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CHAPTER 18 ALLOGENEIC AND AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION

CHAPTER 18 ALLOGENEIC AND AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION
Williams Hematology

CHAPTER 18 ALLOGENEIC AND AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION

ROBERT S. NEGRIN
KARL G. BLUME

History
Theoretical Concepts for Curative Therapy in Hematopoietic Cell Transplantation
Stem-Cell Models of Hematopoiesis
Sources of Hematopoietic Stem Cells

Marrow

Peripheral Blood

Umbilical Cord Blood
Histocompatibility System and Types of Hematopoietic Stem-Cell Donors
Preparative Regimens

Radiation-Based Regimens

Non-Radiation-Based Regimens

Multiple Cycles of High-Dose Chemotherapy Followed by Peripheral-Blood Progenitor-Dcell Support

Radiolabeled Monoclonal Antibodies

Nonmyeloablative Preparative Regimens
Stem-Cell Procurement and Grafting Procedures
Abo Incompatibility
Tumor-Cell Purging
Engraftment and Supportive Care

Hematopoietic Support

Mucositis and Nutritional Support

Infection

Blood Product Support
Clinical Results of Marrow Transplantation

Acute Myelogenous Leukemia

Acute Lymphoblastic Leukemia

Chronic Myelogenous Leukemia

Myelodysplastic Syndromes

Myeloproliferative Disorders

Severe Aplastic Anemia

Chronic Lymphocytic Leukemia

Lymphoma

Hodgkin’s Disease

Multiple Myeloma

Solid Tumors

Fanconi Anemia

Thalassemia

Sickle Cell Anemia

Immunodeficiency Syndromes and Inherited Metabolic Disorders

Autoimmune Disorders
Complications and their Management

Graft-Versus-Host Disease

Veno-Occlusive Disease

Pulmonary Complications

Other Complications
Secondary Malignancies
Treatment and Prevention of Relapse Following Transplantation
Clinical Application of Immunotherapy Following Hematopoietic Cell Transplantation
Quality of Life
Chapter References

Hematopoietic cell transplantation has developed from a treatment of “last resort” to an effective therapy for patients with a variety of hematologic diseases. Developments in this field have dramatically reduced the morbidity and mortality of transplantation. Most notable has been the introduction of peripheral blood progenitor cells as a source of hematopoietic stem cells. Here we emphasize the theoretical framework for curative therapy as the biological basis of transplantation. Important developments in the field include the sources of hematopoietic stem cells, novel approaches to preparative regimens, uses of monoclonal antibodies and nonmyeloablative preparative regimens. Advances in engraftment and supportive care including the utilization of hematopoietic growth factors and other supportive care measures have greatly reduced the morbidity associated with transplantation. In this chapter, the biological basis, as well as clinical results, of both autologous and allogeneic hematopoietic cell transplantation will be discussed. Emphasis will be placed on the biological mechanisms underlying and facilitating transplantation. Results of transplantation in the hematologic diseases are stressed, in particular, acute myelogenous leukemia, acute lymphocytic leukemia, and chronic myelogenous leukemia. Additional information can be found in the individual chapters that focus on specific disease entities (see Chap. 46, Chap. 47, Chap. 92, Chap. 93 and Chap. 94, Chap. 97 and Chap. 103). Novel indications for transplantation are also reviewed with particular reference to the biological basis for these interventions. The major challenges facing patients undergoing transplantation, including complications such as graft-versus-host disease, veno-occlusive disease, infection, and relapse of the underlying disease, remain formidable. Major advances that are likely to have a dramatic impact on the treatment outcome and that will further enhance the field of hematopoietic cell transplantation in years to come continue to be made in the fields of cell biology, hematology, and immunology.

Acronyms and abbreviations that appear in this chapter include: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; ATG, antithymocyte globulin; AT-III, antithrombin-III; BEAM, carmustine (BCNU), etoposide, cytosine arabinoside, and melphalan; BMT, bone marrow transplantation; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMV, cytomegalovirus; CR, complete remission; CSF, colony-stimulating factors; CTL, cytotoxic T lymphocytes; EPO, erythropoietin; FACS, fluorescent activated cell sorting; G-CSF, granulocyte colony-stimulating factors; GM-CSF, granulocyte-macrophage colony-stimulating factor; 4HC, 4-hydroperoxycyclophosphamide; HLA, human leukocyte antigen; IL, interleukin; MACOP-B, Methotrexate, Adiramycin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin; MDS, myelodysplastic syndromes; MHC, major histocompatibility complex; MoAb, monoclonal antibody; NK, natural killer; PCR, polymerase chain reaction; PUVA, psoralen plus ultraviolet radiation; SCF, stem-cell factor; SCID, severe combined immunodeficiency disorder; TNF, tumor necrosis factor; tPA, tissue-type plasminogen activator; TPN, total parenteral nutrition; TPO, thrombopoietin; WBC, white blood count.

HISTORY
The transplantation of marrow to rescue patients from lethal radiation or chemotherapy or to replace abnormal marrow has evolved over the past three decades from an act of desperation administered only to patients with end-stage disease to an acceptable and, in some instances, “first-line” form of therapy employed early in the course of a variety of malignant and nonmalignant disorders. Advances in transplantation biology and supportive care have made that evolution possible and have helped to usher in the modern era of marrow transplantation.
The first documented human marrow transplant was attempted in 1939, when a woman with gold-induced aplasia was given marrow intravenously from a brother with identical blood group antigens. The transplant was not successful, and the patient died five days later.1 In the early 1950s, laboratory experiments demonstrated that splenic shielding or intravenous administration of marrow cells protected animals from lethal radiation.2,3 Subsequently, patients with end-stage hematologic malignancies were treated with myeloablative doses of radiation and chemotherapy followed by marrow infusion. These initial attempts at human marrow transplantation were generally unsuccessful but demonstrated at least transient engraftment in some patients and provided a framework for future studies.4 Sustained engraftment was first documented in 1965 in a patient with acute lymphoblastic leukemia who received irradiation and chemotherapy followed by intravenous infusion of marrow from six different related donors.5 Engraftment from one of the donors was demonstrated by erythrocyte phenotype, acceptance of a skin graft from that donor, and development of graft-versus-host disease. The patient died of recurrent leukemia 20 months after marrow infusion.
Studies in dogs demonstrated the importance of immunological matching for a successful outcome.6 Discovery of the human leukocyte antigen (HLA) system and development of histocompatibility typing methods in the 1960s led to a new phase of marrow transplantation. The first successful marrow transplants were in children with severe combined immunodeficiency performed in 1968,7,8 as was a successful transplant in a patient with Wiskott-Aldrich syndrome.9 The latter report also demonstrated the need for immunosuppressive therapy prior to marrow infusion in order to ensure engraftment in immunocompetent patients. Between 1969 and 1975, increasing numbers of patients with acute leukemia who had failed conventional therapy and patients with advanced aplastic anemia underwent marrow transplantation from identical twin donors10 and histocompatible siblings.11,12 For the first time, a significant percentage of patients became long-term, disease-free survivors.13
Since 1975, patients have been considered suitable candidates for marrow transplantation earlier in the clinical course of their disease. The number of marrow transplant centers continues to increase throughout the world. During the past 15 years, autologous marrow grafting (use of the patient’s own marrow) has also become a viable treatment modality for selected candidates to the extent that autologous marrow transplantation is now more frequently performed than allogeneic marrow transplantation. More recently, the introduction of peripheral blood progenitor cells has reduced the morbidity and mortality associated with transplantation.
THEORETICAL CONCEPTS FOR CURATIVE THERAPY IN HEMATOPOIETIC CELL TRANSPLANTATION
The beneficial effects of hematopoietic cell transplantation are due to both the high-dose chemotherapy that allows for enhanced tumor-cell killing and the ability to overcome drug resistance, as well as the immunological effects referred to as the graft-versus-tumor effect. Dose escalation of chemotherapy and radiation therapy is possible if the dose-limiting effects of hematopoietic toxicity are circumvented with the infusion of the stem-cell graft. This is the underlying concept in autologous hematopoietic cell transplantation, where there are no immunological effects due to the infused stem cells. The dramatic dose escalation of chemotherapy and radiation therapy that can be achieved with autologous transplantation allows for the possibility of curative therapy in malignancies where dose escalation results in significantly greater tumor-cell killing.
In the allogeneic setting, the importance of graft-versus-tumor effects has been central to the success of the transplant procedure. This has been demonstrated in a number of ways. Comparison of results following allogeneic transplantation to those of syngeneic transplantation, where the donor and recipient are genetically identical, have been particularly informative. Here it has been well documented that the relapse rate is significantly higher for patients who undergo syngeneic transplantation than for patients who undergo an allogeneic transplant procedure.14 It is interesting to note that this phenomenon appears to be disease dependent, since those patients with chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) exhibit a much more demonstrable graft-versus-tumor effect than do patients with acute lymphoblastic leukemia (ALL). The cells responsible for the graft-versus-tumor effect include T cells, since depletion of T cells from the allograft results in control of graft-versus-host disease; however, it markedly increases the risk of relapse of the underlying malignancy.15 In addition, a variety of clinical studies have demonstrated that those patients who develop some degree of graft-versus-host-disease, especially chronic graft-versus-host disease, have a reduction in the risk of relapse.16,17 All of these studies are consistent with the concept that immunological effector cells within the donor inoculum are capable of immunological control of the minimal disease that remains following the transplant. Further support of this concept comes from the utilization of donor leukocyte infusions in patients who suffer a relapse following an allogeneic transplant procedure, after which a significant percentage of patients reenter a complete remission (CR).18,19 and 20
STEM-CELL MODELS OF HEMATOPOIESIS
The role of hematopoietic stem cells is central to the biological basis of transplantation. A variety of early in vitro and in vivo assay systems have been developed to identify the biological activity of hematopoietic stem cells. Through these assay systems, it has become clear that immature populations of cells capable of giving rise to all of the hematolymphoid cells are present in the marrow. Various accessory and antigen-presenting cells found in the liver, gastrointestinal tract, lung, and brain are also derived from hematopoietic stem cells. Hematopoietic stem cells are biologically defined as those cells that are capable of rescuing lethally irradiated animals, a definition that is conceptually clear but difficult to apply to humans.
In murine systems, monoclonal antibodies have been developed that recognize proteins on the surface of both immature hematopoietic stem cells and mature progenitor cells. Using fluorescence-activated cell sorting, populations of highly purified murine marrow cells have been identified that are capable of rescuing lethally irradiated animals.21 In murine systems, the phenotype of cells with this biological activity is positive for stem-cell antigen 1 and Thy-1 yet does not express the various markers found on committed cells (lineage negative).21 These cells also have been found capable of excreting the vital dye rhodamine. Cells with this phenotype are present in the murine marrow with the frequency of approximately 1:103 and 1:104. Morphologically, they appear to be similar to normal lymphocytes. These hematopoietic stem cells are capable of self-renewal and multilineage differentiation into progenitor cells that in turn mature into the various committed cells that are released from the marrow. As few as 25 purified hematopoietic stem cells are capable of rescuing more than half of lethally irradiated animals, and 100 stem cells are capable of rescuing virtually all of the animals.21
Using a similar approach of monoclonal antibody staining and fluorescence-activated cell sorting, it has been possible to isolate and characterize a population of human putative hematopoietic stem cells capable of multilineage growth in in vitro and surrogate in vivo assays. Human hematopoietic stem cells express the antigen CD34 and also are lineage negative. They also have been found to express low amounts of Thy-1,22,23 lack DR expression,24 and excrete the dye rhodamine 123.25 More recently, a population of hematopoietic stem cells that do not express CD34 and that are functionally capable of excreting the vital DNA-binding dye Hoechst 33342 has also been described.26 However, in clinical transplantation, the CD34+ cells infused correlated closely with the functional capability of the hematopoietic graft.27 Despite the fact that the most useful marker in clinical marrow transplantation to define cells capable of multilineage hematopoietic reconstitution has been CD34, it is recognized that only a fraction of CD34+ cells are true hematopoietic stem cells. Subset separation of CD34+ cells has been successful on a clinical scale, and preliminary trials using highly purified hematopoietic stem cells demonstrate that this population of cells, despite its relatively rare frequency, is capable of reconstituting multilineage hematopoiesis in a timely fashion.28
SOURCES OF HEMATOPOIETIC STEM CELLS
A variety of sources have been utilized for the collection of hematopoietic stem cells for transplantation procedures. These include marrow; peripheral blood, especially following mobilization; and umbilical cord blood obtained at the time of delivery.
MARROW
Marrow has served as the traditional source of hematopoietic stem cells for both allogeneic and autologous transplantation. The technique of marrow harvesting has become relatively routine.29 Marrow is aspirated from the posterior iliac crests under either regional or general anesthesia. The cell dose required for stable long-term engraftment has not been defined with certainty; however, typical collections contain more than 2 × 108 nuclear cells per kilogram of recipient body weight. This generally requires between 700 and 1500 ml of marrow for an adult recipient. Current guidelines indicate that collection of up to 15 ml/kg is generally considered safe.
Complications of marrow harvesting are rare and generally involve complications of anesthesia. In one report of 1270 allogeneic marrow harvests from normal donors, there were six (0.5%) life-threatening complications.30 This is similar to the rate described in individuals undergoing autologous collection.31 The National Marrow Donor Program has reviewed the experience of volunteer donors in the first 493 harvests. In this cohort of donors, there was only one serious event (apnea), and three patients (0.6%) required a blood transfusion that was from nonautologous sources. However, the marrow collection procedure was not without significant morbidity, since it took up to 16 days for patients to fully recover, and 10 percent of the donors still had not completely recovered at the end of the first month following harvest.32
PERIPHERAL BLOOD
Hematopoietic stem cells circulate in the peripheral blood at extremely low levels. Following the administration of colony-stimulating factors (CSF) and/or chemotherapy, a time-dependent increase in hematopoietic stem cells and progenitor cells—termed mobilization—is observed. The products obtained after stimulation have been termed peripheral-blood progenitor cells. A number of CSF have been found to be effective mobilizing agents, including G-CSF, GM-CSF, IL-3, and thrombopoietin (TPO).33,34 The most common mobilization regimen involves the administration of G-CSF at 10 µg/kg/day, followed by apheresis on the fourth and fifth days.35,36 and 37 A variety of other doses and schedules have been utilized with both CSF alone or in combination with chemotherapy. An earlier-acting cytokine termed stem-cell factor (SCF) or c-kit ligand has been found to synergize with G-CSF in mobilization of CD34+ cells.38 Another novel cytokine, Flt-3 ligand, has been shown to enhance the mobilization of peripheral-blood progenitor cells, as well as dendritic cells, in a time-dependent fashion in synergy with G-CSF.39 Administration of mobilized peripheral-blood progenitor cells has resulted in more rapid hematopoietic reconstitution than has been observed following a marrow transplant.40 This advantage significantly reduced the morbidity and mortality of the transplant procedure, and the use of mobilized peripheral-blood progenitor cells has gained wide acceptance in the autologous setting.
The optimal methodology for mobilizing peripheral-blood progenitor cells has yet to be defined; however, the absolute number of CD34+ cells/kg recipient weight has proven to be a reliable and practical method for determining the adequacy of the stem-cell product. Most laboratories measure CD34+ cell content by FACS. A major effort has been made to standardize and validate this process. The optimal cell dose is controversial. However, most transplant centers have observed that stem-cell products containing more than 2 × 106 CD34+ cells/kg result in rapid hematopoietic recovery. Higher stem-cell doses may lead to more rapid platelet recovery.41 The minimum cell dose required for hematopoietic engraftment has not been defined with certainty; however, cell doses below 1 × 106 CD34+ cells/kg are felt to be inadequate. A significant problem has been that approximately 10 to 40 percent of patients do not mobilize progenitor cells adequately using G-CSF alone or chemotherapy plus G-CSF. In addition, it has been difficult to identify prospectively those patients who are poor mobilizers. To achieve improved CD34+ cell mobilization, higher doses of G-CSF, between 20 and 40 µg/kg, have been utilized to improve the CD34+ cell yield and reduce the number of days of apheresis required to reach the collection goal.42 Compared to G-CSF alone, combinations of cytokines using both G-CSF and SCF have resulted in improved CD34+ cell yields in a randomized study of breast cancer patients undergoing autologous transplantation.43 However, SCF also activates mast cells, which may produce serious unwanted side effects.
The clinical significance of tumor cells in mobilized peripheral-blood progenitor-cell collections has generated considerable debate. There is no doubt that tumor-cell contamination of peripheral-blood progenitor cells does occur, especially when sensitive assays, such as the polymerase chain reaction (PCR) or immunofluorescence techniques, are utilized.44,45 In one comparative study, the difference in tumor burden between the marrow and peripheral blood was measured at less than 1 log.46 Since the absolute number of cells infused with an unmanipulated peripheral-blood progenitor cell graft is on the order of ten- to fifteenfold higher than with marrow, the total number of tumor cells infused could conceivably be greater with peripheral-blood progenitor cells. Therefore, methodologies designed to purge the stem-cell product of possible malignant-cell contamination have been developed, as discussed below.
Mobilized peripheral-blood progenitor cells have been largely utilized in the autologous setting; however, this approach has also been explored in the allogeneic setting in an effort to enhance hematopoietic recovery. The concern with the use of mobilized peripheral-blood progenitor cells in the allogeneic setting is that the large numbers of T cells in the inoculum may increase the risk of graft-versus-host disease. However, despite the large number of T cells in the inoculum, initial studies did not show an increase in the incidence of acute graft-versus-host disease,40,47,48 but the incidence of chronic graft-versus-host disease may be higher.49 The reason for this phenomenon is unclear. However, it may be related to the increased production of cytokines of the TH2 type, such as IL-4 and IL-10, which may decrease the risk of graft-versus-host disease.50 The relative merits of marrow versus G-CSF–mobilized peripheral-blood progenitor cells in allogeneic transplantation are currently being evaluated in randomized prospective clinical trials.
UMBILICAL CORD BLOOD
Umbilical cord blood obtained from the umbilical blood vessels and placenta following delivery has been found to be a rich source of hematopoietic stem cells. The relative immaturity of the cord blood cells may allow for engraftment across immunological barriers more easily than when other stem-cell sources are used.51 Registries that allow for the collection, cryopreservation, typing, and quality control of cord blood products have been established. These can then be accessed following a search of the database. This approach may be particularly useful for securing donors for patients of minority groups that are relatively underrepresented in the donor registries. In addition, since the cord blood samples are collected and cryopreserved, there is less delay once a potential donor has been identified.
HISTOCOMPATIBILITY SYSTEM AND TYPES OF HEMATOPOIETIC STEM-CELL DONORS
The antigens of the HLA system are a series of cell-surface molecules critical for immune function. They are encoded by genes on chromosome 6. Gene clusters have been recognized that have been designated class I, class II, and class III. Class I and class II genes have been shown to be important for the success of organ grafts. The genes of class I and class II HLA molecules are similar and contain a peptide binding groove that is critical for proper cellular immune recognition. A large number of class I genes and pseudogenes have been identified. Those encoding for HLA-A, -B, and -C antigens are the most important. More than 15 different class II genes also have been identified, the most important of which are the HLA-D region genes, which include DR, DQ, DO, DN, and DP, with DR being the most relevant for marrow transplantation.
Typing for the HLA class I and II molecules is routinely performed by serologic assays. More recently, the use of DNA-based genotyping has had a significant impact in establishing identity between donors and recipients, especially when unrelated donors are utilized. Most centers utilize serologic typing for sibling matches; if the identified genes are serologically identical, they are most likely genotypically identical, since the donor and recipient are related. However, in the unrelated setting, there is no such assurance, and multiple different alleles have been identified for a given HLA antigen. Cytotoxic T lymphocyte analysis has also identified minor histocompatibility antigens that have an important additional function following transplantation.52
The importance of HLA matching has been well documented following allogeneic marrow transplantation. With greater HLA incompatibility, the risk of graft-versus-host disease and graft failure increases. For example, in one study, the rate of graft failure using marrows from donors who were only haplotype matched was 12.3 percent. In contrast, the rate of graft failure is only approximately 2 percent in recipients of stem cells from HLA-matched donors.53 Among sibling donors, the degree of incompatibility has been correlated with the severity of graft-versus-host disease. More than one antigen mismatch results in an unacceptable incidence of graft-versus-host disease using conventional unmanipulated marrow transplant techniques. A single antigen mismatch resulted in increased incidence and severeity of graft-versus-host disease; however, overall survival was not impacted.53 Mismatches at HLA-B appear to be tolerated best, followed by those at HLA-A, with mismatches at HLA-DR being the least well tolerated. However, since only approximately 30 percent of potential marrow transplant recipients have an HLA-matched or single antigen–mismatched donor, other sources of marrow cells are required. One approach has been to utilize the large numbers of volunteer donors, either through the National Marrow Donor Program or related registries. To date, more than 3 million altruistic individuals have enrolled in the National Marrow Donor Program and have volunteered to serve as marrow donors.
Such registries have provided large lists of potential donors that can be searched to identify appropriate donors throughout the world. Registry donors are especially useful for Caucasian recipients; minority donors are less represented, although this discrepancy is improving with time. Initial results of transplant procedures performed from unrelated donors demonstrated that this form of transplantation was feasible and successful, although initial results were inferior to those achieved with matched related donors.54 Multiple reasons were associated with these poorer outcomes, including patient candidacy, increased risk of opportunistic infection, increased risk of graft failure, and graft-versus-host disease. With the development of molecular typing, especially at the class II region, results have improved substantially. Molecular donor-recipient identity at the HLA/DR1 and DQB1 alleles has reduced the risk of acute lethal graft-versus-host disease and has improved survival following unrelated donor marrow transplantation.55,56 The use of molecular typing for the class II region has become part of routine practice for identifying appropriate donors for unrelated donor transplantation.
Molecular typing has also been developed for HLA class I alleles. This technology has revealed considerable heterogeneity. Some of the incompatibilities that have been identified by molecular typing and were not recognized by standard serologic typing have been associated with immunological reactions as assessed by cytotoxic T-lymphocyte (CTL) reactivity. In one study, 128 patients and 484 potential unrelated donors were evaluated by both serologic typing and molecular typing. Of the 187 individuals who were identified serologically as being matched, only 52.9 percent were found to be fully matched following DNA typing.57 A higher level of disparity was noted for HLA-B than for HLA-A alleles. It is unclear as to which of these HLA disparities are clinically most important. The effect of matching of class I HLA alleles has been correlated with outcome in one study from Japan. In this study of 440 recipients of unrelated donor transplantation who were serologically identical with respect to recipients for HLA, -A, -B, and -DR antigens, the degree of HLA-A and HLA-C molecular incompatibility was found to be an independent risk factor for severe acute graft-versus-host disease. In addition, mismatching for HLA-A, but not HLA-C, alleles was an independent risk factor for higher mortality, and mismatching of HLA-C alleles was a significant risk factor for relapse of underlying leukemia.58 These data require confirmation in a larger patient population. These clinical studies underline the importance of high resolution typing for identifying donors; however, it is clear that with increasing the requirement for molecular matching, an ever smaller donor pool will be available for each individual patient. Identifying which disparities are clinically relevant is a significant task that must be completed in order to fully evaluate these data.
Another alternative for patients, especially children, who do not have an appropriate HLA-matched sibling donor is the use of placental cord blood obtained from unrelated sources. Following cord blood transplantation, engraftment has been achieved; however, it is considerably delayed compared to engraftment following marrow transplantation. In one study of 562 recipients of placental cord blood transplants from unrelated donors, durable engraftment was achieved in 81 percent of recipients by day 42 for neutrophils and 85 percent by day 180 for platelets. The speed of hematopoietic engraftment was related to the leukocyte content of the graft, whereas transplantation-related mortality was associated with the degree of HLA disparity, the patient’s underlying disease, and the experience of the transplantation center. Severe grade II to IV acute graft-versus-host disease occurred in 23 percent of patients, and chronic graft-versus-host disease occurred in 25 percent.59 The relatively small number of cells collected on routine umbilical cord blood processing has made this type of transplantation primarily useful for children and small adults, although some clinical investigators are attempting to expand umbilical cord blood stem cells in vitro to transplant adult patients.
The use of three-antigen–mismatched or haplotype-matched donors has been mostly unsuccessful due to the high risk of graft-versus-host disease and graft failure. Higher stem-cell doses may overcome the problem of graft rejection in this donor-recipient setting. This has been accomplished with the use of G-CSF mobilized peripheral blood progenitor cells. Using this stem-cell source and highly immunosuppressive preparative regimens that include total body irradiation, high-dose chemotherapy, and antithymocyte globulin, extensively T-cell–depleted haplotype-matched grafts have been successfully engrafted without graft-versus-host disease.60,61 The successful use of haplotype-matched related donors would greatly increase the availability of donors, since virtually all patients have a haplotype-matched donor. Impressive results have been obtained in patients with advanced leukemias; however, prolonged immunosuppression, with resultant risk of infection, remains a significant obstacle.61
The choice between these various sources of hematopoietic stem cells depends largely upon the underlying disease and remission status, as well as the approach chosen by the given transplant center.
PREPARATIVE REGIMENS
The purpose of the preparative regimen is twofold, namely, to eradicate the underlying disease and to provide sufficient immunosuppression to allow for the administration of the graft without subsequent rejection. The transplanted graft provides an immunologic reaction, the graft-versus-tumor effect. The relative contribution of these diverse mechanisms to successful transplantation is not known with certainty. However, it has become increasingly apparent that the graft-versus-tumor effect makes a major contribution. In the autologous setting, the sole purpose of the preparatory regimen is to provide substantial dose escalation in an attempt to overcome drug resistance, with subsequent rescue using hematopoietic cells.
RADIATION-BASED REGIMENS
Total-body irradiation has been utilized in preparatory regimens since the inception of transplantation. Initial approaches used radiation delivered in a single fraction; however, this technique was associated with significant multiple-organ toxicity that occasionally proved life threatening. The advent of fractionated radiation administered over several days has resulted in decreased toxicity in both immediate and long-term complications with respect to nausea, vomiting, and cataract formation.62 The total dose of fractionated total-body irradiation administered ranges from 1200 to 1575 cGy. The major dose-limiting toxicities of fractionated total-body irradiation include mucositis, lung toxicity, and infertility. The maximally tolerated dose of total-body irradiation is approximately 1500 cGy. In randomized studies of two different doses of total-body irradiation (1220 versus 1575 cGy), a decreased relapse rate was noted with the higher radiation dose. However, this advantage was not associated with improved survival due to the increased incidence of regimen-related mortality.63,64 Therefore, most groups have utilized fractionated total-body irradiation in the dose range noted above (1200–1320 cGy). The most commonly utilized regimen includes fractionated total-body irradiation with cyclophosphamide at a total dose of 120 mg/m2.65 Others have used fractionated total-body irradiation with etoposide and have found the maximally tolerated dose of etoposide to be 60 mg/kg.66 In addition, excellent results have been reported combining fractionated total-body irradiation with etoposide and cyclophosphamide in both the autologous and allogeneic settings.67,68 and 69 The major dose-limiting toxicity of fractionated total-body irradiation includes mucositis, lung toxicity, and infertility.
NON-RADIATION-BASED REGIMENS
A variety of regimens that do not include radiation have been developed and utilized in both the autologous and the allogeneic setting. The most widely utilized of these regimens combines the effects of oral busulfan at the dose of 16 mg/kg given over 4 days with cyclophosphamide at 120 mg/kg administered over 2 days.70 A randomized comparison between fractionated total-body irradiation and cyclophosphamide and busulfan and cyclophosphamide did not show significant differences in long-term survival in patients with chronic myelogenous leukemia.71 Because of the overall ease of administration of the busulfan-cyclophosphamide regimen, this continuation may be the preferred approach in some settings.72 Total-body irradiation plus etoposide has been compared to busulfan and cyclophosphamide for patients with advanced leukemias. In this study, both regimens were well tolerated, and no significant differences were noted with respect to toxicity, incidence of acute graft-versus-host disease, overall survival, or disease-free survival. In those patients with good-risk disease, estimated disease-free survival was 55 percent (±11%) for those patients receiving fractionated total-body irradiation and etoposide. In contrast, 34 percent (±10%) of those patients who received busulfan and cyclophosphamide experienced disease-free survival.73 Other regimens utilizing etoposide in combination with busulfan have also had excellent results in autologous marrow transplantation of patients with acute nonlymphocytic leukemia.74,75 and 76
A variety of other regimens that contain carmustine in the range of 300 to 500 mg/m2 in addition to cyclophosphamide and etoposide have been utilized in the autologous setting.77,78 In addition, the BEAM regimen, which contains carmustine (BCNU), etoposide, cytosine arabinoside, and melphalan, has been widely utilized in patients with lymphomas following autologous transplantation.77 Other regimens, including the use of cisplatin and carboplatin, have been explored in patients with breast cancer and ovarian cancer.78,79 and 80
MULTIPLE CYCLES OF HIGH-DOSE CHEMOTHERAPY FOLLOWED BY PERIPHERAL-BLOOD PROGENITOR-dCELL SUPPORT
With the introduction of mobilized peripheral-blood progenitor cells, it has become clear that sufficient numbers of stem cells could be collected to allow for multiple transplant procedures. Pilot studies using this general approach have been reported from a number of different institutions.81,82 and 83 These studies have demonstrated feasibility but have been associated with significant toxicity. A variety of diseases have been treated in this fashion, including metastatic breast cancer, Hodgkin’s disease, and lymphoma, with good response rates. However, long-term studies have not demonstrated improved disease-free survival. In addition, a randomized comparative study between single and double transplants in patients with multiple myeloma did not demonstrate any benefit with the double-transplant approach.84
RADIOLABELED MONOCLONAL ANTIBODIES
Although higher doses of radiation may be associated with better disease-free control of the underlying disease, they have been associated with increased mortality due to toxicity. The fact that higher doses of radiation show an advantage in controlling the malignancy has led to the concept of using targeted radiotherapy to augment the preparative regimen. Several different monoclonal antibodies and radiation isotopes have been utilized, with the goal of delivering increased doses of radiation to the sites of disease, for example, the marrow. In one study, anti-CD33 antibodies conjugated to 131I were utilized in nine patients. In four of these patients, biodistribution studies demonstrated that the marrow and spleen received more radiation than any normal nonhematopoietic organ. Therefore, those patients were treated with between 110 and 130 mCi of 131I conjugated to anti-CD33 followed by the standard transplant regimen of cyclophosphamide plus total-body irradiation. This regimen was relatively well tolerated, with expected toxicities.85 131I-labeled anti-CD45 monoclonal antibodies have also been utilized in combination with cyclophosphamide and total-body irradiation. In one study, 20 patients were treated with a dose of 131I and estimated doses of 3.5 cGy and 7 cGy to the liver, and 4 to 30 cGy to the marrow, followed by 120 mg/kg of cyclophosphamide and 12 cGy of total-body irradiation. The toxicity observed was not thought to be greater than that of cyclophosphamide and total-body irradiation alone. Nine of 13 patients with acute myelogenous leukemia (AML) or refractory anemia with excess blasts and 2 of 7 patients with acute lymphoblastic leukemia were alive and disease-free from 8 to 41 months (median 17 months) after bone marrow transplantation (BMT).86 These innovative studies demonstrate that radiolabeled monoclonal antibodies can be combined with standard preparative regimens and higher doses of radiation can be successfully delivered. Demonstration of improved disease-free survival using radiolabeled antibodies is currently being evaluated.
NONMYELOABLATIVE PREPARATIVE REGIMENS
The demonstration of the beneficial effects of immune-mediated mechanisms in controlling minimal residual disease has challenged the concept of using the relatively toxic myeloablative preparative regimens. Regimens with reduced toxicity may be particularly useful in older patients who may not be able to tolerate the aggressive preparative regimens that are currently in use for allogeneic transplantation and for those patients with relatively indolent disease. Less toxic regimens could also be extremely useful in patients with genetic disorders or autoimmune conditions.
The goal in this therapeutic approach is to use the minimum amount of immunosuppressive therapy required to achieve engraftment and to develop mixed chimerism. Once mixed chimerism is established, additional donor leukocytes could be utilized if required to treat the underlying malignancy by immunological mechanisms. In one study, conditioning included six daily infusions of fludarabine at 30 mg/m2, busulfan at 4 mg/kg/day for 2 consecutive days, and anti-T-lymphocyte globulin at 10 mg/kg/day for 4 consecutive days. Patients then received G-CSF–mobilized peripheral-blood progenitor cells from an HLA-matched sibling donor. This resulted in acceptable, although significant, toxicity in patients who underwent this procedure. Hematopoietic toxicity was minimal, and these patients received only cyclosporine, since graft-versus-host disease prophylaxis resulted in either stable partial or complete chimerism. Using this approach, those patients who achieved some degree of chimerism were eligible for donor leukocyte infusions in an effort to control the underlying disease.87
Another approach has been utilized in 15 patients with chronic lymphocytic leukemia (CLL) who were treated with fludarabine at doses between 90 and 150 mg/m2 and cyclophosphamide at doses between 900 and 2000 mg/m2, followed by an allogeneic hematopoietic cell infusion from an HLA-matched sibling donor. Those patients who developed mixed chimerism then received an additional donor leukocyte infusion if no graft-versus-host disease was present. In this initial study, 11 patients had prompt engraftment of donor cells, and the remaining 4 patients recovered autologous hematopoiesis. Eight of the 11 patients achieved CR, indicating the feasibility and potential clinical efficacy of this approach.88 However, remissions in some patients were not long-lasting, and the procedure was associated with a high morbidity and mortality.
An alternative approach based upon careful experimentation in the canine model has utilized low-dose radiation of 200 cGy followed by immunosuppression with mycophenolate mofetil and cyclosporine in an attempt to suppress the recipient T cells from rejecting the graft. Studies have been initiated in patients with a variety of malignancies, resulting in striking hematopoietic engraftment with chimerism achieved in all lineages.89 These novel concepts require validation in larger numbers of patients with demonstration of long-term control of disease. However, the finding that either stable partial or complete chimerism can be achieved with minimal immunosuppression and low doses of chemotherapy or radiation is a striking finding. It will likely find utility in the future treatment of a variety of malignant conditions that are relatively indolent, as well as the treatment of patients with genetic disorders or autoimmune diseases.
STEM-CELL PROCUREMENT AND GRAFTING PROCEDURES
Details of stem-cell collection and processing are discussed in Chap. 141. Transplant donors must be in generally good health. The donor must have a performance status that will permit the safe collection of the cells, either from the marrow or blood. Thus, the donor must be able to tolerate anesthesia (either general or regional) and have adequate cardiac, pulmonary, hepatic, and renal functions. Pediatric donors are only used for autologous collection or donation to siblings. Donors with ongoing malignancies or a history of a malignant condition other than minor skin cancers (e.g., basal cell carcinomas) are generally excluded from further consideration.
In the unusual situation in which there is more than one sibling donor, cytomegalovirus (CMV) status is usually used to decide which donor to select, especially if the recipient is CMV seronegative. A CMV-seronegative donor is preferred, since the risk of subsequent infection with CMV will be greatly reduced, assuming that the patient receives CMV-seronegative blood products. There is some evidence that transplant procedures from parous female donors have a slightly increased risk of graft-versus-host disease, although this has not been observed in all studies.16
ABO INCOMPATIBILITY
HLA identity does not ensure red blood cell ABO compatibility. Major ABO compatibilities can result in serious hemolytic reactions upon infusion of the graft as a result of infusion of incompatible erythrocytes. Accordingly, the red blood cells must be removed.90 Red cell depletion can be accomplished by a variety of methods, including hydroxyethyl starch sedimentation and cell separation techniques.91 Minor ABO incompatibilities occasionally can lead to hemolytic complications from donor-derived isoagglutinins92; however, generally these types of ABO disparities do not require treatment.
The infusion of marrow and peripheral-blood progenitor cells is generally associated with minimal to minor toxicities of cough, flushing, and low-grade fever. Severe complications are rare but can occur and may occasionally even be life threatening.93 Selection of CD34+ cells has been associated with decreased infusional toxicities.43 However, it is not clear that this reason alone justifies the utilization of this methodology.
TUMOR-CELL PURGING
Tumor cells may be present in the stem-cell products utilized in autologous transplantation. The relative contributions of tumor-cell contamination of the stem-cell product and of residual disease in the patient are difficult, if not impossible, to evaluate. However, it seems reasonable to assume that both sources of tumor cells are capable of contributing to eventual relapse. In addition, as patient selection and treatment are optimized, tumor-cell contamination of the graft is likely to be even more important to address.
A number of retrospective studies have suggested that the infusion of products containing tumor cells is associated with higher rates of relapse. Among patients with acute leukemia, ex vivo treatment with the activated form of cyclophosphamide (4-hydroperoxycyclophosphamide) or the related drug mafosfamide has been associated with a lower relapse rate than seen in historical control patients who received unmanipulated marrow.94,95 Moreover, further analysis of 4-hydroperoxycyclophosphamide–treated marrow grafts revealed that patients who had fewer than 1 percent of pretreatment CFU-GM following the purging procedure had a lower relapse rate and improved leukemia-free survival of 36 percent versus 12 percent, (p = 0.006) in patients with more than 1 percent CFU-GM. These data suggest that the intensity of marrow purging had an impact on relapse rate.96
These studies utilized either historical control subjects or surrogate assays to evaluate the effects of chemical treatment of the marrow. 4-Hydroperoxycyclophosphamide treatment does result in delayed hematopoietic engraftment, however. Other approaches have been utilized to purge the marrow, including monoclonal antibody-mediated methods and positive selection of stem cells. Generally a cocktail of monoclonal antibodies is used for B-cell lymphoma. Sensitive PCR-based methods have been utilized to evaluate the efficacy of tumor-cell removal.45,97
In one study, 114 patients with lymphoma who had the t(14;18) chromosomal translocation underwent marrow purging with monoclonal antibodies and complement. In a retrospective analysis, 57 patients were successfully purged to PCR-negativity and had a dramatically reduced rate of subsequent relapse.98
Direct demonstration that tumor cells contained within the graft can contribute to relapse comes from gene-marking studies in which marrow products were transduced by a retrovirus, allowing for detection of the viral genome PCR following infusion. In some patients who were transplanted with neuroblastoma, acute leukemia, or chronic myelogenous leukemia, tumor cells transduced by the retrovirus were detected following relapse.99,100 Positive selection of CD34+ cells also has been performed using several different column-based techniques. In these studies, it could be demonstrated that tumor-cell contamination can be reduced by 2 to 4 logs.101 Despite these suggestive data, as yet there have been no prospective randomized clinical trials assessing the role of purging in autologous marrow transplantation.
With the emergence of peripheral-blood progenitor cells as the preferred source of stem cells for autologous transplantation, several approaches have been employed to deplete tumor cells from the products. Column-based approaches have been employed to positively select for CD34+ progenitor cells and deplete tumor cells passively.102 An alternative methodology uses an enrichment step for CD34+ cells followed by tumor-cell depletion with monoclonal antibodies and complement,103 column-based techniques,104 or immunomagnetic beads.105 Further purification of human stem cells has also been pursued by selecting for CD34+ cells that coexpress Thy-1. This has resulted in significant depletion of myeloma and other malignant cells.106 These methods are effective in significantly reducing the tumor-cell burden in many different clinical settings; however, further studies are required to demonstrate that a reduction in tumor-cell burden translates into superior disease-free survival.
ENGRAFTMENT AND SUPPORTIVE CARE
Progress in the supportive care of patients has been critically important in improving overall treatment results. Advances in hematopoietic support, antibiotics, antifungal agents, and antiviral drugs, as well as better medications to control such side effects of treatment as nausea, vomiting, diarrhea, and pain, have all had a major beneficial impact on the clinical course of the transplant patient.
Probably the single most important advance in reducing the morbidity and mortality of autologous transplantation has been the introduction of mobilized peripheral-blood progenitor cells as the source of stem cells. The more rapid hematologic recovery observed with the peripheral-blood progenitor cells has significantly reduced the duration of antibiotic therapy, the degree of mucositis, the length of hospitalization, and the risk of the transplant procedure itself. Other developments are discussed below.
HEMATOPOIETIC SUPPORT
Cloned hematopoietic growth factors, including G-CSF, GM-CSF, erythropoietin (EPO), TPO, and megakaryocyte growth and development factor, have been explored in the treatment of the transplant patient. The use of hematopoietic growth factors have been explored in two clinical settings, namely, following transplantation to accelerate hematopoietic recovery and in the mobilization process.
G-CSF AND GM-CSF
G-CSF and GM-CSF have resulted in clear clinical benefits in the transplant setting. The initial studies were performed following autologous BMT. In the phase I and II studies, a reduced number of days required for neutrophil engraftment was observed in all studies, with an associated reduction in the days of antibiotic therapy and length of hospitalization in some studies. Subsequent randomized clinical phase III trials confirmed these benefits derived from both GM-CSF and G-CSF.107,108,109,110 and 111 These results led to the U.S. Food and Drug Administration (FDA) approval of both drugs for the treatment of patients following an autologous BMT to enhance neutrophil recovery. However, the positive results in these trials were limited to neutrophil engraftment and neutropenia-related complications. Red blood cell and platelet engraftment was not enhanced and patient-survival was not demonstrably improved.
MOBILIZATION
As discussed above, the observation that hematopoietic growth factor administration produces a time-limited enhancement in stem-cell mobilization has had a major impact on autologous transplantation with ongoing evaluation in the allogeneic setting. Upon reinfusion of mobilized peripheral-blood progenitor cells, hematopoietic engraftment of all lineages is accelerated significantly.112
A prospective randomized clinical trial comparing the use of G-CSF–mobilized autologous peripheral-blood progenitor cells to that of autologous marrow in 58 patients with relapsed Hodgkin’s disease and lymphoma was performed. The patients who received mobilized peripheral-blood progenitor cells had a shorter time to platelet recovery above 20,000/µl (16 versus 23 days), a shorter time to neutrophil recovery, reduced hospital stays, and lower costs compared to control patients.113,114 Early posttransplant morbidity, mortality, and overall survival (median follow-up 311 days) were similar in both groups.
Accelerated hematopoietic engraftment has also been noted in the allogeneic setting with the use of G-CSF mobilization.47,48,115 However, the overall long-term benefit remains to be determined due to the potential risk of graft-versus-host disease, especially chronic graft-versus-host disease.49 Randomized clinical trials are currently under way in North America and Europe.
The role of CSF following peripheral-blood progenitor-cell transplantation is less well defined. The addition of G-CSF may modestly accelerate neutrophil engraftment. Many centers employ G-CSF following infusion of the peripheral-blood progenitor cell autograft.116,117 The dose of G-CSF used varies between 5 and 10 µg/kg per day. This is generally continued until stable neutrophil engraftment is established.
ERYTHROPOIETIN
Erythropoietin has been used in an effort to accelerate the recovery of red blood cells following transplantation. The rationale for this developed in part from the observation that EPO levels were lower than predicted for the degree of anemia following transplantation.118
In the autologous setting, small randomized studies have not shown reductions in transfusional requirements.119,120 Modest increases in recovery of reticulocytes was observed in one study where patients were treated with both G-CSF and EPO.120 Following allogeneic transplantation, mixed results have been observed. Initial small trials suggested that EPO administration produced more rapid recovery of red blood cells and reduced transfusional requirements.121,122 Larger randomized trials have also been performed. One such trial randomized 215 patients undergoing allogeneic BMT to placebo or EPO therapy (150 U/kg per day as a continuous infusion) from marrow infusion until stable hemoglobin levels were achieved for 7 days. The median time to transfusion independence was reduced from 27 to 19 days, but total transfusion requirements for the two groups were similar. Another trial from Australia evaluated 91 patients who underwent allogeneic hematopoietic cell transplantation followed by randomization to placebo or EPO (300 U/kg three times weekly). Erythropoietin therapy was associated with increases in the reticulocyte count, hemoglobin concentration, and marrow erythropoiesis on day 14; however, red blood cell transfusional requirements were not different in the two groups.123
MUCOSITIS AND NUTRITIONAL SUPPORT
The majority of patients who undergo hematopoietic cell transplantation, especially those who receive fractionated total-body irradiation as part of the preparative regimen, develop significant mucositis and have difficulty maintaining an adequate caloric intake. These patients are generally treated with total parenteral nutrition (TPN) until they are able to maintain adequate oral nutritional intake.124
In a randomized trial of prophylactic TPN therapy in 137 patients, patients who received TPN had improved overall survival compared to hydration with 5% dextrose.125 A second randomized trial administered in the outpatient setting reported different results. In this double-blinded study, 258 patients were randomized to either TPN or hydration. The patients who received TPN had a delay in the resumption of more than 85 percent of their caloric requirement, suggesting that the administration of TPN may suppress normal appetite recovery.126 In this study, there was no effect of TPN on hospital readmission, relapse, or survival. In other studies, supplementation of TPN with glutamine was reported to reduce infection (13% versus 43% in one trial) and microbial colonization following BMT.127 However, a second randomized study did not confirm these results.128
Mucositis remains an important clinical complication and is often regarded as the most difficult problem from the patient’s perspective. Current management approaches include the use of topical and intravenous pain medications, acyclovir, and good oral hygiene. Many patients who undergo hematopoietic cell transplantation require narcotic pain medication. The length of time in which intravenous narcotics are needed is one of the best indicators of the degree of mucositis. New approaches are greatly needed, since the severity of mucositis and the requirement for pain medications is one of the principal reasons that patients undergoing transplantation require hospitalization.
Novel strategies include the use of recombinant growth factors, such as keratinocyte growth factor, which is now entering clinical trials. This agent reduces the degree of mucositis and improves survival in animal models in which the degree of mucositis and associated risk of infection are associated with measurable mortality.129,130
INFECTION
Patients who undergo transplantation, especially allogeneic transplantation, are at risk for bacterial, fungal, and viral infections (see Chap. 17).131 Bacterial infections are frequent during the period of severe neutropenia and are most commonly due to gram-positive organisms, although gram-negative infections also occur. The early administration of broad-spectrum antibiotics in febrile, neutropenic patients is critically important.132 Indwelling catheters and tissue damage from the preparative regimen or graft-versus-host disease, especially to the mouth, skin, and gut, are frequent mechanisms by which organisms enter the circulation. Infections caused by Streptococcus mitis can be particularly virulent following transplantation.133
A variety of measures are instituted at different transplant centers in an effort to reduce the risk for infection. These include protective isolation, handwashing, masking, gowning, and low-microbial diets. Decontamination of the gastrointestinal tract with oral antibiotics, such as ciprofloxacin or nonabsorbable broad-spectrum antibiotics, is utilized in many transplant centers. Immunoglobulin infusions also have been utilized to reduce the incidence of infectious complications following allogeneic BMT. In one trial, 383 transplant recipients were randomized to receive intravenous immunoglobulin (500 mg/kg weekly to day 90, then monthly to day 360) or no intravenous immunoglobulin. Patients treated with intravenous immunoglobulin had a significantly lower incidence of interstitial pneumonia among patients seropositive for CMV (13% versus 22%), a reduced risk of gram-negative septicemia (relative risk 0.38), and, in patients more than 20 years of age, a lower incidence of acute graft-versus-host disease (34% versus 51%) compared to control patients.134 Neither survival nor the risk of relapse was altered by intravenous immunoglobulin. A subsequent randomized trial of 250 patients conducted by the same group of investigators evaluated the effects of intravenous immunoglobulin (500 mg/kg per month) given between days 90 and 360. In this study, no beneficial effects on the incidence of bacteremia, septicemia, localized infection, or obliterative bronchiolitis or on the incidence or mortality of chronic graft-versus-host disease were observed.135 Therefore, many transplant centers utilize biweekly infusions of intravenous immunoglobulin (500 mg/kg) only until day 100 following the transplant.
Fungal infections are particularly worrisome in BMT recipients and are a frequent cause of transplant-related mortality. A variety of different fungal organisms have been observed, with the most common infections caused by Candida and Aspergillus species. However, other fungal infections can occur, such as coccidioidomycosis.136 Treatment of established fungal infections is difficult, and prevention is clearly preferred.
Studies of prophylaxis against severe fungal infections are difficult to perform due to the relatively low incidence of such infections and the challenge in clearly documenting an invasive fungal infection. As a result, other trial endpoints, such as surveillance cultures or colonization, have been utilized. However, they may not be truly predictive. Retrospective analyses from two transplant centers have suggested that low-dose amphotericin B may lower the risk of fungal infections.137,138 Newer agents, such as the liposomal amphotericin products, have been utilized mainly for treatment of established disease and have not been widely used for prophylaxis, due to their high cost.139
Prophylaxis with fluconazole has been explored in a randomized trial of 356 patients. In this study, fluconazole (400 mg/day) or placebo was administered prophylactically from the start of the conditioning regimen until the neutrophil count recovered to more than 1000/µl. By the end of the treatment period, patients treated with fluconazole had a lower incidence of positive fungal cultures from any site (30% versus 67%) and of systemic fungal infections (3% versus 16%).140
VIRAL INFECTIONS
Viral infections are common following transplantation and are an important source of morbidity. Fortunately, major advances in this field have occurred with the introduction of effective drugs.
Cytomegalovirus Infection The most serious viral infection is due to CMV, a complication that typically occurs between 35 to 100 days following transplantation. The incidence of CMV infection following autologous transplantation is not significantly different from that observed following allogeneic transplantation; however, the incidence of CMV disease is clearly higher among patients receiving allogeneic transplants.141 Cytomegalovirus infection can arise from viral activation within the patient or from infusion of CMV-positive blood products. Transfusing exclusively seronegative blood products effectively eliminates the risk of CMV disease in patients who are CMV negative and who have CMV-negative donors.142 The introduction of ganciclovir has ushered in a new era in the prevention and treatment of this previously lethal infection. The early introduction of ganciclovir to patients who are at risk for CMV infection decreases the incidence of clinically significant infection dramatically and is associated with an improved overall outcome.143,144 and 145 In addition, expansion of cytotoxic T lymphocytes directed against CMV have also been effective in preventing CMV disease.146
Despite these successes, a number of issues remain, since ganciclovir prophylaxis is expensive and associated with significant toxicity to the marrow, kidney, and central nervous system. The best method of detecting patients at risk for CMV infection, the optimal dose and timing of ganciclovir therapy, the required duration of treatment, and the benefits of combined therapy with other agents remain the focus of ongoing clinical studies. In addition, some patients develop recurrent CMV disease, which can present challenging clinical problems.
Herpetic Infections Mucocutaneous herpetic infections caused by herpes simplex viruses I and II are extremely common following BMT and result in significant pain and difficulty in alimentation. Intravenous acyclovir (5 mg/kg every 8 h if renal function is normal) is an effective agent against herpes simplex viruses I and II and is typically used prophylactically for patients who are seropositive during the period of neutropenia.147,148
Varicella zoster virus causes another common viral infection (occurring in 30 to 40% of patients) following transplantation.149 Although varicella zoster virus infection is rarely life threatening, it can be a cause of significant pain and disability. Varicella zoster virus infections are usually dermatomal but occasionally disseminate. Infections typically occur within the first 12 months following hematopoietic cell transplantation. Other viral infections, such as respiratory syncytial virus infections, can occur in BMT patients and can result in fatalities.150,151 and 152 Outbreaks of respiratory syncytial virus infections within a medical center have been reported, suggesting a nosocomial spread.153 Respiratory syncytial virus infections can be effectively treated with combination therapy with aerosolized ribavirin and intravenous immunoglobulin.154 The use of intravenous immunoglobulin or antibodies with high titers of antibodies against respiratory syncytial virus may improve upon these results. Human herpes virus 6 has been isolated from patients undergoing transplantation and has been associated with fatalities.155,156 Infection with the BK strain of adenovirus has been associated with hemorrhagic cystitis.157,158
LATE INFECTIONS
Due to prolonged immunosuppression, patients undergoing allogeneic transplantation are at greater risk of infection following neutrophil recovery than are autologous transplant patients. Infections occurring beyond day +50 have been noted to be more frequent following unrelated donor transplantation (84.7%) than following related donor transplantation (68.2%; p = 0.009).159
BLOOD PRODUCT SUPPORT
Virtually all patients undergoing hematopoietic cell transplantation require blood product support in the form of red blood cell and platelet transfusions until the transplanted stem cells engraft. In the allogeneic setting, transfusion requirements are generally greater due to the immunosuppressive effects of drugs such as cyclosporin, methotrexate, and ganciclovir, as well as to complications such as graft-versus-host disease. Following allogeneic hematopoietic cell transplantation, all CMV-negative patients who receive cells from a CMV-negative donor should receive seronegative blood products. In addition, all transplant centers utilize either irradiated or filtered blood products to avoid the risk of transfusion-associated graft-versus-host disease.
The indications for transfusion of red blood cells vary. However, most centers utilize a threshold hematocrit of approximately 30 percent. The need for red cell transfusions may be influenced by a number of factors, including the number of days from hematopoietic cell transplantation, the clinical condition of the patient, evidence of engraftment of other cell types, and the reticulocyte count. Patients with graft-versus-host disease or those being treated with immunosuppressive drugs such as cyclosporin may have continued blood product requirements from bleeding and/or microangiopathic hemolysis.
Patients who are thrombocytopenic and bleeding require platelet transfusions. Such support is required by most transplanted patients. In comparison, the role of prophylactic platelet transfusions remains controversial. Many transplant centers have relied upon threshold values of platelet counts to determine the timing of platelet transfusions. This practice has been questioned due to the risk of alloimmunization, the relatively short life span of transfused platelets, and the expense of transfusion. Seven hundred ninety-eight patients transplanted at 18 centers in the United States and Canada were evaluated for the pace of platelet recovery and incidence of bleeding complications. A number of variables were identified that were associated with accelerated platelet recovery, including a higher CD34+ cell count of the infused stem-cell product, a higher platelet count at the start of myeloablative therapy, and a graft from an HLA-identical sibling donor.160 Platelet recovery was more rapid in patients who received progenitor cells from the peripheral blood than in those who received them from the marrow. Patients who had received prior radiation therapy, who had posttransplant fever, who had hepatic veno-occlusive disease, or who required posttransplant growth factors recovered platelet counts more slowly. In this retrospective study, 11 percent of all patients had a significant bleeding event during the first 60 days following the transplant, contributing to death in 2 percent; however, these deaths were strikingly independent of the platelet count.160 Similar results were observed in studies of patients who become thrombocytopenic after chemotherapy for acute leukemia. Reducing the platelet transfusion threshold from 20,000/µl to 10,000/µl led to decreased utilization of platelet transfusions without any significant effect on morbidity and only a small adverse effect on bleeding.161,162 and 163
A significant concern among patients and their family members is the risk of transfusion-transmitted viral diseases. Fortunately, with improved and systematic testing of blood products, the risks per unit of blood are low and in the range of 1 in 493,000 units for HIV, 1 in 103,000 units for hepatitis C virus, and 1 in 63,000 units for hepatitis B virus (see Chap. 140).164 Ongoing improvements in screening may reduce these risks even further.
CLINICAL RESULTS OF MARROW TRANSPLANTATION
ACUTE MYELOGENOUS LEUKEMIA
Bone marrow transplantation has been extensively studied in patients with AML as postremission therapy. Allogeneic BMT was initially utilized for patients with refractory disease, in whom it was observed that 10 to 20 percent of patients with advanced disease enjoyed long-term disease-free survival, some of whom are now alive for more than 20 years.65 Many other studies have confirmed these early results and demonstrated that the outcome following BMT is highly dependent upon the remission status of the patient. Advances in tissue typing, graft-versus-host disease prophylaxis, and supportive care have made it feasible to consider BMT for patients with more favorable disease. Subsequently, the use of allogeneic BMT early in the course of disease, for example, following remission induction, was studied. Five-year disease-free survival rates range from 45 to 65 percent, with relapse rates varying between 10 and 25 percent.165,166,167,168,169,170,171,172 and 173 In these studies, it was observed that the primary cause of treatment failure was related to complications from hematopoietic cell transplantation and not due to relapse of the underlying disease. This observation is in marked contrast to findings in patients who are treated with chemotherapy or an autologous BMT, where the predominant cause of treatment failure is relapse of AML.
To further document the potential efficacy of allogeneic BMT in AML patients in first CR, randomized studies have been performed. These studies employed a biological randomization whereby those patients with an HLA-matched sibling donor received the transplant and those without received chemotherapy. Some of these studies further randomized patients who did not have an HLA-matched sibling donor between autologous BMT and chemotherapy, which is discussed below. In these studies, it was assumed that having an HLA-matched sibling donor or not was a random event. Many randomized studies comparing allogeneic BMT to chemotherapy have been reported that have demonstrated a consistent, although not always statistical, benefit in disease-free survival for patients who underwent allogeneic BMT (Table 18-1). In six of these trials, a statistically significant difference in disease-free survival was reported.174,175,176,177,178 and 179 In the other studies, a trend toward improved overall survival was evident, with a reduction in the risk of relapse. The primary causes of treatment failure in transplanted patients are graft-versus-host disease, interstitial pneumonitis, and infection.

TABLE 18-1 ALLOGENEIC MARROW TRANSPLANTATION VERSUS AUTOLOGOUS MARROW TRANSPLANTATION VERSUS CHEMOTHERAPY FOR AML IN FIRST REMISSION

More recently, it has become apparent that patients with AML have a variable prognosis and can be placed into risk categories based upon cytogenetic features at diagnosis. Patients with low-risk disease are characterized by the chromosomal abnormalities t(15;17), t(8;21), and (inv16). Due to this relatively favorable prognosis, some centers have elected not to consider transplantation for these patients until first relapse or during second CR. In contrast, patients with a myelodysplastic syndrome; cytogenetic abnormalities involving chromosomes 5, 7, and 8; or complex cytogenetic abnormalities fare poorly with chemotherapy and should be transplanted early in the course of their disease. Patients with intermediate prognosis, which includes the large group of individuals with normal cytogenetics, may be offered allogeneic BMT in first CR. One potential algorithm for the treatment of adults with AML is presented in Fig. 18-1.

FIGURE 18-1 Algorithm for the treatment of acute myelogenous leukemia. (From KE Stockerl-Goldstein, KG Blume,563 with permission.)

Acute myeloblastic anemia patients who do not enter CR with one or two courses of chemotherapy are also considered candidates for allogeneic BMT. In one report, 16 such patients with induction failures underwent allogeneic BMT utilizing HLA-matched sibling donors. With follow-up ranging from 18 months to 11 years, 8 of these patients were alive and free of disease.180 Similar results were reported to the International Bone Marrow Transplant Registry, where 21 percent (CI 14–31%) of patients with induction failures were alive and disease free at 3 years of follow-up.181
The role of autologous transplantation in patients with AML is considerably more complex. Only a few patients with advanced disease (beyond first CR) can be salvaged with autologous BMT.182 One early study demonstrated a disease-free survival rate of 43 percent in a group of patients with AML in second or third remission who underwent transplantation with 4HC-purged marrow.94 A follow-up of this study reported continued disease-free survival for 28 percent of those patients, with minimum follow-up of 4 years.183 Other investigators have reported similar rates of disease-free survival in AML patients who had suffered a relapse.74,184
The role of purging in autologous transplantation has been controversial. In vitro data discussed above have suggested that the intensity of purging with 4HC, as assessed by normal CFU-GM survival, has had an impact on relapse rate and disease-free survival.187 In addition, retrospective analyses also have revealed a benefit for those patients who underwent autologous BMT with mafosfamide-purged marrow, especially early after remission induction.95 Despite the considerable suggestive evidence that purging may have a role in reducing relapse rates following autologous BMT for AML patients, there has not been a randomized trial directly demonstrating the benefit of such graft manipulation. Because of this and the myelotoxicity, 4HC has not yet been approved by the FDA. An alternative approach to purging has been the use of high-dose chemotherapy and transplantation of peripheral-blood progenitor cells early following recovery, a procedure termed in vivo purging.186
The role of autologous transplantation in first CR has been controversial. A number of phase II studies have reported a broad range in disease-free survival from 35 to 76 percent, with relapse rates ranging from 22 to 60 percent.74,75 and 76,95,187,188 and 189 Where allogeneic BMT has been compared directly to autologous hematopoietic cell transplantation in first CR, there is either a better outcome following the allogeneic transplant187,190 or no difference between the two groups.179,191,192 Comparisons between autologous hematopoietic cell transplantation and chemotherapy for first CR AML patients have yielded conflicting results. The Medical Research Council 10 trial of 1966 patients from 163 institutions assigned patients to allogeneic transplantation if they had an HLA-matched sibling donor and randomized the remaining patients to autologous BMT or to four courses of intensive chemotherapy. In this study, 381 patients were randomized, and of the 190 patients who were assigned to the autologous BMT arm, 126 (66%) actually underwent the procedure. Using an intention-to-treat analysis, those patients who underwent autologous BMT had a lower relapse rate (37% versus 58%; p = 0.0007) and superior disease-free survival at 7 years of follow-up (53% versus 40%; p = 0.040) as compared to patients who received intensive chemotherapy (Fig. 18-2).193 In another large study of 623 patients, a similar study design was employed. Here again the relapse rate was lower for patients who underwent autologous BMT than for those who received chemotherapy (41% versus 57%). Disease-free survival was superior in the autologous BMT the group as compared to the group treated with chemotherapy (48% versus 30%). However, overall survival was not different due to the use of salvage therapy with hematopoietic cell transplantation for those patients who relapsed following chemotherapy.179

FIGURE 18-2 Randomized comparison of autologous transplantation versus conventional chemotherapy for acute myelogenous leukemia. (From AK Burnett et al,193 with permission.)

Other randomized clinical trials have not supported the conclusion that autologous transplantation results in a superior outcome than that using chemotherapy alone.192,194,195 In a study of 232 children with AML in first CR who were randomized between autologous BMT and chemotherapy, there were no differences in event-free survival (36% versus 38%). A lower relapse rate was observed following autologous transplantation (31% versus 58%; p < 0.001), but this again was offset by higher treatment-related mortality in the transplanted patients (15% versus 2.7%; p = 0.005).195 The U.S. Intergroup Trial also had a similar three-arm study design. Utilizing an intention-to-treat analysis, no significant differences were observed among the different treatment groups, with a median follow-up of 4 years.192 A significant problem in this study was the low percentage of patients who were assigned to the autologous transplant arm who actually received the therapy (54%), compared to 91 percent of the patients who were assigned to chemotherapy and 81 percent of the patients assigned to allogeneic transplantation.
Ongoing improvement in strategies for autologous transplantation, including the use of peripheral-blood progenitor cells and posttransplant immune modulation (see below), as well as improvements in results with patient selection, chemotherapy, and biological therapies, are likely to make the optimal treatment approach a source of ongoing debate in the twenty-first century.
ACUTE LYMPHOBLASTIC LEUKEMIA
Both allogeneic and autologous hematopoietic cell transplantations have been utilized for patients with ALL. As with patients with AML, results vary markedly, depending upon the remission status at the time of transplantation. Advances in therapeutic efficacy with standard chemotherapy have resulted in effective control of this disease in most children. Treatment of adults with chemotherapy has steadily improved, especially for some subtypes of ALL. However, patients with high risk of recurrence can be defined at diagnosis or once a first remission has been attained. Therefore, hematopoietic cell transplantation studies have focused on patients with relapsed disease or adults with high-risk disease in first CR.
A number of clinical trials indicate that children with ALL who suffer a relapse can be salvaged with allogeneic BMT, with 40 to 64 percent of patients enjoying long-term survival.196,197,198 and 199 Comparative analyses of results expected with chemotherapy have been performed based upon registry data. In one such study, results for allogeneic hematopoietic cell transplantation in 376 children in second CR reported to the International Bone Marrow Transplant Registry were compared to 540 children treated with chemotherapy on Pediatric Oncology Group trials. At a mean of 5 years of follow-up, the relapse rate was significantly lower for the patients undergoing hematopoietic cell transplantation (45% versus 80%; p < 0.001) and the probability of leukemia-free survival higher in the transplanted patients (40% versus 17%; p < 0.001).200
Allogeneic BMT has been compared to chemotherapy for children with high-risk disease, defined as those patients presenting with a WBC greater than 100,000 cells/µl. One hundred ninety-eight children in the United Kingdom were identified, of which 34 patients with an HLA-matched sibling donor went on to allogeneic hematopoietic cell transplantation. A significant reduction in relapse rate was noted for patients who underwent transplantation (12% versus 41%; p = 0.001); however, there was also higher treatment-related mortality in the transplanted patients (18% versus 3%; p = 0.0007), and no statistical difference in overall disease-free survival was observed (69% for BMT versus 52% for chemotherapy).201
In general, adults with ALL have a considerably worse prognosis than children. A number of clinical parameters have been correlated with increased risk of relapse, including advanced age, elevated WBC at diagnosis, non–T-cell disease, extramedullary involvement, more than 4 weeks to achieve remission, and certain cytogenetic abnormalities, especially the Philadelphia (Ph) chromosome. Allogeneic BMT has been utilized to treat adult patients beyond first CR or patients in first CR with high-risk features. Approximately 42 to 71 percent of patients achieve long-term remissions.202,203,204,205 and 206 The use of fractionated total-body irradiation and etoposide has been particularly effective, with approximately 60 percent of adult patients with high-risk disease transplanted in first CR being alive and free of disease with follow-up exceeding 10 years (Fig. 18-3).207

FIGURE 18-3 Long-term follow-up of allogeneic marrow transplantation for patients with high-risk features of acute lymphocytic leukemia. All patients received the preparatory regimen of fractionated total-body irradiation and high-dose etoposide followed by marrow from HLA-matched siblings EFS, event free survival; OS, overall survival; REL, relapse. (From NJ Chao et al,207 reprinted and updated with permission.)

Comparative studies between allogeneic BMT and chemotherapy also have been performed. Similar to studies in children, registry data have confirmed a lower relapse rate for patients undergoing hematopoietic cell transplantation than for patients receiving chemotherapy. However, due to the increased risk of transplant-related complications, no improvement in overall survival was noted.208,209 In another analysis, disease-free survival was improved for younger patients (<30 years of age) who underwent allogeneic hematopoietic cell transplantation as compared to chemotherapy.210
Randomized studies have been performed with a design similar to those of trials performed in AML where patients in first CR with HLA-matched sibling donors were assigned to allogeneic transplantation and those patients without suitable donors were assigned to chemotherapy or were randomized between chemotherapy and autologous hematopoietic cell transplantation. In one such study, 257 eligible patients were evaluated, with 116 individuals undergoing allogeneic hematopoietic cell transplantation and 141 control patients being treated with chemotherapy. Five-year survival rates were not statistically different among the two groups; however, when only patients with high-risk features were evaluated, there was improved disease-free survival (39% versus 14%; p = 0.01) and overall survival (44% versus 20%; p = 0.03) in the transplanted patients.211
Patients with ALL who have the Ph chromosome have an extremely poor prognosis following chemotherapy treatment, with the vast majority of them ultimately suffering a relapse.212,213 In one study of 23 Ph-positive ALL patients prepared with fractionated total-body irradiation and etoposide who underwent transplantation with HLA-matched sibling marrow while in first CR, disease-free survival at 3 years of follow-up was 65 percent.214 Hematopoietic cell transplantation from matched unrelated donors has also been successfully employed for 18 patients with Ph-positive ALL in first CR with a 2-year probability of disease-free survival of 49 percent.215 Patients with remission-induction failure are also a very poor risk group for whom allogeneic hematopoietic cell transplantation has been attempted as salvage therapy. In one study of 21 patients, 16 of whom had AML and 5 of whom had ALL, the probability of disease-free survival at 10 years was 43 percent.180 However, only 1 of the 5 ALL patients was alive and free of disease.
Autologous hematopoietic cell transplantation for patients with ALL has resulted in variable outcomes. In patients with advanced disease (beyond first CR), such treatment has achieved only modest success, with 18 to 46 percent of patients enjoying long-term survival.216,217,218,219,220,221 and 222 In addition, only a subset of relapsed patients (in one study approximately 50%) actually underwent hematopoietic cell transplantation.223 Patients with long first remissions of at least 24 months fared better, with an event-free survival of 53 percent among 51 children who underwent transplantation with purged marrow in second CR.224 Better results have been achieved in first CR patients, varying from 30 to 65 percent.205,217,225,226
The role of purging in autologous transplants for ALL has been controversial, although it is widely utilized. Monoclonal antibody (MoAb)-based techniques, immunotoxins, and chemotherapy in the form of 4-hydroperoxycyclophosphamide have been utilized.218,227,228 In some of these studies, PCR-based methods have been used to document the efficacy of the purging procedure.229 There are no direct comparisons between purged and unpurged stem-cell grafts.
In ALL, unique chromosomal rearrangements, such as the bcr/abl translocation, or immunoglobulin and T-cell receptor genes can be amplified by PCR. Molecular features serve as extremely sensitive markers for disease. Bcr/abl transcripts have been detected following transplantation and found to be a sensitive predictor of relapse, especially for patients with the p190 bcr/abl splice variant.230,231 Rearrangements of immunoglobulin heavy-chain variable loci have also been utilized to detect minimal residual disease and have been found to be useful and sensitive markers for relapse following transplantation.232 Utilizing a semiquantitative PCR technique, children and adolescent patients were grouped as having high-level disease, low-level disease, or no detectable disease using PCR amplification of immunoglobulin or T-cell receptor gene loci prior to allogeneic hematopoietic cell transplantation performed in either first or second CR. Two-year event-free survival for these groups of patients was 0 percent for high level, 36 pecent for low level, and 72 percent for those patients without PCR detectable disease prior to hematopoietic cell transplantation, respectively (p < 0.001).233 In the future, it may be possible to use sensitive minimal residual disease assays for the identification of patients who are at high risk of relapse, in whom innovative new approaches should be considered; of patients likely to benefit from hematopoietic cell transplantation; and of other patients who may already be cured of their disease, in whom the risk of transplantation could be avoided.
CHRONIC MYELOGENOUS LEUKEMIA
Allogeneic hematopoietic cell transplantation for CML has been widely studied and has been established as the primary therapy for this disorder. As discussed in Chap. 94, CML progresses from a relatively indolent disorder readily controllable with oral chemotherapy in chronic phase to a more aggressive disorder in accelerated phase to a frankly acute leukemic condition in blastic phase, which is often refractory to therapy. Many studies have documented that the results obtained with allogeneic hematopoietic cell transplantation are directly related to the phase of disease at the time of the transplant.234,235,236 and 237 Early trials demonstrated that CML could be effectively treated with myeloablative chemoradiotherapy followed by syngeneic10 or allogeneic marrow234 grafting. The finding that relapse rates are higher following syngeneic than following allogeneic transplantation serves as one of the primary observations leading to the concept of a graft-versus-leukemia effect.14,238
The most important prognostic factor for survival following allogeneic hematopoietic cell transplantation for CML is disease phase.235,239,240 Fifty to 75 percent of CML patients transplanted in the first or second chronic phase of their disease achieve long-term remissions.235,237,239,240,241,242 and 243 Disease-free survival falls to 30 to 40 percent of patients with accelerated phase,237,244 and only 5 to 15 percent of patients in blastic phase obtain long-term disease-free survival with allogeneic hematopoietic cell transplantation.
Younger age may also influence survival,239,240 while splenomegaly or splenectomy appears to have no impact on outcome following BMT.240 A number of studies have documented that early hematopoietic cell transplantation during the first year after diagnosis is a favorable prognostic factor in part related to the negative impact of prior exposure to chemotherapy, especially busulfan.237,240 In the subgroup of CML patients under the age of 50 who undergo allogeneic transplantation from an HLA-matched sibling donor BMT during the first year of diagnosis, nearly 80 percent will be alive and free of disease 5 years later. This makes BMT the treatment of choice for younger patients with CML.
Randomized clinical trials exploring the use of non-radiation-containing preparative regimens such as busulfan/cyclophosphamide have been compared to fractionated total-body irradiation with cyclophosphamide. In these studies, there were no differences in disease-free survival.71,245 However, a decreased risk of relapse in busulfan/cyclophosphamide–treated patients was reported in one study.245 Plasma busulfan levels below the median of 917 ng/ml were associated with a higher relapse rate in one small study of 45 patients transplanted with the busulfan/cyclophosphamide regimen.246
Alternative therapies for CML have emerged, such as interferon-a, with documented improvements in long-term disease-free survival for a certain subset of patients (see Chap. 94). However, there have been no prospective trials comparing the role of allogeneic BMT to interferon-a. An analysis of historical data has been performed comparing results obtained for allogeneic BMT submitted to the International Bone Marrow Transplantation Registry (n = 548) to results obtained from the randomized trial of the German CML study group, which had accrued patients to therapy with hydroxyurea (n =121) or interferon-a (interferon-a, n = 75).237 In this analysis, as expected, there was a higher mortality risk in the transplant group for the first 18 months. Approximately 3.5 years after diagnosis, the survival curves crossed, indicating that there was significant improvement in overall survival for the transplanted patients at 4.7 years. At 7 years, the overall survival of the group treated by transplantation was 58 percent, while only 21 percent of those treated with hydroxyurea or interferon-a survived (Fig. 18-4).248 Similar results were obtained for all risk categories. However, those patients with intermediate-, or high-risk disease manifested improved survival at an even earlier timepoint.

FIGURE 18-4 Historical comparison of allogeneic transplantation versus hydroxyurea or interferon-a for patients with chronic myelogenous leukemia. (From RP Gale et al,248 with permission.)

For patients without HLA-matched sibling donors, matched unrelated donor transplantation has been explored. Due to the relatively indolent nature of CML, there is usually adequate time to perform a search. The outcome for matched unrelated donor transplantation for patients with CML in chronic phase was initially reported to be in the range of 35 to 40 percent, with patients with more advanced disease faring worse.54,249 Advances in donor-recipient typing, supportive care, graft-versus-host disease prophylaxis, and infectious disease prevention have resulted in significant improvements in results after matched unrelated donor transplantation. Five-year estimates of survival for patients who are 50 years of age or younger and undergo a transplant procedure within 1 year of diagnosis from an HLA-matched unrelated donor were reported to be 74 percent. This favorable outcome approximates what can be achieved with HLA-matched sibling donors (Fig. 18-5).56

FIGURE 18-5 Results of matched unrelated donor transplantation for patients with chronic myelogenous leukemia in chronic phase stratified by recipient age. (From JA Hansen et al,56 with permission.)

The decision to proceed to unrelated donor transplantation versus the use of interferon-a is often difficult for patients who lack an HLA-matched sibling donor. Decision analysis has been applied to this question. It was concluded that, for younger patients with newly diagnosed CML, transplantation within the first year of diagnosis provided the greatest quality-adjusted expected survival250 and that this modality had an acceptable cost-effectiveness ratio.251 Umbilical cord blood transplantation has also been utilized in small numbers of patients with CML.252,253
An alternative approach to the use of immunosuppressive drugs for the prevention of graft-versus-host disease has been T-cell depletion. This has resulted in less graft-versus-host disease, but a higher risk of leukemic relapse.254 Donor leukocyte infusion has been utilized for those patients who suffer a relapse following the transplant. Comparable results have been obtained using unrelated donors.255,256 Currently, a multi-institutional prospective randomized clinical trial comparing T-cell depletion to conventional marrow transplantation with matched unrelated donors is ongoing.
There has been considerable debate as to whether pretreatment of patients with interferon-a affects outcome following BMT. The argument is complicated by the fact that those patients who delay transplantation have a worse outcome independent of interferon-a usage. Nonetheless, a number of retrospective analyses have addressed this question. In one study, prolonged use of interferon-a was associated with a worse outcome, mainly due to an increased risk of infection and graft failure.257 Another study in the matched unrelated donor setting supported the concept that prolonged interferon-a treatment of more than 6 months was associated with a worse outcome following transplantation.258 Other studies have, however, found no impact of interferon-a use on the outcome of subsequent transplantation.259,260
Autologous hematopoietic cell transplantation has also been explored for a limited number of patients with CML. Registry data and single-institution studies have suggested that patients who undergo autologous hematopoietic cell transplantation while in chronic phase may attain a prolonged chronic phase of their disease and possibly enjoy improved survival.261,262 and 263 These beneficial effects do not appear to extend to patients in accelerated phase or blastic phase.261 A variety of strategies have been employed in an effort to enrich for normal unaffected stem cells in the graft, including in vitro culture,200 cell selection by FACS,264 and collection of cells upon recovery from chemotherapy.263,265,267 Autologous transplantation may serve as a platform for subsequent immunotherapeutic strategies, such as with IL-2, autologous NK cells,267 or CD3+CD56+ effector cells.268
An occasional problem in the management of CML patients is that of massive splenomegaly. This can complicate the posttransplant course by causing refractory cytopenias. Both splenectomy and splenic irradiation have been utilized without an adverse effect on the outcomes.269 One randomized study of splenic irradiation to a total dose of 10 Gy performed in 239 patients with CML did not indicate a significant benefit.270 However, in another study, 37 patients who received splenic radiation (2.5–5 Gy) within 10 days of hematopoietic cell transplantation had an overall survival of 82 percent.271
MYELODYSPLASTIC SYNDROMES
Hematopoietic cell transplantation has been used to treat patients with myelodysplastic syndromes (MDS) but is limited by donor availability and the advanced age of most patients with these conditions. With improvements in supportive care and prevention of graft-versus-host disease, a number of groups have extended the upper age limit for allogeneic BMT to 60 years. However, many MDS patients are older than 60 years of age. Therefore, this treatment modality can only be offered to a subset of individuals with this disease.
In one study, 93 patients were treated with transplantation, all of whom had severe neutropenia, thrombocytopenia, or more than 5 percent marrow blasts. The patients were prepared with either total-body irradiation and cyclophosphamide (total-body irradiation/cyclophosphamide; 88 patients) or busulfan/cyclophosphamide (busulfan/cyclophosphamide; 5 patients). Sixty-five patients received grafts from HLA-matched sibling donors, and 28 patients received either marrow grafts from other family members or unrelated donors. With a follow-up of 4 years, 41 percent of patients were alive and free of disease. Twenty-eight percent of patients relapsed, and 43 percent died of transplant-related complications. Those patients who had the best overall result were younger (<40 years) or had less than 5 percent marrow blasts at the time of hematopoietic cell transplantation.272
Similar results have been reported employing regimens using total-body irradiation-based regimens primarily combined with cyclophosphamide.273,274 and 275 Regimens not employing radiation have the potential advantage of less toxicity and have also been used to prepare patients for allogeneic hematopoietic cell transplantation. Thirty-eight patients were prepared with busulfan/cyclophosphamide. The overall survival rate at 2 years was 45 percent, with a 24 percent probability of relapse.276 The busulfan/cyclophosphamide regimen has been also used in 27 younger patients, where results using grafts from sibling donors were significantly better, with a projected 78 percent of patients alive and free of disease.277
In a retrospective analysis of 131 patients with MDS who underwent allogeneic BMT using HLA-matched sibling donors, the 5-year disease-free survival was 34 percent, and overall survival was 41 percent.278 The same variables reported previously272 were predictive of improved outcome, including younger age, shorter disease duration, and absence of excess marrow blasts.
The results of matched unrelated donor transplantation for patients with MDS were disappointing in early reports. However, with better matching techniques and supportive care, the results have continued to improve. In one series of 52 patients with MDS or MDS-related AML who underwent matched unrelated donor transplantation, a 2-year disease-free survival of 38 percent was reported.279 Transplant-related mortality was 58 percent for a cohort of 118 patients with MDS, including 12 patients with CML. Overall survival at 2 years was 28 percent. Again, patients with low-risk disease had a lower relapse rate.280
Allogeneic hematopoietic cell transplantation carries significant risks, especially in an elderly patient population. In addition, MDS is a highly variable disease. Therefore, predicting which patients are likely to benefit from hematopoietic cell transplantation is important. In one study of 60 patients, those patients with poor risk cytogenetics, as defined by the International MDS Workshop categorization,281 had a much worse outcome (event-free survival 6% versus 40–51% for the intermediate and good risk groups) and significantly higher relapse rate (82% versus 12–19%, p = 0.002).282
T-cell–depleted grafts have also been explored for the treatment of patients with MDS. The advantage of this approach may be the relatively lower transplant-related mortality due to a decrease in the incidence of graft-versus-host disease. In one study of 35 patients, 24 percent were alive and free of disease with 3 years of follow-up.283
Rarely, children develop MDS, and a limited number of pediatric patients have undergone allogeneic hematopoietic cell transplantation. This effort has resulted in long-term survival for a significant percentage.284,285
One question that often arises in patients with MDS, especially in those with advanced disease, is whether leukemic induction therapy should be pursued prior to hematopoietic cell transplantation. Due to the extremely poor outcome and difficulty in successfully inducing patients with MDS into remission, most transplant centers prefer to proceed directly to transplantation without prior chemotherapy.286 Treatment of MDS patients with chemotherapy increases the risk of further complications such as infection and tissue damage. Patients with MDS are chronically immunosuppressed and are at increased risk for a variety of occult infections, including fungal infections. For patients who relapse, small numbers have undergone donor leukocyte infusions (see “Treatment and Prevention of Relapse”), with occasional responses.19,287,288
These studies indicate that a subset of MDS patients can be cured following allogeneic hematopoietic cell transplantation. This observation is in contrast to all other treatment modalities that have been evaluated for this difficult disease. However, because of the advanced age of the majority of MDS patients, only a small percentage of patients are candidates for transplantation. The development of less toxic preparative regimens capable of inducing a state of mixed chimerism may allow for the treatment of older patients with this disorder, especially those patients with relatively indolent disease. However, this novel concept requires further evaluation.
Autologous hematopoietic cell transplantation has been attempted in some patients with MDS. However, it has been evaluated in only limited numbers of patients due to the low CR rates obtained with induction chemotherapy. Therefore, any positive results are tempered by the fact that these patients are highly selected. Nevertheless, efforts have been made to develop strategies to collect normal stem cells in these patients. The use of in vivo mobilization and purging, similar to the strategy used in CML, has been attempted in small numbers of patients with defined karyotypic abnormalities. Karyotypically normal leukapheresis products were collected from six of nine patients following recovery from intensive chemotherapy.265 Results of autologous transplantation for 79 patients with MDS or secondary AML who were successfully induced into CR revealed a disease-free survival of 39 percent at 2 years.289 Therefore, autologous transplantation may be considered for those unusual patients who are successfully induced into CR and who do not have an HLA-matched donor.
MYELOPROLIFERATIVE DISORDERS
Patients with myeloproliferative disorders other than CML are occasionally considered for BMT. The variability of these disorders, as well as the small number of patients who have undergone hematopoietic cell transplantation, make it difficult to come to firm conclusions. Due to the relatively favorable prognosis of patients with polycythemia vera, there has been no role for BMT except for those patients who progress to acute leukemia. Occasionally, patients with myelofibrosis are suitable candidates for hematopoietic cell transplantation, although the decision of when to consider transplantation is often difficult. The presence of marrow fibrosis has been associated with delayed engraftment.290 Nevertheless, occasionally patients demonstrated that long-term remission can be achieved in this disorder. It is interesting to note that, following the transplant, the marrow fibrosis resolves over a period of several months.291
The reported experience with 12 patients with agnogenic myeloid metaplasia further supports the view that allogeneic hematopoietic cell transplantation can be effective in patients with this disease.292 With a median follow-up of 25 months, the 4-year overall survival was 71 percent and event-free survival was 59 percent, despite the fact that these patients were heavily pretreated. Other reports also have documented the potential utility of allogeneic hematopoietic cell transplantation for the treatment of myeloproliferative disorders other than CML.
SEVERE APLASTIC ANEMIA
Allogeneic hematopoietic cell transplantation has been extensively evaluated in patients with severe aplastic anemia. The largest single-center experience in this disease comes from Seattle, where a number of reports have highlighted the progressive increase in survival achieved by utilizing improved regimens for prophylaxis for graft-versus-host disease and the addition of antithymocyte globulin (ATG) to the preparative regimen. Using cyclophosphamide and ATG in the preparative regimen has resulted in approximately 90 percent disease-free survival for patients with severe aplastic anemia who underwent hematopoietic cell transplantation with marrow derived from an HLA-matched sibling donor.294 A recent update demonstrates that those patients continue to enjoy excellent long-term disease-free survival, with an actuarial estimate of survival of 92 percent at 8 years posttransplantation.295 Excellent long-term results have also been observed from other groups of investigators using similar approaches.296
A report from the International Bone Marrow Transplantation Registry has highlighted continued improvements in the treatment of severe aplastic anemia patients using hematopoietic cell transplantation. In this study of 1305 patients who had undergone allogeneic hematopoietic cell transplantation between 1976 and 1992 and were reported to the registry, survival was compared in three different intervals between the years 1976 and 1980, 1981 and 1987, and 1988 and 1992. Five-year survival increased from 48 percent for the earliest cohort of patients to 66 percent for those patients transplanted between 1988 and 1992.297 The improvements in disease-free survival were due mainly to reductions in mortality in the first 3 months following hematopoietic cell transplantation, with the introduction of cyclosporine being the most important factor.
Improvements have also occurred in the therapy of severe aplastic anemia with immunosuppressive agents without hematopoietic cell transplantation. There are no prospective randomized trials comparing immunosuppressive therapy with hematopoietic cell transplantation. However, several studies have attempted to compare historical results achieved with hematopoietic cell transplantation to immunosuppressive therapy with ATG or more recently ATG, cyclosporine, and prednisone. The advantage of the immunosuppressive approach is that it can be applied to all patients and does not carry the risk of graft-versus-host disease. The difficulties with this analysis are the long follow-up required; the variability of the patients treated with the two approaches, with the more severely affected patients generally being referred for BMT; and the overall improvements ongoing with both treatments. Nevertheless, a number of retrospective analyses have been performed. Of 155 patients who were treated with ATG, 71 percent of patients with moderate aplastic anemia were alive at 6 years, compared to 48 percent of patients with severe aplastic anemia and 38 percent of patients with very severe aplastic anemia.298 When the outcomes of BMT for patients with severe and very severe aplastic anemia were compared, no significant differences were noted. However, it was clear from the analysis that patients who were transplanted in the more recent era, 1984 to 1989, had an overall survival of 72 percent, compared to 43 percent for those patients transplanted prior to 1984. A similar result was found in children. Estimated survival rates for pediatric patients who underwent transplantation were 75.6 percent, compared to 73.8 percent for those patients who underwent immunosuppressive therapy.299
In a retrospective study of 395 patients with severe aplastic anemia, actuarial survival at 15 years was 69 percent for the patients who underwent BMT, compared to 38 percent for patients who received immunosuppressive therapy (Fig. 18-6).300 The quality of life of patients who underwent hematopoietic cell transplantation was recently reviewed with up to 26 years of follow-up. Two hundred twelve patients who survived for more than 2 years were studied in greater detail. Survival at 20 years was 69 percent for those patients who developed chronic graft-versus-host disease, compared to 89 percent for those patients who did not.301 It is interesting to note that at least half of the patients preserved or regained the ability to become pregnant or father a child. This fact is in marked contrast to other patients who undergo hematopoietic cell transplantation with more aggressive regimens for malignant diseases.

FIGURE 18-6 Historical comparison of long-term results of allogeneic marrow transplantation and immunosuppressive therapy for patients with severe aplastic anemia. (From K Doney et al,300 with permission.)

A significant long-term problem that has been identified following successful treatment for severe aplastic anemia has been the development of new malignancies. The 10-year cumulative risk of developing new cancers following therapy was 18.8 percent after immunosuppressive therapy and 3.1 percent after BMT.302 Another series of 700 patients transplanted for severe aplastic anemia or Fanconi anemia was subsequently reported. In this cohort of patients, 23 developed a new malignancy at a median of 91 months following hematopoietic cell transplantation. The actuarial estimate at 20 years was found to be 14 percent.303 In the patients who were transplanted and did not have Fanconi anemia, the major risk factors were the use of azithioprine for prevention or therapy of graft-versus-host disease and total-body irradiation in the preparative regimen. Since neither of these approaches is any longer routinely utilized in the treatment of severe aplastic anemia with hematopoietic cell transplantation, it is reasonable to expect the risk of new malignancies to drop with subsequent cohorts of patients.
CHRONIC LYMPHOCYTIC LEUKEMIA
Patients with CLL are generally elderly and, due to the relatively benign course of the disease, until recently generally have not been considered candidates for transplantation. With improvements in long-term survival of patients with other diseases of B-cell origin, such as lymphoma and multiple myeloma, and with the reduction in procedure-related morbidity and mortality, especially with autologous hematopoietic cell transplantation, an increasing number of patients are being considered for transplantation for CLL. Both allogeneic and autologous hematopoietic cell transplantations have been explored. In CLL, patient selection is of primary importance. This limits the interpretation of results with transplantation.
One of the first reports was a study of 17 patients with a median age of 40 years who underwent allogeneic hematopoietic cell transplantation. The preparative regimen consisted of fractionated total-body irradiation and cyclophosphamide, with additional chemotherapy given to some patients. With follow-up of 2 years, nine patients were alive and in continued remission.304 An additional eight patients were prepared with fractionated total-body irradiation and cyclophosphamide and underwent transplantation with HLA-matched sibling donor marrow. Seven of these patients entered CR, and six of them were alive and free of disease at the time of the report; however, follow-up was only approximately 1 year.305 Similar results were reported elsewhere.306 These studies demonstrate the feasibility of performing allogeneic hematopoietic cell transplantation in patients with CLL and underscore the important finding that the majority of patients enter CR following the treatment, something that is rarely observed with conventional chemotherapy. However, patient selection, the limited number of patients treated, and the short follow-up limit the interpretation of these findings. Larger studies that utilize uniform criteria for patient selection are in progress.
Autologous hematopoietic cell transplantation has also been explored in patients with CLL. Again, the criteria used to select patients were variable and in some instances not reported, complicating the interpretation of the results. In some studies, the stem-cell grafts were treated in an effort to purge CLL cells, and the methodology used varied among centers. In one report of 12 patients who underwent autografting with marrow purged with MoAb and complement, 10 achieved CR.305 A follow-up study evaluating minimal residual disease using PCR demonstrated that persistence of PCR positivity following either autologous or allogeneic transplantation was correlated with a high risk of subsequent relapse.307 Clearly, much work still needs to be done in order to determine the role of hematopoietic cell transplantation in the treatment of patients with CLL.
LYMPHOMA
Hematopoietic cell transplantation for patients with lymphoma has met with considerable success. The most extensive experience has been utilizing autologous hematopoietic cell transplantation in patients with relapsed intermediate-grade lymphoma. A number of phase II studies have documented improved disease-free survival for patients with chemosensitive relapses who underwent autologous hematopoietic cell transplantation, with disease-free survival ranging from 20 to 60 percent.67,68,308,309,310,311,312 and 313
A criticism of these studies has been the lack of control groups and the possibility that the improved results were due to patient selection. To address these issues, a prospective randomized clinical trial utilizing an intention-to-treat analysis has been performed. In this study, called the PARMA trial, a total of 215 patients were enrolled, of whom 109 patients (58%) had a response to combination chemotherapy and were randomized to either an additional cycle of chemotherapy or autologous hematopoietic cell transplantation. At 5 years of follow-up, event-free survival was 46 percent in the transplant group and 12 percent in the chemotherapy group (p = 0.001). Overall survival was 53 percent for the transplant group and 32 percent for the chemotherapy group (p = 0.038), mainly due to the fact that some of the patients in the chemotherapy group could be salvaged upon relapse with stem-cell transplantation (Fig. 18-7).314 These results have clearly documented the benefit for autologous hematopoietic cell transplantation for patients with chemosensitive relapsed lymphoma. With the introduction of peripheral-blood progenitor cells, transplant-related morbidity and mortality have decreased considerably.315 In addition, techniques have been developed to purge peripheral-blood progenitor cells and reduce tumor burden, as discussed above. These advances are likely to result in additional improvements in results with transplantation.

FIGURE 18-7 Results of a prospective randomized controlled trial comparing autologous transplantation with conventional chemotherapy for patients with chemotherapy-sensitive relapsed lymphoma. (From T Philip,314 with permission.)

A significant problem in the application of hematopoietic cell transplantation to patients with relapsed lymphoma has been the high level of drug resistance observed in this patient population. Since approximately 40 percent of patients with lymphoma enjoy long-term disease-free survival with standard chemotherapy,316 attempts have been made to predict which patients are at high risk for relapse based upon clinical parameters of their disease at presentation. A large international effort has produced such a scoring index, based upon age, tumor stage, serum lactate dehydrogenase, performance status, and number of extranodal disease sites, which identified four risk groups.317
Autologous hematopoietic cell transplantation has been pursued in patients as up-front therapy, and it has been observed that patients with high-risk disease appeared to benefit from the procedure.318,319 Randomized prospective clinical trials to formally test this hypothesis are underway.
In a randomized trial of 916 patients with lymphoma who achieved CR, the patients were assigned to either sequential chemotherapy or autologous hematopoietic cell transplantation. In the first analysis of this study, no differences were observed.320 Subsequent analysis with additional follow-up revealed a significant 5-year disease-free survival rate for the higher-risk patients, with 57 percent of the transplanted patients and 39 percent of the patients treated with chemotherapy (p = 0.01) alive and free of disease.321 This observation not only helps guide therapy but also demonstrates the requirement for adequate follow-up to observe differences in outcome when relapse is the major cause for treatment failure. In addition, further analysis of the PARMA trial based upon the international prognostic index demonstrated benefit primarily for patients with at least one high-risk feature.322
Other studies have also addressed this issue. Utilization of autologous hematopoietic cell transplantation in patients with a slow response to conventional chemotherapy did not result in improved disease-free survival.323 Another approach utilized high doses of sequential chemotherapy followed by autologous hematopoietic cell transplantation in comparison to conventional chemotherapy with MACOP-B (see Chap. 103) for patients with aggressive lymphoma. In this study, event-free survival was 76 percent for the transplanted patients versus 49 percent for the patients who received chemotherapy (p = 0.004).324
Hematopoietic cell transplantation has been explored in a limited number of patients with low-grade lymphoma. Due to the natural history of this disorder, extreme caution must be exercised in the interpretation of the data because of the requirement for many years of follow-up. There are no randomized studies comparing hematopoietic cell transplantation to conventional therapy in this histologic subtype of lymphoma. Nonetheless, both autologous and allogeneic hematopoietic cell transplantations have been utilized in selected patients with this disorder.
Autologous hematopoietic cell transplantation has been explored in patients with both recurrent and first-CR low-grade lymphoma. At least three studies have reached 4 or more years of follow-up with between 40 and 50 percent disease-free survival and 65 to 70 percent overall survival rates.325,326 and 327 Although no randomized study has been performed, patients who received an autologous purged marrow transplant prepared with fractionated total-body irradiation and cyclophosphamide have been compared to a historical cohort of patients treated with chemotherapy who were matched for disease status characteristics. There were no survival differences; however, those patients who underwent transplantation had improved freedom from progression.325
Allogeneic hematopoietic cell transplantation has also been utilized in patients with relapsed low-grade lymphoma. In an initial study of 10 patients with chemotherapy-refractory and recurrent low-grade lymphoma, 8 patients achieved CR without relapse for over 2 years.328 A larger experience of 113 patients transplanted at 50 different centers reported to the International Bone Marrow Transplantation Registry reported three year probability of disease-free survival of 49%. Those patients with Karnofsky performance status greater than 90 percent, chemotherapy-responsive disease, age below 40, and preparation with a total-body irradiation–based regimen fared better. In another small study of 28 patients comparing allogeneic to autologous hematopoietic cell transplantation, those patients who underwent allogeneic transplantation had a much lower relapse rate (0% versus 93%; p = 0.002) and improved progression-free 2-year survival (68% versus 22%; p = 0.049).330 Therefore, allogeneic hematopoietic cell transplantation should be considered for patients with relapsed low-grade lymphoma who have an HLA-matched sibling donor.
In studies of the use of autologous hematopoietic cell transplantation with purged marrow in patients with low-grade lymphoma in first CR or partial remission, excellent disease-free survival was reported, and after 5 years of follow-up approximately 85 percent of patients were alive.331,332 Clearly, continued observation of transplanted patients and randomized trials are required to determine clinical benefit in this indolent yet life-threatening disease.
Mantle-cell lymphoma has emerged as a more commonly diagnosed subtype of lymphoma. These patients respond poorly to standard-dose chemotherapy, and many are elderly.333 Several studies utilizing autologous hematopoietic cell transplantation have been reported, with widely variable results, depending primarily on the remission status of the patients prior to transplantation. In one study of 28 patients, 8 of whom were in first CR, the estimated 4-year disease-free survival was only 31 percent.334 Similar results were reported in another investigation.335 In contrast, others have reported much more optimistic results in this disorder.322,336,337 and 338 Clearly, additional studies are required to better define the role of autologous hematopoietic cell transplantation in this disorder. However, it appears clear that, if transplantation is to be considered, it should be pursued early in the clinical course of the disease.
Burkitt’s lymphoma is successfully treated with standard chemotherapy in the majority of cases; however, patients with recurrent disease can be salvaged with autologous hematopoietic cell transplantation.318,339,340
Patients with advanced-stage lymphoblastic lymphoma have a poor outcome with standard chemotherapy, and autologous hematopoietic cell transplantation has been successful in patients in first CR and patients with chemosensitive relapse.341,342 and 343 Allogeneic hematopoietic cell transplantation has been applied to limited numbers of patients with lymphoma, as discussed above. Similar to other diseases, the relapse rate is generally lower following allogeneic hematopoietic cell transplantation; however, overall survival is offset by the increased risk of procedure-related complications. In patients with high-risk lymphoblastic lymphoma, results with allogeneic hematopoietic cell transplantation are similar in first CR but appear to be superior to autologous hematopoietic cell transplantation in patients with recurrent disease.341,344
HODGKIN’S DISEASE
Since the majority of patients with Hodgkin’s disease respond well to chemotherapy, hematopoietic cell transplantation has been reserved for patients who do not enter CR (induction failures) and for patients with relapsed disease. The development of a prognostic score in Hodgkin’s disease may allow for the identification of a high-risk group of patients in whom hematopoietic cell transplantation could be considered in first CR.345 Patients with induction failures respond poorly to standard chemotherapy, and 35 to 50 percent of such patients can be salvaged with autologous hematopoietic cell transplantation.346,347,348,349 and 350
Patients who relapse following chemotherapy fare poorly.351 A number of studies have addressed the issue of whether high-dose therapy with autologous hematopoietic cell transplantation can improve the outcome for these patients. Both radiation-containing and chemotherapy-only preparative regimens have been utilized. Four studies of more than 100 patients have been reported with greater than 3-year progression-free survival of 25 to 50 percent.349,352,353 and 354 As in all phase II studies, there is the potential for patient selection that may bias results. Matched case-control analyses have been performed comparing 60 patients who underwent autologous hematopoietic cell transplantation at Stanford University with a group of patients selected with similar clinical characteristics from a database. Overall survival, event-free survival, and freedom from progression at 4 years favored the patients who underwent transplantation (overall survival 54% versus 47%, p = 0.25; event-free survival 53% versus 27%, p < 0.01; freedom from progression 62% versus 32%, p < 0.01).355
There has been only one prospective randomized clinical trial in which autologous hematopoietic cell transplantation was compared to salvage chemotherapy. Patients with relapsed or refractory Hodgkin’s disease were randomized to receive mini-BEAM, which was the conventional dose arm, or to receive the same drugs at higher doses followed by autologous hematopoietic cell transplantation. At 3 years, event-free survival favored the patients who received the higher doses of BEAM.356
MULTIPLE MYELOMA
High-dose therapy and hematopoietic cell transplantation has been used in the treatment of patients with multiple myeloma. Since the majority of patients respond to standard-dose chemotherapy, the concept of using high-dose therapy to treat multiple myeloma is intellectually attractive. The use of high-dose therapy followed by autologous hematopoietic cell transplantation has been studied, and response rates of 60 to 80 percent and CR rates of 20 to 75 percent have been documented.357,358,359,360,361 and 362 High-dose sequential chemotherapy similar to that used in patients with lymphoma also has been applied to patients with multiple myeloma, with a CR achieved in 10 of 13 patients (77%). Overall survival using this approach was superior to that of historical controls.363 Tandem autologous transplants utilizing high-dose melphalan followed by fractionated total-body irradiation and melphalan has been explored. In one study of 496 newly diagnosed patients, 95 percent completed the first transplant with high-dose melphalan (200 mg/m2), and 73 percent completed the second transplant with fractionated total-body irradiation and melphalan. Complete remission was achieved in 36 percent, with 7 percent treatment-related mortality.364 Median event-free survival and overall survival were 26 and 41 months, respectively, with low b2-microglobulin and C-reactive protein being the most significant prognostic factors associated with prolonged event-free survival. In a subsequent analysis, 123 previously untreated patients who underwent this treatment strategy and also received interferon-a following hematopoietic cell transplantation were compared to 1123 matched patients drawn from clinical trials. The event-free survival was 49 months for the transplanted patients, compared to 22 months (p = 0.0001) for historical patients who had standard chemotherapy. Overall survival was also prolonged (62 versus 48 months; p = 0.01).365 These results have recently been updated and confirmed.366 In the meantime, the use of historical control patients has been challenged in another analysis. The median survival of patients with multiple myeloma who are considered candidates for hematopoietic cell transplantation was found to be 5 years, similar to that achieved with hematopoietic cell transplantation.367 High-dose therapy with autologous hematopoietic cell transplantation has also been utilized in patients with late-stage multiple myeloma and found to be primarily of benefit early in the course of the disease.368,369
Two hundred previously untreated patients with multiple myeloma less than 65 years of age were randomized to receive either conventional chemotherapy or high-dose therapy and autologous hematopoietic cell transplantation. Analysis was performed on an intent-to-treat basis with 75 of the 100 patients randomized to undergo hematopoietic cell transplantation actually receiving the therapy. Complete remission was achieved in 22 percent of the hematopoietic cell transplantation patients and 5 percent of the patients treated with conventional chemotherapy. At 5 years, both event-free survival (28% versus 10%; p = 0.01) and overall survival (52% versus 12%; p = 0.03) was superior for patients undergoing hematopoietic cell transplantation, with similar treatment-related mortality for the two groups of patients (Fig. 18-8).370 This seminal study has demonstrated the clinical benefit of hematopoietic cell transplantation in multiple myeloma; however, in contrast to studies in other disorders, it is not clear whether patients are in fact cured of their disease, since a plateau state has not been reached and patients continue to relapse. Therefore, additional approaches are needed to address the minimal residual disease state achieved by hematopoietic cell transplantation.

FIGURE 18-8 Prospective randomized trial of autologous transplantation compared to conventional chemotherapy for patients with newly diagnosed multiple myeloma. (From M Attal et al,370 with permission.)

To improve upon the results obtained with hematopoietic cell transplantation in multiple myeloma, a number of approaches have been explored. Since clonal B cells are readily detected in the marrow and peripheral-blood progenitor-cell collections obtained from these patients,371,372 and 373 a number of techniques have been explored to decrease the tumor burden in the graft. The use of monoclonal antibody– and complement-based methods has demonstrated that the marrow samples can be depleted of antigen-positive cells below the limits of detection of cell sorting (approximately 1%).374 Positive stem-cell collection has also been pursued in this disease by CD34+ cell columns or by FACS to purify the CD34+Thy1+ stem cells. A randomized trial comparing CD34+ selected versus unmanipulated grafts has been performed, with preliminary results showing equivalent engraftment, no change in infection risk, and similar event-free survival, although further follow-up is required to evaluate any impact on relapse rates and survival.375
In another approach, interferon-a has been used following hematopoietic cell transplantation, since this agent has shown efficacy in some studies following standard chemotherapy. In one randomized study of 85 patients, no differences in progression-free survival in the two groups were noted.376 Vaccination is an attractive concept, since the immunoglobulin produced is monoclonal and may be recognizable by the immune system. Healthy sibling donors have been shown to have anti-idiotypic responses that could be transferred to the recipient.377 Idiotypic vaccination has also been explored in the autologous setting by isolating the patient’s idiotype protein, pulsing dendritic cells, and reinfusing the pulsed dendritic cells into the patient. Immune responses against the paraprotein have been observed in a minority of patients.378
Allogeneic hematopoietic cell transplantation has also been pursued in patients with multiple myeloma in an effort to exploit a graft-versus-myeloma effect.379 Results have generally been disappointing because of significant transplant-related mortality.380,381 A retrospective case-matched analysis comparing allogeneic versus autologous hematopoietic cell transplantation in multiple myeloma has been performed. Overall survival was superior for autologous hematopoietic cell transplantation (46 months for autologous, 30 months for allogeneic; p = 0.0003), mainly due to higher treatment-related mortality following allogeneic hematopoietic cell transplantation (41% versus 13%; p = 0.0001).382 In addition, late relapses continue to be observed following allogeneic hematopoietic cell transplantation. These results have limited the application of allogeneic hematopoietic cell transplantation to patients with multiple myeloma. Other approaches utilizing either T-cell–depleted allogeneic hematopoietic cell transplantation or nonmyeloablative approaches with reduced toxicity are worthy of further exploration.
SOLID TUMORS
High-dose chemotherapy and autologous hematopoietic cell transplantation have been employed in a number of solid tumors, with the largest experience being in patients with breast cancer. Autologous hematopoietic cell transplantation has been explored in both metastatic and high-risk primary stages II and III disease. Studies in patients with metastatic breast cancer have demonstrated CR rates of 45 to 60 percent and long-term disease-free survival in 15 to 25 percent of patients.383,384,385 and 386 A small randomized study demonstrated a modest benefit for patients who received high-dose as opposed to conventional-dose chemotherapy.387 Larger randomized trials are currently in progress. Limited numbers of patients with metastatic breast cancer have undergone allogeneic hematopoietic cell transplantation, and evidence of graft-versus-tumor effect has been observed.388
High-dose chemotherapy and autologous hematopoietic cell transplantation has also been evaluated in patients with high-risk breast cancer, defined as stage II with 10 or more positive axillary lymph nodes or stage III disease. Patients undergoing autologous hematopoietic cell transplantation appear to have improved survival compared to historical control subjects.80,386 Two large randomized trials that should help provide more definitive evidence of the potential efficacy of autologous hematopoietic cell transplantation in this clinical setting are in progress. High-dose chemotherapy with autologous hematopoietic cell transplantation has also been explored in breast cancer patients with four to nine axillary lymph nodes, with promising results.389 A randomized study comparing high-dose therapy with autologous hematopoietic cell transplantation to conventional, albeit high-dose, therapy without transplantation is currently being performed.
Autologous hematopoietic cell transplantation has also been utilized in patients with recurrent or refractory ovarian cancer, with disease-free survival rates of approximately 10 to 33 percent.390,391 Ongoing studies continue to evaluate this form of therapy in patients earlier in the course of this disease. Patients with recurrent or refractory germ-cell tumors have also undergone autologous hematopoietic cell transplantation.392 In one recent study of 21 patients, 52 percent are alive and free of disease.393
In pediatric patients, the use of autologous hematopoietic cell transplantation has resulted in prolonged disease-free survival in patients with advanced stage, poor-prognosis neuroblastoma who are not likely to be cured with standard therapy.394,395,396 and 397 Since neuroblastoma cells can be found in the marrow and blood progenitor cells, strategies have been developed to “purge” these stem-cell products.396,398
FANCONI ANEMIA
Early attempts at hematopoietic cell transplantation for the treatment of Fanconi anemia with high-dose cyclophosphamide resulted in unacceptable toxicity and only modest success rates of 20 to 50 percent.399,400 Improved outcomes have been reported utilizing much lower doses of cyclophosphamide combined with low-dose total-body irradiation401 or without total-body irradiation.402 All potential related marrow donors must be screened for chromosomal changes indicative of Fanconi anemia. Patients with Fanconi anemia appear to be at increased risk of developing malignancies following hematopoietic cell transplantation. In one study of 79 patients with this disorder, the actuarial risk of developing any malignancy by 20 years after hematopoietic cell transplantation was 42 percent.303
THALASSEMIA
Hematopoietic cell transplantation has been very successful for the treatment of selected patients with severe thalassemia who have an HLA-matched sibling donor. In one report of 222 patients who underwent allogeneic hematopoietic cell transplantation, event-free survival of 75 percent was achieved.403 Patients with hepatomegaly and portal fibrosis had a worse outcome. Those individuals with both of these risk factors had an event-free survival of 61 percent, compared to an event-free survival of 94 percent for those patients without either of these problems.403 Initial results of allogeneic hematopoietic cell transplantation in thalassemic patients more than 16 years of age were poor. However, refinements have resulted in improved outcomes, with event-free survival of approximately 75 percent.404,405
SICKLE CELL ANEMIA
The eradication of sickle cell anemia in an 8-year-old child who underwent allogeneic hematopoietic cell transplantation for AML was reported in 1984.406 Since then, several reports have appeared detailing the use of allogeneic hematopoietic cell transplantation to treat this disorder. The major challenge has been in identifying patients with sufficiently advanced disease to warrant accepting the risks inherent in allogeneic hematopoietic cell transplantation, yet not so far advanced that they are unable to tolerate the procedure. In one study of 22 children with symptomatic sickle cell disease who were under 16 years of age and had an HLA-matched sibling donor, 20 patients were alive at a median follow-up of 2 years. Sixteen of the patients had stable engraftment of donor hematopoietic cells. Actuarial estimates of event-free survival at 4 years was 73 percent.407,408 A larger study of 50 patients with this disorder reported similarly impressive results.409 Further exploration in this area is clearly warranted.
IMMUNODEFICIENCY SYNDROMES AND INHERITED METABOLIC DISORDERS
A variety of other diseases have been treated with allogeneic hematopoietic cell transplantation. In fact, one of the first successful reports of a marrow transplant procedure was for the treatment of children with immunodeficiency syndromes in 1968.7,8 and 9 Hematopoietic cell transplantation has become the treatment of choice for patients with severe combined immunodeficiency disorder (SCID), with success rates of 70 to 80 percent.410 It is interesting to note that patients with SCID do not require conditioning prior to allogeneic hematopoietic cell transplantation but generally need some form of immunosuppression to avoid graft rejection if T-cell depletion is performed. Unrelated donor transplants have also been performed to treat SCID patients.411,412 Long-term follow-up of 193 SCID patients who underwent allogeneic hematopoietic cell transplantation was recently reported. At 6 months following transplantation, 116 patients (60%) were alive. Normal T-cell function was achieved at a median of 8.7 months following the transplant procedure, while normal B-cell reconstitution required a median of 14.9 months.413
Allogeneic hematopoietic cell transplantation has also been utilized in an effort to correct a wide array of other inherited metabolic disorders. These disorders include Gaucher’s disease, mucopolysaccharidosis (Hurler’s syndrome), metachromatic leukodystrophy, infantile osteopetrosis, and congenital erythropoietic porphyria.414,415,416 and 417
AUTOIMMUNE DISORDERS
Considerable interest has centered around the application of hematopoietic cell transplantation to the treatment of autoimmune disorders. Studies in animal models have demonstrated the potential for this treatment modality, as have anecdotal reports of patients with concomitant autoimmune disorders who underwent hematopoietic cell transplantation for treatment of another disease and appeared to derive benefit. Other reports have appeared, however, that have shown early recurrence or no effect on the autoimmune disease.418 Studies designed for direct evaluation of the effect of hematopoietic cell transplantation on autoimmune disorders are underway. Early reports using autologous hematopoietic cell transplantation for the treatment of multiple sclerosis and other autoimmune diseases have been encouraging.419,420 Clearly, further evaluation is required. Major questions concerning the source of the graft (allogeneic versus autologous), preparative regimen, and the requirement for and extent of T-cell depletion in the autologous setting all need to be addressed with carefully conducted clinical trials.
COMPLICATIONS AND THEIR MANAGEMENT
GRAFT-VERSUS-HOST DISEASE
Graft-versus-host disease remains one of the most serious and challenging complications following hematopoietic cell transplantation. Graft-versus-host disease results from immunologically competent donor-derived T cells that react with recipient tissue antigens. In 1966, Billingham formulated the requirements for developing graft-versus-host disease, including (1) the graft must contain immunologically competent cells; (2) the recipient must express tissue antigens not found in the donor; and (3) the recipient must be immunologically suppressed enough that an effective response against the transplanted cells cannot be made.421 Risk factors for developing graft-versus-host disease include HLA disparity between donor and recipient, age, gender disparity, type and status of underlying disease, and prophylaxis utilized.
By definition, acute graft-versus-host disease occurs prior to day 100, while chronic graft-versus-host disease occurs beyond day 100. Graft-versus-host disease primarily affects three organs: the skin, gastrointestinal tract, and liver. A severity system ranging between grades 0 and IV has been established that takes into account the degree of involvement of each organ system and defines an overall grade between II and IV for clinically significant disease. Graft-versus-host disease is a clinical diagnosis, although tissue biopsy results can be helpful in making a definitive diagnosis. However, severity on pathological specimens must always be tempered by an assessment of the clinical condition of the patient.
Clinically significant acute graft-versus-host disease occurs in 9 to 50 percent of patients who receive an allogeneic hematopoietic cell transplant from a histocompatible sibling donor. Patients who develop moderate (grade II) to severe (grades III–IV) acute graft-versus-host disease have a significantly enhanced risk of mortality. Established acute graft-versus-host disease is difficult to treat, and intensive efforts have been extended toward prophylaxis. Two general approaches have been utilized in an effort to prevent acute graft-versus-host disease, namely, immunosuppressive medications and T-cell depletion.
A number of different drugs have been utilized as prophylaxis against graft-versus-host disease. Methotrexate, cyclosporine, and prednisone have been the mainstays of prophylaxis, generally in combination. A series of randomized clinical trials have established cyclosporine given over at least 6 months and methotrexate administered on days 1, 3, 6, and 11 following the transplant as an effective regimen.422,423 Subsequent updates of these studies have documented that effective prophylaxis with cyclosporine/methotrexate did not result in a significant increase in the risk of relapse, which is always a concern with any agent that prevents acute graft-versus-host disease.424
In an initial prospective study, cyclosporine and prednisone prophylaxis resulted in a reduced rate of grade II to IV graft-versus-host disease of 28 percent, compared to methotrexate and prednisone.425 The regimen of cyclosporine/prednisone was compared to methotrexate/prednisone, with the methotrexate administered on days 1, 3, and 6 in a randomized trial and with all patients receiving the preparative regimen of fractionated total-body irradiation and etoposide. Patients who received the two-drug regimen had an incidence of grade II to IV graft-versus-host disease of 23 percent, compared to 9 percent for patients who received the three-drug regimen (p = 0.02).426 No differences in the relapse rate of the risk of chronic graft-versus-host disease were observed in the two groups.427 A trial comparing cyclosporine/methotrexate to the three-drug regimen is underway.
Tacrolimus (FK506) has also been utilized to prevent acute graft-versus-host disease. Prospective randomized clinical trials have been performed in the setting of an HLA-matched sibling and matched unrelated allogeneic hematopoietic cell transplantation. In the former study, 329 patients from 16 transplant centers were randomized to receive FK506 or cyclosporine, with both groups also receiving methotrexate. The incidence of grade II to IV acute graft-versus-host disease was significantly lower in the group of patients randomized to FK506 (31.9% versus 44.4%, respectively; p = 0.01).428 No differences in severe (grade III–IV) acute graft-versus-host disease, chronic graft-versus-host disease, or relapse rates were noted. However, paradoxically, 2-year disease-free survival was superior in the cyclosporine arm, a result thought to be due to a larger number of patients with advanced disease randomized to receive FK506.
FK506 has also been utilized with methotrexate for the prevention of acute graft-versus-host disease in the unrelated donor setting. Phase II studies have resulted in a 42 to 50 percent incidence of grade II to IV acute graft-versus-host disease, which appears promising.429,430 In a randomized trial, 136 patients received either FK506 or cyclosporine-based regimens. For those 69 patients who received unrelated donor transplants, the incidence of acute graft-versus-host disease was reduced from 51.4 percent in the cyclosporine group to 20.6 percent in the FK506 group (p < 0.05).431 These results will require confirmation in a larger group of patients but are consistent with a reduction in the incidence of acute graft-versus-host disease with the use of FK506 over cyclosporine.
An alternative approach to the prevention of graft-versus-host disease has been to deplete donor T cells from the graft prior to infusion. A variety of techniques have been employed, including physical separation such as elutriation or density gradient centrifugation, MoAb-based depletion, or CD34+ cell selection. As discussed above, extensive removal of donor derived T cells has been very effective in eradicating graft-versus-host disease but has been associated with an unacceptably high risk of graft rejection and relapse.15,254,432,433,434 and 435 Modifications of T-cell depletion that result in only partial removal have met with considerable success.
Thirty-nine patients with AML underwent T-cell depletion utilizing the soybean lectin agglutination and sheep red blood cell rosetting, which results in approximately a 3-log depletion of T cells. They were prepared for transplantation with fractionated total-body irradiation, thiotepa, and cyclophosphamide, with many also receiving additional immunosuppression with antithymocyte globulin. No cases of rejection or acute graft-versus-host disease were noted. Disease-free survival at a median follow-up of 4 years or more was 77 percent for patients treated in first remission and 50 percent for patients who underwent hematopoietic cell transplantation in second remission.436
Partial T-cell depletion with monoclonal antibodies resulted in significant reductions in graft-versus-host disease without a high incidence of graft failure or relapse.437,438 and 439 Patients who receive T-cell–depleted hematopoietic cell transplantation are at higher risk of Epstein-Barr virus–associated lymphoproliferative disease and have delayed T-cell reconstitution, which is especially true in adults, presumably due to thymic involution.440
A somewhat different approach is the use of CAMPATH antibodies in which an IgM (CAMPATH-IM) is used for in vitro depletion of the graft and an IgG (CAMPATH-IG) is used for in vivo depletion of the recipient prior to graft infusion. Fifty patients treated with CAMPATH antibodies were compared to 459 patients reported to the International Bone Marrow Transplantation Registry who received nondepleted grafts and conventional graft-versus-host disease prophylaxis with cyclosporine/methotrexate. The incidence of acute graft-versus-host disease, chronic graft-versus-host disease, and transplant-related mortality were all lower in the patients who received the CAMPATH antibodies. Survival of the patients who were treated with the T-cell depletion approach was better at 6 months (92% versus 78%); however, at 5 years there was no difference (60% versus 52%).441
T-cell depletion has also been employed in the unrelated donor setting with encouraging results.256,442 Clearly, the only effective way of comparing these two very different strategies for reducing the incidence of graft-versus-host disease is through a prospective randomized clinical trial. Such a trial is underway comparing T-cell depletion using the T10B9 MoAb and complement with unmanipulated marrow in the unrelated setting.
Treatment of established acute graft-versus-host disease is often a difficult clinical problem. The mainstay of treatment of established graft-versus-host disease is corticosteroids. Dosing generally ranges between 1 to 2 mg/kg of prednisone, with subsequent tapering depending upon response. Low-dose intravenous 6-methylprednisolone (2 mg/kg per day) has been compared to high-dose (10 mg/kg per day) in 95 patients with acute graft-versus-host disease. Response in the two groups was similar (68% versus 71%), with no differences noted in evolution to grade III to IV graft-versus-host disease, CMV infection, or survival.443 A variety of other approaches have been explored in the treatment of acute graft-versus-host disease, including anti-T-cell antibodies such as ATG, OKT3 directed against CD3, BT1-322 directed against CD2 or the IL-2 receptor.293,444 Responses have been noted in many of these studies. However, progression of graft-versus-host disease occurs following discontinuation of the antibody in most of the patients. Elevated levels of cytokines, in particular tumor necrosis factor (TNF), are thought to be central to the pathogenesis of graft-versus-host disease. In murine models, anti-TNF monoclonal antibodies prevent graft-versus-host disease. The use of anti-TNF MoAb has been explored in limited clinical trials of 19 patients with moderate to severe acute graft-versus-host disease, of whom 14 responded.445
A variety of newer pharmacologic agents are under investigation for the treatment of both acute and chronic graft-versus-host disease. Mycophenolate mofetil has been explored in combination with cyclosporine and prednisone. In one study of 17 patients with established acute graft-versus-host disease who were treated with 2 g of mycophenolate mofetil per day, improvements were observed in 11 patients (65%). In addition, three of six patients with chronic graft-versus-host disease also had clinical improvements.446 Myelosuppression was the most common side effect, although discontinuation of the drug was not required by any patient.
Chronic graft-versus-host disease is another significant complication following hematopoietic cell transplantation. By definition, chronic graft-versus-host disease occurs beyond 100 days from the transplant. The clinical manifestations of chronic graft-versus-host disease are broad and resemble those of autoimmune disorders such as scleroderma and dermatomyositis.447,448 Patients with extensive chronic graft-versus-host disease have an increased mortality rate, especially patients with platelet counts less than 100,000 platelets/µl on day +100, patients who progress from acute to chronic graft-versus-host disease, patients with lichenoid changes on skin biopsy, and patients with significant liver involvement.449 Treatment for chronic graft-versus-host disease involves the use of immunosuppressive drugs, with cyclosporine or FK506 and prednisone being the mainstays of treatment.450 Due to the chronic nature of the disease, long-term treatment is often required. Alternate-day dosing has been found to help reduce some of the toxicity of the immunosuppressive medications.451
A number of other medications have been explored for the treatment of chronic graft-versus-host disease. Thalidomide, which was initially used as a sedative but abandoned because it produced phocomelia in the offspring of pregnant women taking the drug, was found to have immunosuppressive properties and has been used to treat chronic graft-versus-host disease in both adults and children, with encouraging responses observed.452,453,454 and 455 Side effects have included somnolence and constipation. It is interesting to note that thalidomide was not effective in preventing the onset of chronic graft-versus-host disease. Instead, there was a paradoxically higher incidence in patients treated with the drug in a small randomized trial.456 Psoralen plus ultraviolet radiation (PUVA) has shown encouraging results in small numbers of patients with chronic graft-versus-host disease.457 The use of etretinate, which is a synthetic vitamin A derivative, has recently been reported in a series of 32 patients with refractory sclerodermatous chronic graft-versus-host disease. Response was evaluated after 3 months, and positive effects were observed in 20 of 27 evaluable patients.458 Low-dose total lymphoid irradiation (100 cGy) has also been reported to result in significant improvement in chronic graft-versus-host disease in small numbers of patients.459
Infection, especially by gram-positive organisms, is a common problem in patients with chronic graft-versus-host disease. Monthly intravenous immunoglobulin or rotating antibiotics is sometimes helpful in patients with recurrent infections, especially patients who are hypogammaglobulinemic as a result of chronic graft-versus-host disease. Graft-versus-host disease remains a significant and often debilitating clinical problem. New approaches to the treatment of this complication are clearly needed.
VENO-OCCLUSIVE DISEASE
Veno-occlusive disease of the liver is one of the most feared complications of allogeneic and autologous hematopoietic cell transplantations. The incidence of veno-occlusive disease varies significantly from center to center, depending upon which diagnostic criteria are used.460,461 The typical signs and symptoms of veno-occlusive disease include unexplained weight gain, jaundice, right upper quadrant pain, and ascites. Definitive diagnostic tests are not available. However, reversal of hepatic blood flow, elevated hepatic wedge pressure, and elevated serum plasminogen activator inhibitor-1 have all been associated with patients who have or develop clinically significant veno-occlusive disease.462 A definitive diagnosis often requires a liver biopsy, which is frequently dangerous and impractical early after hematopoietic cell transplantation in patients with liver dysfunction. Approximately 25 to 30 percent of cases are severe, and mortality in these patients is almost universal. Patients with prior hepatic B or C infection and liver function abnormalities or those with seropositive donors are at increased risk for developing veno-occlusive disease.463,464 No single preparative regimen has been implicated as being causative in the development of veno-occlusive disease. However, a higher incidence of veno-occlusive disease appears to occur in patients who receive busulfan-containing regimens, especially if busulfan levels reach an area under the curve of greater than 1500 µmol/min per liter.72,463,465 No therapy for veno-occlusive disease has been shown in a controlled study to be effective, and, as a result, treatment of this disorder is largely supportive.
Patients with mild to moderate veno-occlusive disease may respond spontaneously without any particular treatment. In one series, for example, survival at day +100 was 91 percent with mild veno-occlusive disease and 77 percent with moderate disease.460 Most patients who recover from veno-occlusive disease of any severity regain normal liver function and do not develop sequelae of chronic liver disease, such as portal hypertension or esophageal varices. In contrast, the prognosis in patients with severe veno-occlusive disease, which occurs in 25 to 30 percent of cases, is typically poor. Such patients develop fulminant acute liver failure, coagulopathy, hepatic encephalopathy, hepatorenal syndrome, and multiorgan failure.
Attempts have been made to identify risk factors associated with disease progression and death in patients who develop clinical features of veno-occlusive disease. In one study, risk factors associated with the development of severe veno-occlusive disease at different time points following hematopoietic cell transplantation were ascertained in a cohort of 355 patients.466 This model was then validated prospectively by predicting outcomes in a separate cohort of 392 patients. A logistic regression model identified the serum bilirubin and percent weight gain within 1 to 2 weeks of hematopoietic cell transplantation as the most important independent predictors of progression to severe disease.
Treatment of established veno-occlusive disease has had limited effectiveness. Several studies have evaluated the use of recombinant tissue-type plasminogen activator (tPA) and heparin based upon the hypothesis that damage to the vascular endothelium produces localized hypercoagulability and clotting. In general, a response rate of approximately 30 to 40 percent was seen in association with a significant risk of hemorrhage.389,467,468 Based upon these findings, the authors recommended that treatment with tPA and heparin not be used in patients with severe veno-occlusive disease who already have developed multiorgan dysfunction. In most studies, the dose of tPA utilized has been relatively low, with a median of 60 mg total dose administered over 2 to 4 days followed by infusion of heparin.469 Higher-dose tPA is associated with a greater risk of bleeding and does not appear to improve response.470 Similar results have been obtained in children.468
Defibrotide is a polydeoxyribonucleotide derived from mammalian tissue with multiple antithrombotic and fibrinolytic activities.471 Defibrotide has little systemic anticoagulant activity, suggesting that it might have a therapeutic advantage over tPA and heparin. Encouraging results were obtained in a retrospective study of 19 patients with severe veno-occlusive disease and multiorgan dysfunction.472 Treatment was begun a median of 6 days after diagnosis. Defibrotide was given intravenously in doses ranging from 5 to 60 mg/kg per day for 14 days, with resolution of veno-occlusive disease in 8 patients (42%). No significant treatment-related toxicities were observed. A larger prospective study is in progress.
A number of other agents have been explored for the treatment of veno-occlusive disease. Antithrombin-III (AT-III) concentrates have been used in patients with veno-occlusive disease who have documented deficiency of this plasma protein. In one report, 10 patients with severe veno-occlusive disease and AT-III levels less than 88 percent of normal were treated with AT-III, with clinical improvement observed in all patients 1 to 10 days after beginning therapy.473
Surgical approaches also have been explored for the treatment of severe veno-occlusive disease. Insertion of a transjugular intrahepatic portosystemic stent-shunt has been performed in small numbers of patients with veno-occlusive disease, with some patients having regression of the hepatic and renal symptoms.474 Orthotopic liver transplantation has been successfully performed in selected patients with severe veno-occlusive disease475; however, the majority of patients are not capable of undergoing such a rigorous surgical procedure.
In the absence of specific effective therapy, efforts have been made to develop nontoxic prophylactic regimens to reduce the incidence and severity of veno-occlusive disease. Protocols using ursodeoxycholic acid and heparin appear promising. A pilot study and a subsequent randomized controlled trial demonstrated that ursodeoxycholic acid used prophylactically can reduce the incidence of veno-occlusive disease.476,477 In the controlled study, 67 patients undergoing allogeneic hematopoietic cell transplantation were randomized to receive ursodeoxycholic acid or placebo prior to the preparative regimen of busulfan/cyclophosphamide. The incidence of veno-occlusive disease was significantly lower in patients randomized to receive ursodeoxycholic acid (15% versus 40%; p = 0.03).
The efficacy of a low-dose continuous infusion of heparin has been evaluated in a prospective randomized clinical trial of 161 patients who underwent allogeneic or autologous hematopoietic cell transplantation. Patients were randomized to either low-dose heparin (100 units/kg total dose per day by continuous intravenous infusion) or placebo. The infusion of heparin was initiated prior to the start of the preparative regimen and continued until 30 days after hematopoietic cell transplantation. A lower incidence of veno-occlusive disease was noted in the heparin-treated group (2.5% versus 13.7%; p < 0.01); this benefit was most pronounced in those undergoing allogeneic hematopoietic cell transplantation (0 versus 18%). There was no increase in bleeding risk or other toxicities in the patients treated with heparin.478,479
A second study of heparin prophylaxis in children also found a statistically significant reduction in veno-occlusive disease for patients who received heparin prophylaxis compared to a historic control group.480 Another randomized trial did not confirm the benefit of heparin therapy; however, heparin was initiated on the day of stem-cell infusion, not at the beginning of the preparative regimen.481 Other retrospective analyses have also not found benefit for the prophylactic use of heparin.482
Treatment with low-molecular-weight heparin was associated with a lower incidence of veno-occlusive disease in a pilot study of 61 patients undergoing BMT who were randomized to receive low- molecular-weight heparin (enaxaparin 40 mg/day) or placebo from prior to conditioning until day +40 posttransplant.483
PULMONARY COMPLICATIONS
Lung toxicity is a relatively common problem following either allogeneic or autologous hematopoietic cell transplantation. The causes of lung injury or interstitial pneumonitis can be infection (bacterial or viral, e.g., CMV), chemical (BCNU, or carmustine, being the most common), bleeding, or idiopathic. Interstitial pneumonitis occurs in 10 to 15 percent of patients, the etiology of which can often be difficult to discern.484,485 Diagnostic bronchoscopy is usually required to rule out bacterial or viral (especially CMV) infection. Risk factors for developing interstitial pneumonitis include increasing age and prior history of lung irradiation.486 Idiopathic interstitial pneumonitis is typically treated with corticosteroids. Pulmonary toxicity has been associated with carmustine in patients with solid tumors and can be fatal if not treated promptly with corticosteroids, generally with a daily dose of prednisone of 1 mg/kg with weekly taper.487 Pulmonary function tests with carbon monoxide diffusion capacity measurements generally are required to confirm this diagnosis.
Diffuse alveolar hemorrhage is a clinical syndrome that generally occurs within the first 40 days following hematopoietic cell transplantation and is characterized by dyspnea, hypoxia, diffuse pulmonary infiltrates on chest x-ray, and progressive blood fluid on bronchoalveolar lavage. Diffuse alveolar hemorrhage has been reported in up to 20 percent of patients undergoing autologous hematopoietic cell transplantation, but the incidence varies significantly among transplant centers.488 Prompt treatment with high-dose corticosteroids has been successful in this disorder, which otherwise carries a high mortality risk.489
OTHER COMPLICATIONS
Cardiac complications, which can often be life threatening, can occur following hematopoietic cell transplantation.490,491 In one retrospective analysis of 170 patients, fatal cardiac toxicity, which could not be predicted with routine noninvasive cardiac evaluation, occurred in 2 percent of patients.492 Use of high doses of cyclophosphamide has been implicated in some cases of cardiac dysfunction that have occurred early in the posttransplant setting.493
Neurologic complications occur infrequently in patients undergoing hematopoietic cell transplantation but occasionally can be severe and even life threatening. Infection and drug toxicity are the usual causes of neurologic complications in this setting. Cyclosporine has been associated with neurologic toxicity, which can vary from tremor to significant neurologic effects.494,495 Ganciclovir also has been associated with neurologic toxicity.
Cystitis can occur following hematopoietic cell transplantation, usually as a consequence of high-dose cyclophosphamide. The BK strain of adenovirus has been found in the urine of some patients with hemorrhagic cystitis.158
Endocrine toxicity is a major concern, due to the high incidence of infertility and the generally young age of many patients who undergo hematopoietic cell transplantation. Sperm banking in men is an acceptable solution and should be offered to all prospective patients. Successful pregnancies after allogeneic hematopoietic cell transplantation using embryos collected prior to the transplant have been reported; however, this approach is obviously far from ideal.496
Gynecologic abnormalities, such as atrophic vaginitis and problems related to ovarian failure, are commonly observed yet can be effectively reversed with estrogen administration.497 Growth and developmental problems can occur in pediatric patients, with total-body irradiation being implicated as the likely causative agent.498 Hypothyroidism is also occasionally observed and is readily correctable with thyroid replacement therapy.499
Cataracts occur in patients who receive total-body irradiation–based preparatory regimens.62 Fractionation of the total-body irradiation reduces but does not eliminate this problem.500
Transplantation-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have occurred following both allogeneic and autologous hematopoietic cell transplantations.501 Cyclosporine has been implicated in this disorder. Withdrawal of the drug and plasmapheresis have been used as treatment; however, this complication is associated with a significant mortality risk.
SECONDARY MALIGNANCIES
The success of transplantation has led to the unfortunate realization that patients who are long-term survivors are at increased risk for second malignancies. This is especially true in patients with severe aplastic anemia and Fanconi anemia, as discussed above, but has also been observed following hematopoietic cell transplantation for a variety of malignancies. For example, following autologous hematopoietic cell transplantation for lymphoma or Hodgkin’s disease, the estimated risk of secondary MDS and AML at 5 years is 8 to 18 percent.502,503,504 and 505 Occult cytogenetic abnormalities detected in the marrow prior to stem-cell collection may help identify patients at risk for this complication.506 The chemotherapy administered to patients prior to hematopoietic cell transplantation has been implicated as a likely cause of MDS by the observation that patients with multiple myeloma who were exposed to prolonged alkylator therapy had a much higher risk of developing MDS following transplantation.507 Secondary malignancies also occur following allogeneic hematopoietic cell transplantation. In one retrospective analysis of 557 patients, 9 patients developed 10 secondary cancers for a cumulative actuarial risk of 12 percent at 11 years after hematopoietic cell transplantation. The age-adjusted incidence of secondary cancer was 4.2 times higher than that expected from a similar population of individuals in the general population.508 In another large retrospective analysis of 19,229 patients who underwent allogeneic or syngeneic hematopoietic cell transplantation, the risk of developing new solid cancers was 8.3 times higher at 10 years after transplantation than that for age-adjusted individuals.509 Despite the higher risk, the cumulative incidence at 10 years was only 2.2 percent.
TREATMENT AND PREVENTION OF RELAPSE FOLLOWING TRANSPLANTATION
Relapse of the underlying disease is an unfortunate and ominous event following hematopoietic cell transplantation. Typically, patients who suffer a relapse do so within the first 2 years following transplantation. Once a patient relapses, the likelihood of curative therapy is very low. Many patients are able to tolerate and are capable of responding to chemotherapy or radiation therapy, which may result in prolonged survival, especially for those patients who relapse several years after the transplant procedure.510 A number of novel therapies are under consideration in an effort to treat or preferentially prevent relapses. Second transplants have rarely been successful, due to toxicity and tumor resistance.511,512,513 and 514
A major goal is to harness the immune system to prevent and/or treat patients who develop recurrent disease. The rationale for utilizing immunotherapy following hematopoietic cell transplantation is based upon the demonstration of a graft-versus-tumor effect, the minimal residual disease state that most patients enter following hematopoietic cell transplantation, and the rapid advances in our understanding of basic tumor immunology. Both CTL and natural killer (NK) cells have been implicated in the graft-versus-tumor effect. The CTL recognize target cells through the appropriate expression of specific peptides in the context of major histocompatibility complex (MHC) molecules. In order for a productive interaction to occur, costimulation through the CD28-B7 system or other costimulatory molecules must occur or anergy develops.515 The discovery of highly efficient antigen-presenting cells, termed dendritic cells, has opened an exciting new path of investigation (see Chap. 84).516 The NK cells, in contrast, are inhibited by the appropriate expression of certain MHC class I molecules, and the lack of expression or altered peptide presentation results in the loss of a “no-kill” signal, which triggers lysis.517 Upon appropriate engagement, both CTL and NK cells lyse target cells through the exocytosis of cytolytic granules that contain perforin and granzymes. Perforin induces pore formation in the membrane of the target cells. This allows for the introduction of granzymes, which induce apoptosis of the target cell.518 In addition, CTL and NK cells express fas ligand (fasL), which can induce target-cell apoptosis through engagement of the fas receptor on the target cell.519
These insights into tumor cell recognition have identified a number of potential mechanisms by which tumor cells may evade immunological recognition. With respect to T-cell recognition, the lack of tumor-specific antigens or the down-regulation of HLA class I molecules could result in an inability of the T cells to recognize and respond to tumor cells. The lack of costimulatory molecules on the tumor cells may result in the development of anergy. In addition, a number of tumor cells have been found to express fasL, which could theoretically inactivate fas-expressing effector cells.520,521 In addition, functional defects in T cells, the heterogeneity of human tumor cells, and the possibility of ongoing mutations add complexity to the potential application of immunotherapy. With respect to NK-cell–mediated attack, the appropriate expression of self-MHC class I molecules could inactivate host NK cells. In addition, soluble factors have been described that are capable of inhibiting NK cells in vitro.522
CLINICAL APPLICATION OF IMMUNOTHERAPY FOLLOWING HEMATOPOIETIC CELL TRANSPLANTATION
Following autologous transplantation it has been observed that IL-2 production is impaired. Yet, peripheral-blood lymphocytes isolated from patients retain the ability to respond to IL-2.523,524 Phase I and II clinical trials with IL-2 with or without in vitro activated cells suggest a clinical impact of IL-2 therapy.205,525,526,527 and 528 Another approach has been to combine IL-2 with interferon-a. This combination has had considerable toxicity. However, in one study of patients who underwent hematopoietic cell transplantation for lymphoma, 80 percent of the IL-2/interferon-a-treated patients were alive and free of disease at a median follow-up of 34 months, compared to 52.5 percent of historical control subjects after a median follow-up of 23 months (p < 0.01).529 This approach is currently under evaluation in a randomized clinical trial. IL-2 therapy was not beneficial in a modest-sized randomized clinical trial following autologous hematopoietic cell transplantation for ALL.530 Other cytokines, such as IL-12 and IL-15, also are in the early stages of clinical development.
An alternative approach has been to utilize cellular immunotherapy to treat malignancies. For example, patients who have suffered a relapse following allogeneic hematopoietic cell transplantation have been treated with donor leukocyte infusions. Since the initial reports in the 1980s, a number of studies have documented that reinfusion of unmanipulated leukocytes derived from the HLA-matched donor can result in significant clinical responses in relapsed patients, especially those with CML.18,20,531,532 and 533 Responses have also been noted in other diseases such as AML or multiple myeloma, but have been less effective in patients with ALL. Two large retrospective studies have highlighted both the promise and the problems associated with donor leukocyte infusion. In an analysis of results obtained from 135 patients treated at 27 transplant centers,19 73 percent of patients with relapsed CML were reinduced into a CR with donor leukocyte infusion. Patients with AML did not respond as well, with only five (29%) developing a CR. None of the ALL patients responded. Remissions were durable, with many of the patients continuing in complete hematologic and molecular remission for years. Donor leukocyte infusion treatment had considerable toxicity, with 42 percent of the patients developing clinically significant graft-versus-host disease and 34 percent of the patients developing myelosuppression. Seventeen (12.6%) of the patients died of causes other than their underlying malignancy. In a second large retrospective analysis of results from donor leukocyte infusion, a similar response rate of 60 percent among CML patients was observed.288 As expected, responses were superior either for patients with only cytogenetic relapses or for patients treated with donor leukocyte infusion while in chronic phase, compared to patients who had progressed to either accelerated phase or blastic phase. Results were not favorable for patients with AML (15.4% CR) or ALL (18.2% CR). Again, complications included graft-versus-host disease (60%) and pancytopenia (18.6%).
Overall, these results confirm the favorable clinical results of donor leukocyte infusion, especially for patients with CML that have not progressed to an advanced stage. An interesting approach will be to study those patients who develop only molecular relapses, which have been shown to be predictive of eventual relapse, especially if persistently positive and found after 6 months from the transplant.232 The use of donor leukocyte infusion in patients with relapsed acute leukemia has been less successful, possibly due to the more rapid proliferative capacity of the malignant cells, while donor leukocyte infusion reactions often take months for full benefit. Some investigators have advocated the use of chemotherapy to first “debulk” the disease prior to donor leukocyte infusion.
As discussed above, a major complication of donor leukocyte infusion is the risk of graft-versus-host disease. This is frequently manifested as chronic graft-versus-host disease. The development of graft-versus-host disease is further complicated by the difficulty of evaluating the appropriate time to intervene with treatment, since graft-versus-host disease has been related to leukemic response in most studies, although patients have clearly been identified who develop a graft-versus-leukemia response without graft-versus-host disease. One approach to limiting the risk of graft-versus-host disease has been to explore the dose of cells infused in an effort to find a dose that has effective antileukemic properties without causing significant graft-versus-host disease. In one study of CML patients who relapsed following a T-cell–depleted transplant, a dose of 1 × 107 CD3+ T cells/kg was defined that resulted in excellent efficacy without causing significant graft-versus-host disease.534 However, it remains unclear whether this dose level also applies to patients who relapse following transplantation of a non–T-cell-depleted graft. Attempts have been made either to deplete CD8+ cells or to enrich for CD4+ cells in an effort to reduce the risk of graft-versus-host disease while retaining a graft-versus-leukemia effect.535 Another approach to graft-versus-host disease after donor leukocyte infusion has been to modify the donor leukocytes so that they are susceptible to certain drug treatments that allow for their eradication if graft-versus-host disease develops.536 The major complication observed following donor leukocyte infusion has been myelosuppression and, in some instances, aplasia, which has been encountered primarily in patients who had no evidence of donor hematopoiesis at the time of donor leukocyte infusion treatment.537
Excellent results have also been obtained with interferon-a in patients with CML who have relapsed following allogeneic hematopoietic cell transplantation, especially when patients are treated early following a relapse at a time of only cytogenetic relapse.538,539 Whether such patients will benefit from donor leukocyte infusion remains to be evaluated.
The specificity of CTL for tumor cells has made isolating cells with antitumor activity an attractive clinical goal. The potential clinical efficacy of CTL has been demonstrated in pilot studies directed against defined viral antigens, such as CMV and Epstein-Barr virus.146,540,541 and 542 Whether these results can be extended to patients with malignancies where there are not clearly defined antigens remains to be determined. Tumor-specific HLA-restricted CTL have developed against metastatic breast cancer and leukemic cells.543,544 and 545
Another approach has been to expand T cells termed cytokine-induced killer cells, which share functional and phenotypic properties with NK cells.546,547 Cytokine-induced killer cells have been shown to have in vivo activity in animal model systems, and clinical trials are underway.268,548
The successful isolation and expansion of professional antigen-presenting cells, such as dendritic cells, which express all of the molecules required for a productive immunological reaction, has generated considerable interest. The in vivo application of dendritic cells with defined experimental antigens has been explored in murine model systems with clear efficacy. Early clinical trials have been performed in which dendritic cells were pulsed with idiotype proteins in patients with follicular lymphomas and multiple myeloma.378,549 Antitumor cellular responses have been observed in vitro, with clinical responses noted in some patients. Despite the obvious appeal of dendritic-cell–mediated immunotherapy, technical and theoretical problems need to be addressed. These include the requirement for cell culturing, individualized therapy, and HLA restriction of the peptide antigens. The optimal approach to dendritic-cell–based immunotherapy remains to be established. Issues that require optimization include the choice of dendritic cells, method of expansion and activation, source of antigen (peptide, whole protein, tumor cell extract, or genetic transfection), and the immunological competence of the recipient.550
Immunomodulation therapies have also been explored in the post-hematopoietic cell transplantation setting. Following withdrawal of cyclosporine, animals develop a syndrome similar to graft-versus-host disease.551 This strategy of inducing autologous graft-versus-host disease has been extended to clinical trials, where a reduction in relapse rate and an event-free survival benefit was observed in patients with lymphoma who were treated with cyclosporine compared to historical control subjects.552 Additional studies have been performed in patients with breast cancer treated with cyclosporine in combination with interferon-a.553
Monoclonal antibodies are also attractive reagents for immunotherapy due to their high degree of specificity. Humanized anti-CD20 MoAb has been used to treat patients with relapsed lymphoma.554 Clinical trials using the anti-CD20 MoAb and anti-Her2/Neu MoAb are underway in patients with lymphoma and breast cancer, respectively. Bispecific antibodies that couple tumor-cell markers with T cells also may be useful in the clinic in the future.555
QUALITY OF LIFE
The success of hematopoietic cell transplantation has resulted in long-term survival of a rapidly rising number of patients, bringing issues of quality of life to the forefront. A number of studies have evaluated the quality of life of hematopoietic cell transplantation survivors. The first study examining survivors of allogeneic hematopoietic cell transplantation revealed that the majority of individuals were employed and in good health, with acceptable objective and subjective levels of functioning. However, a minority of individuals (10–15%) had evidence of psychosocial stress.556 Another study revealed mild to moderate cognitive dysfunction among patients who received total-body irradiation as part of the preparative regimen.557 Other reports have confirmed that the quality of life of long-term survivors of allogeneic hematopoietic cell transplantation is generally excellent, with more than 90 percent of patients having Karnofsky performance scores of 80 percent or higher.558,559 The major limitations in quality of life were generally associated with chronic graft-versus-host disease.560 Similar results were obtained for patients who survive for more than 5 years after allogeneic hematopoietic cell transplantation, in whom 93 percent of patients were in good health and 89 percent had returned to full-time work or school.561 Quality of life of patients following autologous hematopoietic cell transplantation is generally excellent. In one study at 1 year after hematopoietic cell transplantation, 88 percent of patients who were surveyed reported a quality of life of above average or excellent, and 78 percent were employed.562
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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