematopoietic stem cell harvesting (marrow or peripheral blood). The donation takes place convenient to the donor's home. The collected cells are taken to the recipient's hospital, by commercial airlines when flight is involved. The cells are escorted by a representative of either the donor or recipient institution and infused within 24 to 30 hours of donation. UMBILICAL CORD BLOOD CELLS AS A SOURCE OF HEMATOPOIETIC STEM CELLS A more recent development is the collection and cryopreservation of umbilical cord blood cells from volunteer donors. At birth, the newborn's blood is rich in hematopoietic stem cells. The placental and umbilical cord blood, when salvaged, have sufficient precursor cells to consistently support patients weighing 40 kg or less. An aliquot of these cells is analyzed for HLA typing and screened for several infectious diseases. Because newborns are in a relatively immunodeficient state, the risk for developing GVHD is reduced, even when the recipient and cord blood cells are mismatched at 1 or 2 of the 6 major HLA antigen sites. The reduced stringency of HLA matching required for cord blood enhances the likelihood of identifying an appropriate unit for HSCT. A finite number of umbilical cord blood cells can be collected from each donor, usually limiting the use of this source to pediatric patients The propagation of progenitor cells from a cord blood sample and the combined administration of 2 or more units of umbilical cord blood are both under study. Commercial preservation and storage of umbilical cord blood are available for interested families and would be advantageous if a previous child has a disease potentially treatable with HSCT, or if there is a family history of a congenital hematopoietic stem cell defect (e.g., immunodeficiency, hemoglobinopathy, etc.). Children's Hospital of Oakland (Oakland, Calif.) has a National Institutes of Health-supported program for cryopreservation and tissue typing of umbilical cord blood from newborn siblings of children with diseases potentially treatable with HSCT. Umbilical cord blood is collected by the obstetrician and shipped by overnight express to Oakland where the cells are prepared, cryopreserved, and stored at no cost to the family. LATE EFFECTS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION The multiple potential long-term complications that can afflict the survivors of HSCT represent the "Agony of Victory." Virtually any organ system can be affected with detriment to the child's growth and development, cognitive function, or psychological well-being. Multiple endocrine deficiencies are possible—growth hormone deficiency, hypothyroidsim, delayed or absent puberty, and infertility. Although high-dose chemoradiotherapy is a prime culprit for inflicting injury, both acute peri-transplant infection and the repeated infections of chronic immune dysfunction (primarily in allogeneic HSCT recipients) also cause tissue injury. Secondary malignant neoplasms also can develop as a result of the cumulative therapy and immune suppression. Surviving patients must be monitored for late side effects by comprehensive long-term follow up. Families and older children frequently are overwhelmed by the immediate risks of the disease and treatment, and may not be able to appreciate information about late effects.The hematologist and primary pediatrician should take responsibility for coordinating the recommendations of the other medical specialists involved. FUTURE DIRECTIONS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION The Odyssey of the hematopoietic stem cell continues as the new millenium begins. The plasticity of developmental commitment of hematopoietic stem cells is yet to be elucidated. Donor-origin cells have been demonstrated in mesenchymal (bone and muscle), ectodermal (neural), and endodermal (bronchial mucosa) derived tissues of HSCT recipients. These tissues may "stem" from a single progenitor capable of differentiation to any cell type or may arise from de-differentiation of a cell-type previously committed to mesenchymal (more specifically, to hematopoietic) cells under microenvironmental influence. Genetic manipulation of multipotential cells to correct congenital genetic abnormalities or to enhance selective immunoreactivity to host malignancies continues to be investigated. Sustained expression of the inserted gene in a high percentage of the engrafted cells has eluded efforts thus far. Another area of research interest is the manipulation of hematopoietic stem cell products in order to generate cultures producing unlimited (or greatly expanded) numbers of hematopoietic progenitor cells. The clinical outcome might be a "pharmaceutical warehouse" of cell aliquots for transplantation into closely matched recipients. Efforts continue to exploit the graft-vs.-tumor effects of allogeneic HSCT, particularly following reduced dosage, nonmyeloablative or immunoablative therapies. Less toxicity, greater specificity, broader applicability and improved outcomes are the goals for refinement of HSCT. Odysseus' travels took 10 years; the past 30 years have seen enhancements in HSCT, but the quest for further improvement continues. HEMATOPOIETIC STEM CELL TRANSPLANTATION AT CHILDREN'S MEMORIAL HOSPITAL The Hematopoietic Stem Cell Transplant Team at Children's Memorial Hospital provides comprehensive care for children and young adults who could benefit from HSCT. Autologous HSCT is considered for patients with high-risk neuroblastoma, Ewing's sarcoma, recurrent Wilms' Tumor, and high-risk central nervous system malignancies. Other malignancies, less frequently seen, are also considered based on prognosis, published experience at other centers, and the ability to collect sufficient precursor cells. See the Table for a list of diseases considered for HSCT treatment. TABLE
PNET = primitive neuroectodermal tumors Dr. Kletzel is the principal investigator for the neuroblastoma treatment protocols (3 cycles of therapy with hematopoietic stem cell rescue following each treatment). Dr. Paul Haut is the principal investigator for treatment protocols for high-risk, solid tumor patients. Dr. Stewart Goldman developed a new approach for treating children with high-risk central nervous system malignancies (defined as recurrent or poor prognosis with conventional therapy). Each of these treatment plans includes 2 cycles of high-dose therapy and HSCT. Further services include allogeneic HSCT from matched siblings, other relatives, or alternative donors (particularly umbilical cord blood sources). Leukemia remains the most frequent diagnosis for which patients undergo HSCT. Patients with thalassemia or sickle cell disease are increasingly candidates for HSCT, as high-dose therapy becomes more refined and the acute risks for morbidity and mortality are reduced. 8 Click here for more information about the stem cell transplantation program at Children's Memorial Hospital. BIBLIOGRAPHY Drobyski WR, et al. T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing HLA-identical sibling marrow transplantation. Blood 1999; 94(2):434–441. Figuerres E, Haut PR, Ozewshi M, Kletzel M. Analysis of parameters affecting engraftment in children undergoing autologous peripheral blood stem cell transplants. Bone Marrow Transplantation 2000;5:583–588. Matthay KK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 1999;341(16):1165–73. Petersdorf EW, et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 1998;92(10): 3515–3520. Ratanatharathorn V, et al. Phase III study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for GVHD prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 2302–2314. Rocha V, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 2001; 97(10):2962–2971. Rubenstein P, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998;339(22):1565–77. Slavin S, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;91(3): 756–763. Thomas ED, et al. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 1957;257 (11): 491–496. |