ACP medicine, 3rd Edition


Hematopoietic Cell Transplantation

Frederick R. Appelbaum MD1

Professor and Head

1Division of Medical Oncology, University of Washington School of Medicine, Director, Clinical Research Division, Fred Hutchinson Cancer Research Center

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

The therapies G-CSF, GM-CSF, cyclophosphamide, busulfan, thiotepa, melphalan, carmustine, etoposide, cytarabine, total body irradiation, antithymocyte globulin, fludarabine, prednisone, methotrexate, tacrolimus, rapamycin, mycophenolate mofetil, azathioprine, and thalidomide have not been approved by the FDA for uses described in this chapter.

October 2006

Hematopoietic cell transplantation can replace abnormal but nonmalignant hematopoietic stem cells with cells from a healthy donor, making transplantation an effective therapy for a variety of nonmalignant diseases of the lymphohematopoietic system (e.g., severe combined immunodeficiency disease, Wiskott-Aldrich syndrome, aplastic anemia, thalassemia, sickle cell anemia, and Gaucher disease). In addition, hematopoietic cell transplantation is used to treat a number of malignancies for two reasons. It allows administration of higher and potentially more effective doses of chemotherapy and radiotherapy that would otherwise cause unacceptable myelosuppression. Further, allogeneic transplantation also confers its own immunologically mediated graft-versus-tumor effect beyond that of chemoradiotherapy. Worldwide, an estimated 45,000 to 50,000 patients underwent hematopoietic cell transplantation in 2005.1

The Hematopoietic Stem Cell

Three features of the lymphohematopoietic system make transplantation feasible: its regeneration capacity, the homing of stem cells to sites that promote survival and proliferation, and the ability of stem cells to survive, with little damage, the freezing and thawing process entailed in cryopreservation. In mice, a single hematopoietic stem cell can reconstitute a lethally irradiated recipient.2 In humans, transplantation of considerably less than 10% of a donor's marrow regularly results in complete and sustained replacement of the recipient's entire lymphohematopoietic system, including red cells, platelets, granulocytes, T cells, and B cells, as well as pulmonary alveolar macrophages, Kupffer cells of the liver, osteoblasts, Langerhans cells of the skin, and microglial cells of the brain. Although there is some controversy, the bulk of evidence indicates that hematopoietic stem cells are incapable of transdifferentiating into tissues of nonhematopoietic origin.3,4

The mechanism of homing is not entirely understood, but it appears to be a multistep process that includes signaling by the marrow microenvironment using stromal-derived factor 1 (SDF-1) and stem cell factor (SCF); this signaling directs migration of stem cells to the bone marrow and increases adhesion molecules (e.g., CXCR4 and VLA-4) on the stem cell.4

The human hematopoietic stem cell expresses distinctive surface antigens.5 One of these, the CD34 antigen, is expressed on only 1% to 5% of normal adult bone marrow cells, but when marrow is cultured in vitro, virtually all colonies derive from the CD34+ population. Successful transplantation in humans can be carried out using only positively selected CD34+ cells. Over 90% of CD34+ cells also express CD38, but the 10% that are CD34+ and CD38- are the population best able to support long-term hematopoiesis in vitro and are thus considered a more primitive population. Human hematopoietic stem cells also express c-kit and Thy-1, and they stain poorly with rhodamine 123 (Rh123), a mitochondrial dye; low-intensity fluorescence of Rh123 can be used to predict stable, long-term hematopoiesis after transplantation. These cells also lack known markers of B cell or T cell lineage and are therefore said to be lineage negative.

Types of Hematopoietic Cell Transplantation

Hematopoietic cell transplantation can be categorized according to the relation between the donor and the recipient and according to the anatomic source of the stem cell. Hematopoietic stem cells for transplantation may derive from bone marrow, peripheral blood, or umbilical cord blood and may be harvested from a syngeneic, allogeneic, or autologous donor.

Syngeneic Transplantation

A syngeneic transplantation is one in which the donor and recipient are identical twins. When syngeneic donors are used, neither graft rejection nor graft versus host disease (GVHD) will develop in the recipient. Syngenicity is easily established by DNA typing, using one of two techniques—either restriction fragment length polymorphisms (RFLPs) or variable nucleotide tandem repeats. Only about one in 100 patients undergoing transplantation will have an identical twin.

Allogeneic Transplantation

Allogeneic transplantation, which involves a related or unrelated donor, is more complicated than syngeneic or autologous transplantation (see below) because of immunologic differences between donor and host. With allogeneic hematopoietic cell transplantation, the clinical challenges are both to prevent graft rejection by host cells that survive the pretransplant preparative regimen and also to prevent donor cells from causing immune-mediated injury to the patient (i.e., GVHD).

Immunologic reactivity between donor and host is largely mediated by immunocompetent cells that react with human leukocyte antigens (HLAs), which are encoded by genes of the major histocompatibility complex. HLA molecules display both exogenous peptides (e.g., from an infecting virus) and endogenous peptides, presenting them to T cells, an important step in the initiation of an immune response. If two persons do not share the same HLA antigens, T cells taken from one person will react vigorously to the mismatched HLA molecules on the surface of the cells from the other. These reactions are against so-called major HLA determinants. Even when two persons who are not identical twins have identical HLA types, the endogenous peptides presented by the HLA antigens will differ, triggering a response against so-called minor HLA determinants.

The genes encoding HLA class I and class II antigens are tightly linked and tend to be inherited together as haplotypes with low recombination frequencies. For any given patient, there is a 25% probability that any one sibling has inherited the same paternal and maternal haplotype, making the siblings identical with regard to HLA genotype. Given that the average number of children per family in the United States is slightly more than two, the average chance that a patient has an HLA-matched sibling is approximately 35%. The formula for calculating the probability that a patient has an HLA-identical sibling is 1 - (0.75)n, where n equals the number of siblings.

Allogeneic transplantation has been performed using HLA-identical sibling donors, other matched and mismatched family-member donors, and matched unrelated donors. The best results generally have been achieved with HLA-identical sibling donors. With transplantation from family-member donors who are identical for one haplotype but mismatched for a single locus (i.e., HLA-A, HLA-B, or HLA-D) on the other haplotype, the survival rate is nearly equal to that with HLA-identical donors, although there is a higher incidence of GVHD.6 Transplants using family-member donors mismatched for two or more loci have worse results—a higher incidence of GVHD and graft rejection and a lower probability of survival.6

Because of the highly polymorphic nature of HLA antigens, the probability that two unrelated persons will match is extremely low. Matched unrelated donor transplantation was first performed in the late 1970s. The broader application of this technique was made feasible by the creation of large donor registries in the late 1980s. Since then, the number of unrelated-donor transplantations has rapidly increased [seeFigure 1]. Currently, more than seven million healthy persons have volunteered to serve as marrow donors in the United States alone, making the odds of finding an unrelated donor matched for HLA-A, HLA-B, and HLA-D approximately 50%. On average, it takes about 3 months from the time a search is initiated to identify a donor and begin transplantation. In 2005, approximately 3,000 unrelated-donor transplantations were performed in the United States.7


Figure 1. Total Numbers of Hematopoietic Cell Transplantations 1970–2002

Depicted are the estimated total numbers of allogeneic and autologous hematopoietic cell transplantations performed worldwide from 1970 to 2002, according to estimates of the International Bone Marrow Transplant Registry. The drop in autologous transplantations in 1999 was due to decreased transplantation for breast cancer, whereas the flattening in growth of allogeneic transplantation is the result of fewer transplantations for chronic myelogenous leukemia since the introduction of imatinib mesylate.

Results of early transplantations suggested that GVHD was more common and graft rejection more frequent with unrelated donors than with related donors matched for HLA compatibility.8 The difference in incidence of GVHD may be partially explained by the increased disparity in minor HLA determinants in unrelated individuals. Undetected disparities in HLA types between supposedly matched unrelated donor-recipient pairs may also have contributed to the increased incidence of GVHD. Before 1998, HLA typing for HLA-A, HLA-B, and HLA-C was conducted using serologic methods. Since then, studies using automated direct sequencing of these genes have demonstrated specific nucleotide differences in 30% of pairs previously defined as HLA identical.9,10 Such “allele-level” mismatching in class I antigens has been shown to be associated with increased GVHD, whereas mismatches at class II have been shown to be associated with an increased risk of graft rejection. Currently, outcomes of transplantation using fully matched donors approach those seen with matched sibling transplants in many disease categories.

Autologous Transplantation

Compared with allogeneic transplantation, autologous transplantation has the advantage of avoiding GVHD and associated complications; disadvantages are that the autologous cells lack the immunologically-mediated antitumor effects of allogeneic transplantation and may contain viable tumor cells. Removal of tumor cells by use of antibodies to tumor-specific antigens together with complement, toxins, or immunomagnetic beads is very efficient, reducing the number of tumor cells 1,000-fold to 10,000-fold.11 Other methods of purifying stem cells that are currently under investigation are antibody adherence and flow techniques that select normal hematopoietic stem cells while leaving tumor cells behind; in vitro treatment of the autologous cells with selective chemotherapeutic agents; and in vitro culturing to selectively grow hematopoietic cells. Gene-marking studies have demonstrated that remaining tumor cells can contribute to relapse12; however, it remains unknown which, if any, methods of cell purification can prevent relapse. Further, many of the techniques result in delayed hematologic and immunologic recovery after transplantation. Several retrospective analyses suggest that in vitro marrow treatment may be effective in acute myeloid leukemia (AML) and B cell non-Hodgkin lymphoma (NHL), but sufficiently large prospective, controlled studies have not been reported.11

Peripheral Blood Cell Transplantation

Hematopoietic stem cells normally circulate in the peripheral blood, albeit at very low numbers. Early experiments in animal models showed that at least 10 times more mononuclear cells are needed to rescue animals from lethal total body irradiation when the cells are collected from peripheral blood rather than from marrow of untreated animals. Initial attempts to use peripheral blood stem cells as a source of hematopoietic grafts were complicated by the large number of collections (phereses) required—often seven or more—and by slow engraftment. Subsequently, it was shown that a marked increase in the number of hematopoietic progenitors in the blood, measured either as hematopoietic colony-forming units or as CD34+ cells, occurs during recovery from previous chemotherapy or shortly after exposure to hematopoietic growth factors.13,14 This led to studies of the use of peripheral blood stem cells as a substitute for marrow. These studies were initially conducted in the autologous setting because peripheral blood stem cell collections contain a large number of T cells, which could induce GVHD if the collections were used for allogeneic transplantation. In the autologous setting, cells sufficient in number to achieve engraftment can usually be collected with one to three leukaphereses of 4 hours' duration after treatment of the patient with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The exact mechanism by which myeloid growth factors cause the remarkable increase in number of peripheral blood stem cells is unclear; however, murine studies suggest that myeloid growth factors activate neutrophils to release serine proteases, and serine proteases in turn proteolytically cleave vascular adhesion molecules in the marrow, releasing hematopoietic stem cells.15 If more than 2.5 million CD34+ cells/kg are collected and subsequently used for autologous transplantation, recovery to 500 granulocytes/mm3 within 12 days after transplantation and recovery to 20,000 platelets/mm3 within 14 days after transplantation almost always occur.16 This rate of recovery is significantly faster than the rate with autologous marrow stem cells [see Figure 2]. Although it is not yet known whether peripheral blood is more likely or less likely than marrow to be contaminated with transplantable tumor cells, mobilized peripheral blood has almost entirely replaced marrow as the source of stem cells for autologous transplantation.


Figure 2. Patterns of Myeloid Recovery

Shown are the typical patterns of myeloid recovery after hematopoietic cell transplantation using marrow alone, marrow plus posttransplant myeloid growth factors, and growth factor-mobilized peripheral blood stem cells.

Peripheral blood stem cells have also been used for allogeneic transplantation. Initial studies with G-CSF-mobilized peripheral blood stem cells from HLA-identical matched donors suggested that they engraft more rapidly, and the incidence of acute GVHD did not appear to be greater than would be expected with marrow, despite the transplantation of at least 10 times more mature T cells.17 Randomized trials have confirmed that the use of peripheral blood stem cells accelerates engraftment without increasing the incidence of acute GVHD.18,19,20Although the incidence of chronic GVHD may be somewhat higher with peripheral blood stem cells, the incidence of tumor recurrence appears to be less and overall disease-free survival tends to be higher with use of peripheral blood stem cells, particularly in patients with higher-risk leukemias.18,19,20

Umbilical Cord Blood Transplantation

Umbilical cord blood is rich in CD34+ cells, and these cells can thus serve as an alternative source of stem cells. The first human umbilical cord blood transplantations were performed in the late 1980s for patients with Fanconi anemia. In a series of 44 children treated with cord blood from siblings, the speed of myeloid engraftment was similar to that seen with marrow transplantation, but platelet recovery was slower. The incidence of GVHD was 6%, which was low; this probably reflected both the young ages of the recipients and the fact that umbilical cord blood is relatively devoid of mature T cells. Subsequently, several studies were undertaken that entailed banking unrelated umbilical cord blood and using it for subsequent transplantation.20 A summary of the first 562 unrelated cord blood transplants facilitated by the New York Blood Center's program reported engraftment in approximately 80% of patients, but the time to engraftment was significantly prolonged—24 days for neutrophils and 72 days for platelets.21 The overall incidence of severe acute GVHD was 23%.

Currently, umbilical cord blood is used as the source of stem cells for between 15% and 20% of pediatric allogeneic transplantations. Advantages of umbilical cord blood as a source of stem cells include an apparent ability to use donors with greater HLA disparity, a seemingly lower risk of GVHD, and the rapid availability of stored unrelated units. Disadvantages include slower engraftment, a higher incidence of graft failure, slower immune reconstitution, and a trend toward higher disease-recurrence rates. Studies comparing the outcomes of matched unrelated donors with those of unrelated cord blood transplants for pediatric patients have, in some cases, shown equivalent survival, but others have shown a trend toward improved survival with the use of unrelated marrow donors.22 The total nucleated cell number and CD34+ cell content of cord blood predict speed of recovery and are highly associated with overall transplant outcome. A threshold dose of 2.5 × 107 cells/kg recipient weight or 1.7 × 105 CD34+ cells/kg is now recommended.

Given the limited number of total nucleated and CD34+ cells in any one unit of cord blood, it has been difficult to apply this technology in larger children and adults. When it has been tried, in general, survival has been somewhat poorer than that seen with the use of adult unrelated donors.23,24 Reports suggest that engraftment in adults can be improved by combining two umbilical cord units.25

Transplantation Procedure

Preparative Regimens

A preparative regimen is administered before hematopoietic stem cells are transplanted. The purpose of this regimen is to eliminate the abnormal or malignant cells causing disease and to suppress the immune system sufficiently to avoid graft rejection. The appropriate regimen for any particular patient is determined by the disease to be treated, the age and health of the patient, and the source of the stem cells to be grafted.

At one extreme, patients undergoing transplantation for the treatment of severe combined immunodeficiency disease with stem cells from an HLA-matched sibling require no preparative regimen, because there are no abnormal cells to eliminate (the disease being caused by a lack of normal cells) and because the patients' immune systems are already sufficiently suppressed to avoid graft rejection. Patients with aplastic anemia lack a normal hematopoietic system but are sufficiently immunocompetent to reject allogeneic marrow if no immunosuppression is given. In this setting, treatment with high-dose cyclophosphamide plus antithymocyte globulin is sufficiently immunosuppressive to ensure engraftment as long as the donor is an HLA-identical sibling. When the transplant is from an unrelated donor, greater immunosuppression is required; thus, low-dose total body irradiation is often added to the treatment. When transplantation is used to treat diseases characterized by an abnormal but nonmalignant population of cells, such as thalassemia and sickle cell anemia, the preparative regimen must eliminate the abnormal population and suppress the patient's immune system. To accomplish this, high-dose busulfan (16 mg/kg divided over 4 days) is often added to cyclophosphamide in the preparative regimen.

In developing preparative regimens for transplantation to treat malignancies, most investigators have focused on the use of agents that are highly active against the malignancy being treated and whose dominant dose-limiting toxicity in the nontransplant setting is myelosuppression. Thus, the therapies most commonly used are alkylating agents (e.g., cyclophosphamide, busulfan, thiotepa, melphalan, carmustine), etoposide, cytarabine, and total body irradiation.

High-dose preparative regimens are typically used when allogeneic transplantation is performed to treat malignancy; however, the allogeneic graft-versus-tumor effect suppresses tumor growth independently of the preparative regimen. This has led investigators to ask whether less intensive, nonmyeloablative regimens may be effective and less toxic. Allogeneic engraftment has been achieved with lower-dose regimens that combine fludarabine with busulfan, cyclophosphamide, or total body irradiation. In one study, for example, patients with hematologic malignancies were treated with fludarabine and 200 cGy of total body irradiation, with encouraging results.26

Complete responses were achieved in a variety of malignancies, particularly in patients with more indolent hematologic malignancies, with much less toxicity than is seen with standard transplant approaches.26 The decreased toxicity associated with this approach has permitted its study in patients 70 years of age and older. The appropriate role of nonmyeloablative transplants in the treatment of specific malignancies is still being defined.27,28

Stem Cell Collection and Infusion

Marrow is usually obtained from the donor's anterior and posterior iliac crests with the donor under spinal or general anesthesia. A total marrow volume equivalent to 10 to 15 ml/kg is withdrawn; withdrawal of marrow volume is limited to 3 to 5 ml at each aspiration site to avoid excessive dilution with peripheral blood circulating within the iliac crest. The marrow is filtered through 0.3 mm and 0.2 mm screens to remove bone spicules and fat. The marrow may require further in vitro treatment to remove other cells, such as donor red cells to prevent a hemolytic transfusion reaction in the setting of ABO incompatibility; donor T cells to prevent GVHD; and tumor cells from autologous marrow (see above). The risks associated with marrow donation are small; in one series, there were six serious but nonfatal complications out of 1,220 consecutive marrow donations.29

Peripheral blood stem cells are usually collected by use of continuous-flow apheresis from donors previously treated with hematopoietic growth factor alone or, in the case of autologous transplantation, after chemotherapy plus treatment with growth factors. Attempts are made to collect a minimum of 5 × 106 CD34+ cells/kg; there is consistent rapid engraftment with this dose.16

Marrow and peripheral blood stem cell infusions are usually well tolerated, though patients sometimes develop fever, cough, or mild shortness of breath. Slowing the infusion usually alleviates these symptoms.


The rate of engraftment depends on the source of the stem cells, the choice of prophylaxis against GVHD, and whether hematopoietic growth factors are used. The most rapid engraftment is seen with peripheral blood stem cells; in this setting, engraftment is typically achieved by day 12. In marrow or umbilical cord blood transplantation, the granulocyte count usually reaches 100 cells/mm3 by about day 16 and 500 cells/mm3 by day 22. The rate of myeloid recovery can be accelerated by 4 to 6 days with the use of G-CSF or GM-CSF after marrow transplantation, but posttransplant growth factors have less of an effect when mobilized peripheral blood is the source of transplanted stem cells [see Figure 2].30 The use of methotrexate after allogeneic transplantation delays recovery by an average of 4 days. Platelet recovery generally occurs shortly after granulocyte recovery.

Complications of Transplantation

Early Direct Toxicities of Ablative Preparative Regimen

Pretransplant ablative preparative regimens are associated with a substantial array of toxicities, which vary considerably depending on the specific regimen used. For example, nausea, vomiting, and mild skin erythema develop immediately in almost all patients after the standard cyclophosphamide-total body irradiation regimen. Occasionally, hemorrhagic cystitis is seen despite bladder irrigation or therapy with a sulfhydryl compound (MESNA); in rare instances (fewer than 2% of cases), acute hemorrhagic carditis develops. Oral mucositis inevitably develops about 5 to 7 days after transplantation, usually requiring narcotic analgesia. Patient-controlled analgesia provides the greatest patient satisfaction and, surprisingly, results in a lower cumulative dose of narcotics. Keratinocyte growth factor (KGF, palifermin) can significantly shorten the duration of severe mucositis following an ablative transplant regimen.31 Within 10 days after transplantation, complete alopecia and profound granulocytopenia develop in most patients.

Veno-occlusive disease of the liver (also referred to as sinusoidal obstruction syndrome) is a serious complication of high-dose chemoradiotherapy; it develops in approximately 10% to 20% of patients.32 Veno-occlusive disease of the liver, characterized by the development of ascites, tender hepatomegaly, jaundice, and fluid retention, may occur at any time during the first month after transplantation; the peak incidence occurs at around day 16. Histologic features of veno-occlusive disease of the liver include concentric narrowing or fibrous obliteration of terminal hepatic venules and sublobular veins and necrosis of zone 3 hepatocytes [see Figure 3]. Predisposing factors are pretransplant hepatitis (e.g., as evidenced by elevated markers of hepatitis B and hepatitis C) of any cause and the use of more intensive conditioning regimens.33,34 Although the precise sequence of events leading to the clinical presentation of veno-occlusive disease is unknown, direct cytotoxic injury to hepatic venular and sinusoidal endothelium occurs early on, with subsequent deposition of fibrin and the development of a local hypercoagulable state. Direct cytotoxic injury to zone 3 hepatocytes is a contributing factor. Approximately 30% of patients who develop veno-occlusive disease of the liver die as a result of the disease, with progressive hepatic failure leading to a terminal hepatorenal syndrome. Antithrombotic and thrombolytic agents, including prostaglandin E1 and tissue plasminogen activator, with or without heparin, have been evaluated as treatment. These therapies have been associated with significant toxicities, and randomized trials demonstrating efficacy are lacking. Defibrotide, a polydeoxyribonucleotide, reduces the thrombogenicity of vascular endothelium and, in prospective nonrandomized trials, appears to be of some benefit without significant toxicity.35


Figure 3. Photomicrograph showing Veno-occlusive Disease of the Liver

Photomicrograph of a liver biopsy stained with Trichrome shows the typical changes of veno-occlusive disease of the liver. A sublobular vein is outlined by dense, blue connective tissue in the outer adventitial layer. There is marked narrowing of the lumen of the vein by a widened and edematous subendothelial zone containing trapped red cells and loose extracellular matrix. The hepatocyte cords surrounding the vein are necrotic, and the intervening sinusoids are hemorrhagic. Deposition of coagulants in the sinusoids and in the subendothelial zone of the vein obstructs outflow of blood from the liver, producing sinusoidal hypertension and hepatomegaly.

Most pneumonias that occur after transplantation are caused by microbial agents, but idiopathic interstitial pneumonia occurs in up to 5% of patients.36 Most experts consider idiopathic interstitial pneumonia to be a direct toxicity of intensive chemotherapy, but evidence for a role of soluble cytokines is growing. Biopsies reveal some cases to be characterized by diffuse alveolar damage, whereas other cases have a more clearly interstitial component. Treatment with high-dose glucocorticoids is often attempted, but randomized trials evaluating their efficacy have not been performed.

Late Direct Toxicities of Ablative Preparative Regimen

Direct complications of chemoradiotherapy seen late after transplantation include a decreased growth rate in children and a delay in the development of secondary sex characteristics.37 Most children will have a deficiency in growth factor and should undergo replacement therapy. Ovarian failure develops in most postpubertal women. Azoospermia develops in most men. Aseptic osteonecrosis occurs in as many as 10% of transplant patients, particularly in those with chronic GVHD necessitating corticosteroid treatment. Similarly, cataracts develop in 10% to 20% of patients; the risk is higher in patients who take steroids to treat chronic GVHD.38 Recovery from the effects of transplantation is a gradual process, and full recovery may require 3 to 5 years.39

Patients treated with high-dose chemoradiotherapy and hematopoietic cell transplantation are at increased risk for the development of secondary malignancies.40,41 The risk is highest in patients receiving T cell-depleted marrow and those who receive multiple cycles of highly immunosuppressive drugs after transplantation to treat GVHD; in such cases, a high incidence of Epstein-Barr virus-associated lymphoproliferative disease is seen. A smaller increase is seen in the incidence of solid tumors after transplantation, with a 2.9% 10-year cumulative rate. The actuarial incidence of myelodysplasia after autologous transplantation for NHL and Hodgkin disease may be as high as 10%.42

Direct Toxicities of Non-Myeloablative Preparative Regimens

The spectrum of toxicity seen after allogeneic transplantation using nonmyeloablative preparative regimens differs significantly from that seen after ablative preparative regimens. With nonmyeloablative preparative regimens, patients require fewer red cell and platelet transfusions, have a lower incidence of veno-occlusive disease and idiopathic interstitial pneumonia, and have fewer bacterial infections. However, nonmyeloablative regimens do not reduce the incidence of fungal or viral infection. The cumulative incidence of acute and chronic GVHD is similar to that seen after ablative regimens, but the onset of GVHD may be delayed in nonmyeloablative transplantation. These differences translate into an overall lower incidence of nonrelapse mortality after nonmyeloablative transplantation, particularly for patients who have a higher degree of comorbidity at the initiation of the transplant procedure.43,44,45

Graft Failure

Although complete and sustained engraftment is the general rule after transplantation, marrow function does not return in some cases; and in other cases, after temporary engraftment, marrow function is lost. Graft failure after autologous transplantation can result from marrow damage before harvesting, during ex vivo treatment, during storage, or after exposure to myelotoxic agents after transplantation.46Infections with cytomegalovirus (CMV) or human herpesvirus type 6 may also result in poor marrow function. Graft failure after allogeneic transplantation may be the result of immunologically mediated graft rejection and is more common after conditioning regimens that are less immunosuppressive, in recipients of T cell-depleted marrow, and in recipients of HLA-mismatched marrow.

The treatment of graft failure begins with removal of all potentially myelosuppressive agents. A reasonable second step is to attempt a short trial of a myeloid growth factor (GM-CSF or G-CSF); 40% to 50% of patients respond.47 Identification of persistent host lymphocytes in peripheral blood or marrow of the patient suggests immunologic rejection. These patients should receive further immunosuppression before a second transplant is performed. Several studies have reported successful second transplants after a regimen of cyclophosphamide and antithymocyte globulin or fludarabine plus low-dose total body irradiation.48

Graft Versus Host Disease

Acute GVHD

When allogeneic T cells that are transferred with the graft or that develop from it react with targets of the genetically different host, GVHD results.49 GVHD that develops within the first 3 months after transplantation is categorized as acute and is characterized by an erythematous maculopapular skin rash that, unlike many rashes, often appears on the palms and soles [see 2:VI Cutaneous Adverse Drug Reactions]. Acute GVHD is also characterized by persistent anorexia or diarrhea, or both, and by liver disease, evidenced by increased levels of bilirubin, alanine and aspartate aminotransferases, and alkaline phosphatase. Also characteristic of acute GVHD is epithelial damage to the skin, liver, and intestines [see Figure 4]. Skin, liver, and endoscopic intestinal biopsies are the usual methods of establishing a diagnosis; they may reveal damaged epidermis and hair follicles, segmental disruption in small bile ducts, and intestinal mucosal ulceration caused by destruction of intestinal crypts. The most widely used system of clinical staging of acute GVHD includes the extent of involvement of skin, liver, and gut [see Table 1]. Variations of this system have been developed in an attempt to improve its utility for specific purposes.50,51,52 The incidence of acute GVHD increases in older patients, in recipients of mismatched marrow, and in patients who are unable to receive full doses of the drugs used to prevent GVHD.53

Table 1 Clinical Staging of Acute Graft versus Host Disease*


Skin Changes




Maculopapular rash < 25% body surface

Bilirubin 2–3 mg/dl

Diarrhea 500–1,000 ml/day


Maculopapular rash 25%–30% body surface

Bilirubin 3–6 mg/dl

Diarrhea 1,000–1,500 ml/day


Generalized erythroderma

Bilirubin 6–15 mg/dl

Diarrhea > 1,500 ml/day


Desquamation and bullae

Bilirubin > 15 mg/dl

Pain and ileus

*Overall severity ranges from mild skin involvement (stage I) to severe multiorgan involvement, usually with a fatal outcome (stage IV).


Figure 4. Photomicrograph of Skin Biopsy in Acute Graft versus Host Disease

This photomicrograph of a skin biopsy stained with hematoxylin and eosin demonstrates the features of acute graft versus host disease of the skin. Both intercellular edema (spongiosis) and intracellular edema (reticular degeneration) of the lower epidermis are evident. Mononuclear cells are scattered throughout the epidermal area along with many bodies that have undergone apoptosis, including dead epidermal cells with hypereosinophilic cytoplasm and dense basophilic pyknotic nuclei. The inflammatory process has produced incontinence of melanin pigment into the papillary dermis, as well as coarse intraepidermal blocks of melanin, leading to hyperpigmentation. Because the apoptosis and basal layer damage are extensive, the epidermis will become grossly scaly and will possibly slough.

Two general approaches are used to prevent acute GVHD: use of immunosuppressive agents during the early posttransplant period and removal of T cells from the transplanted cell population. Methotrexate alone and cyclosporine alone are equally effective as prophylaxis, but their use in combination is more effective.54 Prednisone, FK 506 (tacrolimus), rapamycin, and mycophenolate mofetil have also been used in various combinations.55 Removal of T cells from the allogeneic marrow is effective in preventing acute GVHD, but in most circumstances, it has been associated with an increased incidence of graft rejection and leukemic relapse. Accordingly, several potential therapies are now under study, including partial T cell depletion and complete T cell depletion followed by the reintroduction of a fraction of the T cells. Once acute GVHD develops, it can be treated with glucocorticoids, antithymocyte globulin, and monoclonal antibodies targeted against T cells or their receptors.

Chronic GVHD

GVHD that develops or persists 3 months or more after transplantation is termed chronic GVHD. Chronic GVHD has features in common with collagen vascular diseases, including a malar rash, sclerodermatous changes, sicca syndrome, arthritis, obliterative bronchiolitis, and, in some cases, bile duct degeneration and cholestasis. Chronic GVHD develops in 20% to 40% of patients, more often in older patients and in those who previously had acute GVHD.56 Prednisone, cyclosporine, or the two in combination is the usual treatment57; in some studies, azathioprine or thalidomide was useful.58 In most patients, chronic GVHD eventually resolves and immunosuppressive therapy can be withdrawn, but 1 to 3 years of treatment may be required. Patients with chronic GVHD who are on immunosuppressive therapy are susceptible to bacterial infections and should receive prophylactic antibiotics.

Infectious Diseases

During the first 2 to 3 weeks after transplantation, all myeloablative transplant recipients are severely granulocytopenic. To reduce the risk of disseminated bacterial infections, posttransplantation patients are usually placed on broad-spectrum antibiotics once they become granulocytopenic. In addition, the prophylactic administration of fluconazole reduces the incidence of Candida albicans infection.59Itraconazole has some effect in preventing aspergillus disease but is often poorly tolerated. Prophylaxis with other mold-active agents such as voriconazole is being studied. The treatment of patients who become febrile despite prophylactic antibiotic and antifungal therapy is a difficult challenge; in such cases, therapy is guided by individual aspects of the patient's condition and by the institution's experience. For example, if fever develops in a patient who received prophylactic treatment with levofloxacin, the subsequent choice of antibiotic might be guided by whether an intra-abdominal source of infection is suspected, in which case meropenem or imipenem is appropriate therapy; when intra-abdominal infection is not a concern, ceftazidime might be selected.60 If fever persists for more than 72 hours, amphotericin B derivatives, caspofungin, or voriconazole is often added to the treatment regimen.61 Granulocyte transfusions can be effective in treating specific infections, particularly now that donors can be treated with G-CSF before donation to greatly increase the number of granulocytes that can be collected and transfused.61 There is no established role, however, for prophylactic granulocyte transfusions. Laminar airflow isolation can reduce the incidence of infection but has no impact on survival in transplant patients treated for malignancy. With current methods of supportive care, the risk of death from an infectious cause during the period of granulocytopenia is less than 5%.

In the past, CMV infection frequently occurred after transplantation, particularly in recipients of allogeneic marrow. It has been shown, however, that primary CMV infection can be prevented in CMV-seronegative patients by the use of CMV-seronegative blood products. In CMV-seropositive patients, treatment with ganciclovir as soon as virus excretion is evident can diminish the incidence of CMV-associated disease and death, but in some patients, CMV disease develops before or at the same time as viral excretion is noted. Ganciclovir prophylaxis beginning at the time of engraftment can prevent the development of CMV infection in most patients, but ganciclovir causes significant marrow suppression in at least 30% of patients.62 At most centers, after transplantation, peripheral blood is monitored for the development of CMV antigenemia or CMV DNA by polymerase chain reaction, and preemptive therapy with ganciclovir or foscarnet is initiated only if and when patients test positive for the presence of CMV. Foscarnet is also effective for patients who develop CMV antigenemia or infection despite ganciclovir therapy or for patients who cannot tolerate ganciclovir.

Herpes simplex virus infection, when not prevented, contributes to the severity of early oral mucositis and esophagitis. However, the prophylactic use of acyclovir at a dosage of 250 mg/m2 I.V. every 8 hours or 800 mg twice daily orally can prevent herpes simplex virus reactivation in almost all seropositive patients.63

Respiratory viruses, including respiratory syncytial virus (RSV), parainfluenza virus, influenza virus, human metapneumovirus, and other agents that cause community-acquired upper and lower respiratory infections, are also seen in the transplant recipient and can be life threatening. Of primary importance is the protection of patients from infected visitors and staff by avoiding such contacts, careful hand washing, and use of facemasks and annual influenza vaccination of staff and family members.63 Inhaled ribavirin may be effective for RSV; intravenous immune globulin (IVIg) or palizumab has also been used for lower respiratory tract disease. Neuraminidase inhibitors are effective for influenza infections. Human herpesvirus type 6 (HHV-6) has been associated with graft failure, encephalitis, enteritis, and pneumonia. High levels of papovavirus BK viremia are associated with hemorrhagic cystitis. Adenovirus infections are associated with pneumonia, hepatitis, and renal failure and are less often seen in patients who have received ganciclovir for CMV prophylaxis or preemptive therapy.

Pneumocystis jiroveci once caused pneumonia in 5% to 10% of patients after transplantation, but now this complication can be prevented in virtually all patients by first treating the patient with oral trimethoprim-sulfamethoxazole for 1 week before transplantation and then resuming treatment 2 days a week once engraftment occurs and continuing it for as long as immunosuppressive therapy is given.63Desensitization should be attempted in patients with allergic reactions to trimethoprim-sulfamethoxazole. Dapsone (50 mg p.o., b.i.d.), although not as effective as trimethoprim-sulfamethoxazole, can serve as a substitute but must be avoided in patients with glucose-6-phosphate dehydrogenase deficiency. Other alternative agents include atovaquone or pentamidine.

More than 3 months after transplantation, patients are still at risk for varicella-zoster virus infections and, if they have chronic GVHD, for recurrent bacterial infections. Varicella-zoster virus infection usually occurs initially as localized disease (i.e., herpes zoster, or shingles), but it can disseminate; disseminated infection is often fatal if left untreated. Thus, patients with localized varicella-zoster virus infection should be treated with acyclovir to prevent dissemination. Many centers now routinely place all allogeneic transplant recipients on prophylactic acyclovir therapy for the first year after transplantation. In an effort to reduce late bacterial infections, many centers place patients with chronic GVHD receiving immunosuppression on daily trimethoprim-sulfamethoxazole therapy.

Hematopoietic Cell Transplantation for Specific Diseases

Treatment of Immunodeficiency States

The widest experience in treating immunodeficiency with hematopoietic cell transplantation has been in the treatment of severe combined immunodeficiency disease.64,65 When current techniques of supportive care are used, the expected outcome of transplantation from an HLA-identical donor is excellent, with a better than 90% probability of long-term survival [see Table 2].64,65 Very good results (approximately 80% survival) can be expected using matched related or unrelated donors. In patients without matched related or unrelated donors, transplantation from a haplotype-mismatched parent results in engraftment and survival longer than 2 years in 50% to 70% of patients. The experience in the treatment of Wiskott-Aldrich syndrome and other immunodeficiency states is limited.66 Cures have been noted in more than half of patients, with the best results seen in patients who undergo transplantation when they are younger than 5 years.

Table 2 Disease-Free Survival after Hematopoietic Cell Transplantation


Five-Year Disease-Free Survival (%)

Chronic myeloid leukemia


   Chronic phase


   Accelerated phase


   Blastic phase


Acute myeloid leukemia


   First remission


   Second remission


Chronic lymphocytic leukemia


Acute lymphocytic leukemia


Multiple myeloma


Non-Hodgkin lymphoma


   After first relapse, chemosensitive tumors


Hodgkin disease


   First treatment after standard treatment


   Advanced disease


Myelodysplastic syndromes


Severe aplastic anemia

> 90

Thalassemia major


Fanconi anemia


Sickle cell disease


Severe combined immunodeficiency disease


Breast cancer (stage IV disease)


Treatment of Nonmalignant Diseases of Hematopoiesis

Aplastic Anemia

Transplantation from matched siblings after a preparative regimen of high-dose cyclophosphamide and antithymocyte globulin, together with the use of methotrexate and cyclosporine for GVHD prophylaxis, is a very effective regimen for patients with aplastic anemia. Current results suggest a cure rate greater than 90% [see Table 2].67 Results with mismatched or unrelated matched donors are somewhat worse; therefore, patients with aplastic anemia who are without sibling donors are often given a trial of immunosuppressive therapy before transplantation.


Marrow transplantation from an HLA-identical sibling after a preparative regimen of busulfan and cyclophosphamide can cure from 70% to 90% of patients with thalassemia major [see Table 2].68 The best results have been obtained in patients who undergo transplantation before they develop hepatomegaly or portal fibrosis and who have been given adequate iron chelation therapy. In one study of 121 such patients, the probabilities of survival and disease-free survival 5 years after transplantation were 95% and 90%, respectively.68 Prolonged survival can also be achieved with aggressive chelation therapy, but transplantation remains the only curative treatment. Fewer than 30% of patients with thalassemia have an HLA-identical sibling. Outcomes with the use of alternative donors of hematopoietic stem cells (i.e., unrelated persons or HLA-nonidentical family members) have been aided by the establishment of worldwide donor registries, by improvements in the methods of controlling GVHD, and by prevention of fungal and cytomegalovirus infection.

Sickle Cell Anemia

Experience in transplantation for sickle cell disease is small but growing. In a European study of 100 patients with sickle cell disease who received transplants from HLA-matched siblings, the survival rate at 4 years was 88%, and disease-free survival was 80%.69 In a study of 59 patients in the United States, similar rates were reported—93% and 84%, respectively.70

Other Nonmalignant Diseases

Hematopoietic cell transplantation has been used successfully to treat a variety of other nonmalignant but nonetheless fatal diseases. Included in this group are congenital disorders of white cells, including Kostmann syndrome, chronic granulomatous disease, neutrophil actin defects, leukocyte adhesion deficiency, and Chédiak-Higashi syndrome. Congenital anemias, including Fanconi anemia and Blackfan-Diamond anemia, are likewise treatable with hematopoietic cell transplantation.71,72

Osteopetrosis is a rare inherited disorder caused by an inability of the osteoclast to resorb bone. Because the osteoclast is a specialized macrophage derived from the marrow, it follows that osteopetrosis can be treated with marrow transplantation.73

A final category of treatable nonmalignant diseases are storage diseases caused by enzymatic deficiencies, including Maroteaux-Lamy syndrome, metachromatic leukodystrophy, Gaucher disease, Hurler syndrome, and Hunter syndrome [see 5:VII Nonmalignant Disorders of Leukocytes]. Transplantation for these disorders has not been universally successful, but treatment early in the disease course, before irreversible end-organ damage occurs, increases the chance for a successful outcome. Studies have been done on the use of transplantation in the treatment of severe autoimmune disorders. These studies are based on the demonstration that transplantation can cure autoimmune diseases in some animal models and on the observation that some patients with coexistent hematologic malignancies and autoimmune disorders have been cured of both with transplantation.73

Treatment of Malignant Diseases

Acute Myeloid Leukemia

Allogeneic marrow transplantation cures 15% to 20% of patients with AML in whom induction therapy fails and, indeed, is the only therapy that can cure such patients.74 Thus, all patients 60 years of age or younger with newly diagnosed AML should have their HLA type determined, as should their families, soon after diagnosis to enable transplantation for those in whom induction therapy fails. Allogeneic transplantation from matched siblings or matched unrelated donors can cure approximately 30% of patients in second remission and 35% of patients in untreated first relapse—situations that are clear indications for the procedure, because these results are superior to those achieved without transplantation.75,76

The role of hematopoietic cell transplantation for patients with AML in first remission remains unsettled. Several large trials have prospectively compared the outcomes of match sibling transplantation, autologous transplantation, and further chemotherapy.77,78,79 In general, these trials have suggested a slight advantage in disease-free survival with allogeneic transplantation. For patients categorized according to their cytogenetic risk group, there was no evidence that allogeneic or autologous transplantation offers an advantage for patients categorized as being at good risk. However, allogeneic transplantation was found to provide a sizable benefit for patients categorized as being at poor risk; these patients included those with del(5q)/-5, del(7q)/-7, t(9; 22), inv(3q), or complex karyotypes.80,81With continued improvements in chemotherapy and transplantation, as well as the identification of additional risk factors beyond conventional cytogenetics, the comparative roles of chemotherapy and transplantation for AML in first remission will likely continue to be redefined. Nonmyeloablative allogeneic transplantation has recently been reported to result in favorable outcomes in selected older patients with AML in first or second remission.27

Acute Lymphocytic Leukemia

As with AML, allogeneic transplantation can cure 15% to 20% of patients with acute lymphocytic leukemia (ALL) in whom induction therapy fails or in whom chemotherapy-resistant disease develops; thus, these patients are candidates for the procedure. The results of transplantation for patients in second remission are better, with cure rates of 30% to 50% [see Table 2]. However, further intensive chemotherapy also can cure some patients who suffer an initial relapse. This is particularly true for children who experience a relapse more than 18 months after initial induction chemotherapy. In a study comparing the use of allogeneic transplantation in 255 children with the use of chemotherapy in an equal number of children, the rates of disease-free survival at 5 years were found to be 40% in transplant patients and 17% in chemotherapy patients.82 The relative benefits of transplantation were similar for children with short and long initial remissions. Thus, allogeneic transplantation can be recommended for all patients with ALL in second complete remission who have appropriate donors.

Allogeneic transplantation for ALL in first remission results in long-term disease-free survival in 40% to 70% of adult patients. In a retrospective study comparing these results with those achieved with chemotherapy, no clear advantage could be found for either approach.83 In the largest prospective, randomized study published to date (involving 572 patients), the 10-year survival rate for patients undergoing allogeneic transplantation was 46%; for those undergoing autologous transplantation, 34%; and for those receiving continued chemotherapy, 31%.84 In standard-risk patients, there was no difference in outcome between the three approaches (i.e., 10-year survival of 49% with allogeneic transplantation, 49% with autologous transplantation, and 40% with chemotherapy), whereas for high-risk patients, allogeneic transplantation provided the best results (44% versus 10% versus 11%).84 Because children with ALL, in general, respond well to chemotherapy, there is no role for transplantation at first remission except for those with very high risk disease (e.g., Philadelphia chromosome-positive ALL).85

Myelodysplastic Syndromes

The myelodysplastic syndromes are generally considered to be incurable except with marrow transplantation. In some patients, the myelodysplastic syndromes have a relatively indolent course, and transplantation can be safely withheld until the disease progresses. However, once significant granulocytopenia (fewer than 1,000 cells/mm3) or thrombocytopenia (fewer than 40,000 cells/mm3) develops or the proportion of blast cells in the marrow exceeds 5%, transplantation should be seriously considered, because without transplantation, the expected survival time is short. When an HLA-matched sibling is available to serve as a donor, the chance of long-term survival with transplantation is roughly 55%, with better results being obtained in younger patients and in those who receive transplants earlier in the course of their disease.86 Similar results have been reported with matched unrelated donor transplants.87 No role has been established for autologous transplantation in the myelodysplastic syndromes.


Allogeneic hematopoietic cell transplantation can cure patients with primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia or polycythemia vera. In one study, 5-year progression-free survival was seen in approximately two-thirds of patients treated with a preparative regimen combining busulfan and cyclophosphamide followed by allogeneic transplantation.88 Graft failure was rare, despite the presence of splenomegaly and marrow fibrosis.

Chronic Myeloid Leukemia

Allogeneic and syngeneic marrow transplantation are the only forms of therapy known to cure chronic myeloid leukemia (CML). Five-year disease-free survival rates are 15% to 20% for patients who undergo transplantation in blast crisis, 30% to 40% for patients who undergo transplantation during the accelerated phase, and approximately 70% for patients who undergo transplantation during the chronic phase [see Table 2].89

Time from diagnosis influences the outcome of transplantation during the chronic phase. The best results are obtained in patients who receive transplants within 1 year of diagnosis; progressively worse results are seen the longer the procedure is delayed.90 A growing number of patients between 55 and 65 years of age with CML have undergone transplantation, with results not significantly worse than those seen in younger patients.91 Although the initial experience with the use of unrelated-donor transplantation in CML was substantially worse than the experience with matched-sibling transplantation, subsequent results at some centers have demonstrated a 70% probability of disease-free survival at 3 years.92

The overall role of hematopoietic cell transplantation in CML has changed with the introduction of imatinib mesylate, a very effective, relatively nontoxic oral agent used for treatment of CML.93 Imatinib does not result in complete, molecular-level remissions in most patients, and therefore, some experts would argue that early allogeneic transplantation remains the treatment of choice for younger patients with matched donors. For older patients or those without matched sibling donors, an initial trial of imatinib is generally preferred. Current evidence suggests that exposure to imatinib before transplantation poses no additional risk to the transplant procedure. Strategies of initial therapy with imatinib mesylate combined with careful molecular monitoring and transplantation at the moment of disease progression are being developed.94

Chronic Lymphocytic Leukemia

Use of marrow transplantation in chronic lymphocytic leukemia (CLL) has received only limited attention, probably because of the indolent nature of the disease and its propensity to occur in older patients. Of the small number of patients receiving allogeneic transplantation, many have had complete remissions, and approximately half have remained disease free.95,96 However, the transplant-related mortality in this group of patients has been substantial. Enduring complete responses with less transplant-related toxicity have been reported with the use of nonmyeloablative allogeneic transplantation.97 The number of patients treated with autologous transplantation is limited.95,98Complete remissions have been achieved, some of which appear to be sustained.

Non-Hodgkin Lymphoma

Patients with disseminated intermediate or high-grade NHL in whom conventional therapy fails can seldom be cured without transplantation. High-dose therapy followed by autologous or allogeneic marrow transplantation can cure a substantial number of such patients. A number of studies have documented cure rates of 40% to 50% in patients who receive transplants after an initial relapse and whose tumors remain sensitive to chemotherapy [see Table 2].99 In the initial randomized study testing the role of autologous transplantation in intermediate or high-grade NHL, the 5-year disease-free survival rate for patients who underwent autologous transplantation for chemosensitive disease was 46%, compared with 12% for patients in the chemotherapy group (P = 0.001). Cure rates decrease substantially once the disease becomes resistant to conventional-dose chemotherapy.99 A poor performance status and large tumor bulk are additional adverse risk factors. As in other diseases, patients who receive transplants of allogeneic marrow have a lower relapse rate but a higher risk of nonrelapse mortality than patients who receive autologous transplants.100 For most categories of intermediate- and high-grade NHL, the outcomes for allogeneic and autologous transplantation appear roughly similar, though an advantage has been suggested for the use of allogeneic transplantation in patients with lymphoblastic lymphoma. The role of transplantation for patients in first remission is unsettled. Of the randomized studies that have thus far been performed, some have found a significant benefit, some have found no benefit, and others have found a benefit only for the subgroup of patients with intermediate- to high-risk disease or high-risk disease.101,102

For patients with recurrent disseminated low-grade NHL, high-dose therapy supported by autologous transplantation results in high response rates and improved progression-free survival compared with standard dose therapy. In a European study, overall survival at 4 years was 46% with chemotherapy compared with 74% with autologous transplantation.103 The role of autologous transplantation in the initial treatment of patients with indolent lymphomas is under study. Results to date demonstrate higher complete response rates and improved event-free survival, but conclusions about an effect on overall survival remain premature.104 Myeloablative allogeneic transplantation results in a greater antitumor effect than autologous transplantation, but at the expense of greater toxicity. Nonmyeloablative or reduced-intensity preparative regimens followed by allogeneic transplantation have been reported to result in high response rates with substantially less toxicity than seen with ablative transplants.105

Hodgkin Disease

The results of transplantation for Hodgkin disease are similar to those for intermediate and high-grade NHL. For patients with primary progressive Hodgkin disease (defined as progression during induction treatment or within 90 days after completion of therapy), high-dose chemotherapy followed by autologous transplantation resulted in a 5-year disease-free survival rate of 42%—results that appear superior to those achieved with conventional chemotherapy.106 Prospective randomized trials have similarly shown an advantage for high-dose chemotherapy followed by autologous transplantation, as compared with conventional-dose chemotherapy, for patients with relapsed or refractory Hodgkin disease.107,108 There is currently no established role for autologous transplantation as part of the initial treatment strategy for patients with Hodgkin disease, although several trials testing this approach are being performed. As with NHL, patients with Hodgkin disease who are treated with ablative preparative regimens followed by allogeneic transplantation have lower relapse rates but higher nonrelapse mortality.109 The use of nonmyeloablative or reduced-intensity preparative regimens followed by allogeneic transplantation has been reported to result in complete enduring responses with acceptable levels of toxicity in selected patients who have recurring Hodgkin disease, including some for whom previous autologous transplantation failed.110

Multiple Myeloma

High-dose chemotherapy followed by autologous transplantation in patients with recurrent multiple myeloma can result in a substantial reduction in tumor burden and, in many cases, at least temporary complete remissions. Two prospective randomized trials have demonstrated that inclusion of high-dose chemotherapy followed by autologous transplantation in the initial treatment of patients with multiple myeloma results in a significant prolongation in patient survival.111,112 Prospective randomized trials have suggested that there is a further advantage in treating patients with two cycles of high-dose therapy, each supported by autologous transplantation, compared to a single transplant.113,114 Allogeneic hematopoietic cell transplantation following ablative preparative regimens has been used to treat myeloma patients in whom first-line chemotherapy failed; this approach achieved overall survival rates averaging 35% at 5 years [see Table 2].115 An important finding was that there appeared to be a plateau in the rate of disease-free survival, suggesting that some of these patients were cured. Transplant-associated complications, however, were substantial and occurred more frequently than in most other hematologic malignancies.116 A decrease in transplant-associated morbidity and mortality without loss of the allogeneic graft-versus-myeloma effect can be achieved with the use of nonmyeloablative or reduced-intensity preparative regimens. A strategy of treating multiple myeloma patients with a single autologous transplant followed by nonmyeloablative allogeneic transplantation is currently being tested.111

Other Hematologic Malignancies

Long-term survival has been documented after allogeneic marrow transplantation in patients with hairy-cell leukemia, various myeloproliferative syndromes, and other hematologic malignancies, but the number of patients reported in any single disease category is small.

Breast Cancer

Based on the hypothesis that breast cancer may respond better to higher-dose therapy, multiple clinical trials have explored the outcome of very high dose chemotherapy administered with autologous hematopoietic stem cell support. Encouraging results were reported from phase II trials for patients with metastatic disease, inflammatory breast cancer, and high-risk stage II disease.117,118 However, subsequent randomized trials have been somewhat less encouraging. For patients with metastatic disease, high-dose therapy followed by autologous transplantation has no effect on overall survival. Several randomized trials of this approach in high-risk stage II or stage III disease have been completed. In trials from Germany and the Netherlands, high-dose alkylating therapy followed by transplantation improved relapse-free survival rates in patients with stage II or stage III disease who had 10 or more positive nodes, but this approach has not yet resulted in improved overall survival.119,120 In an Eastern Cooperative Oncology Group study, the use of intensive chemotherapy reduced the risk of relapse of disease but did not improve disease-free survival rates or overall survival.121

Testicular Cancer

Although standard-dose chemotherapy for testicular cancer is very effective, conventional regimens fail in 30% to 40% of cases. High-dose chemotherapy with autologous marrow support has resulted in a 2-year disease-free survival of approximately 20% in patients with advanced recurrent disease—a rate seemingly better than that achieved with conventional approaches.122

Other Solid Tumors

The utility of high-dose chemotherapy with autologous stem cell support for several other solid tumors, including ovarian cancer, small cell lung cancer, neuroblastoma, and pediatric sarcomas, is being studied. As in virtually all other situations, best results occur in patients with limited tumor bulk in whom the tumor remains sensitive to conventional-dose chemotherapy. Randomized trials have shown that children with high-risk neuroblastoma appear to benefit from myeloablative therapy followed by autologous transplantation, but randomized trials addressing the utility of this approach in the other solid tumors mentioned above have not been reported.123

Treatment of Posttransplant Relapse

Patients with malignancies who experience relapse after autologous transplantation occasionally respond to further conventional-dose chemotherapy, particularly when the interval from transplantation to relapse is long. There are more options available to the patient who experiences relapse after allogeneic transplantation. Patients with CML frequently respond to therapy with interferon or imatinib mesylate, and other patients occasionally respond to withdrawal of immunosuppression. Patients who experience relapse after allogeneic transplantation sometimes respond to nonirradiated donor lymphocyte infusions. In a summary of 258 patients reported by a European registry, complete responses were seen in 75% of patients with CML, 38% with myelodysplasia, 24% with AML, and 15% with myeloma.124Responses were seldom seen in patients with ALL. The major complications of posttransplant donor lymphocyte infusions have been GVHD and myelosuppression, both of which can be severe or fatal. Starting the transfusion with a low cell dose and then gradually increasing the dose can lessen the risk of severe toxicity. A second hematopoietic cell transplantation can occasionally be effective, particularly in younger patients and in patients who experience a longer interval from first transplant to relapse and who do not have advanced disease.


Figures 1 and 2 Marcia Kammerer.

Figures 3 and 4 Courtesy of the Fred Hutchinson Cancer Research Center.

This work was supported in part by grants CA-18029, CA-47748, and CA-26386 from the National Institutes of Health, U.S. Department of Health and Human Services.


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Editors: Dale, David C.; Federman, Daniel D.