Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section D – Preventing and Treating Cancer

Chapter 32 – Hematopoietic Stem Cell Transplantation

Michael R. Bishop,Steven Z. Pavletic




Allogeneic or autologous hematopoietic stem cell transplantation (HSCT) is established and curative therapy for many patients with high-risk hematologic malignancies and a critical part of their treatment algorithms.



Hematopoiesis and immune function can be restored after marrow ablative therapy with hematopoietic stem cells obtained from the bone marrow, peripheral blood, or fetal cord blood.



The major complication and contribution to mortality and morbidity of allogeneic transplants is acute and chronic graft-versus-host disease (GVHD), which occurs in about 50% of patients; however, most patients ultimately are able to discontinue systemic immunosuppression. GVHD also contributes to the immune-mediated graft-versus-tumor effects. Adequately assessing risk and benefits is a critical part of therapeutic decision-making when deciding whether to recommend transplantation.



The use of allogeneic transplantation to treat malignancy is limited by lack of a donor—only one fourth to one third of Americans have a human leukocyte antigen (HLA)-matched sibling. However, the unrelated marrow donor volunteer registry continues to grow, and chances of finding a matched unrelated donor today are about 50%; with improving techniques, results of matched unrelated donor transplants today are similar to outcomes when using sibling donors.



Reduced-intensity (i.e., mini- or nonmyeloablative allogeneic) transplants use less-intensive preparative regimens aimed at the host T cells in an attempt to allow engraftment (and the subsequent immune attack on the cancer) while reducing the early toxicity and mortality. Such procedures permit allogeneic transplantation in older patients (up to age 70 years), in whom cancer is more common, who would not have been eligible for conventional high-dose transplant treatments.



Autologous transplantation has become standard therapy for recurrent Hodgkin's disease and chemotherapy-sensitive aggressive non-Hodgkin's lymphoma, consolidation of initial response in multiple myeloma, some pediatric malignancies, and refractory testicular cancer. Although autologous transplant is much safer than allogeneic HSCT, the limiting problem is tumor recurrence.



Adequate supportive care, and prevention and treatment of infections by a well-coordinated multidisciplinary team of subspecialists are critical for a successful transplant procedure. Due to increasing number of long-term survivors after transplantation, oncologists should be aware of late effects of transplantation therapy such as chronic GVHD, second cancers, endocrine, bone metabolism, or other organ system effects.


Hematopoietic stem cell transplantation (HSCT) is the process and intravenous infusion of hematopoietic stem and progenitor cells to restore normal hematopoiesis and/or treat malignancy. [1] [2] The termHSCT has replaced the archaic term bone marrow transplantation (BMT), because hematopoietic stem cells can be derived from a variety of sources other than the bone marrow, including the peripheral blood and umbilical cord blood. [3] [4] Stem cells used for HSCT are of hematopoietic origin; the distinction is made due to the growing interest in using more primitive stem cells for regenerative therapy due to their plasticity and unique biologic characteristics.[5] Hematopoietic stem cells are further characterized according to their source, that is, from whom they are obtained ( Table 32-1 ). Hematopoietic stem cells obtained from the patient him- or herself are referred to as autologous. [1] [3] Hematopoietic stem cells obtained from an identical twin are referred to as syngeneic HSCT, and hematopoietic stem cells obtained from someone other than the patient or an identical twin are referred to as allogeneic. HSCT is most commonly used to restore normal hematopoiesis following the treatment of cancer with chemotherapy and/or radiation at doses that result in severe, often irreversible, damage to bone marrow. The healthy new cells transplanted from a syngeneic or allogeneic source also may allow the restoration of an intact immune system, provide an antitumor effect or, in the case of HSCT for congenital diseases, provide cells that are no longer deficient in certain vital components.

Table 32-1   -- Comparison of Allogeneic and Autologous Hematopoietic Stem Cell Transplantation




Oldest age to which applicable




40–60 y

60–70 y


65–75 y


Major problem in finding a donor

Finding a closely HLA-matched sibling or unrelated donor

Ability to collect sufficient numbers of hematopoietic progenitor cells uncontaminated by tumor cells

Most important complication

Graft-versus-host disease

Relapse of original disease

Anti-cancer effect of infused cells

Proved or suspected in a number of malignancies

Probably no

Most commonly treated cancers

Acute leuekemias

Multiple myeloma



Non-Hodgkin's lymphoma



Hodgkin's disease

Modified from Armitage JO: Bone marrow transplantation. N Engl J Med 1994;330:827.




The clinical application of HSCT originated in the identification of the severe myelosuppressive effects of radiation that were observed among nuclear bomb survivors at Hiroshima and Nagasaki.[6]Intensive research efforts were made at that time to develop methods to reverse the myelosuppressive effects of radiation, including the infusion of bone marrow. [7] [8] [9] [10] [11] In 1949, Jacobson and colleagues[7] at the University of Chicago reported on the effects of shielding the spleen of mice from lethal does of irradiation. Shielding of the spleen protected nearly all mice at a total body irradiation dose of 700cGy, whereas unshielded mice all died from marrow aplasia. As the dose of radiation was raised to 1050cGy, approximately one third of the shielded mice survived, and a dose of 1200cGy was lethal to all mice. At autopsy, these latter radiation groups were found to have died from fibrosis of the lungs, liver, and kidneys. The authors unfortunately concluded that shielding the spleen was protecting a humoral factor that affected hematopoiesis; however, it subsequently was determined that early hematopoietic progenitors actually were protected from the effects of radiation. From these early studies, theories evolved into the concept that radiation and chemotherapy could be administered at controlled yet highly myelosuppressive doses, which were capable of eliminating malignant hematopoietic clones, and normal hematopoiesis could be re-established by the infusion of normal bone marrow. Early animal studies of HSCT were thwarted by incompatibility between bone marrow recipients and donors, which led to a high degree of graft rejection.[11] Among animals that did not reject their marrow grafts, a syndrome of weight loss, alopecia, diarrhea, and eventually death was commonly observed. This syndrome, originally referred to as “runting” disease, now is referred to clinically as graft-versus-host disease (GVHD) and is discussed in more detail later in this chapter.[12] Understanding of the major histocompatibility complex (MHC) and human leukocyte antigens (HLA) as the major determinants of graft rejection, which was developed subsequently, significantly advanced laboratory studies and clinical application of allogeneic HSCT.[13]

The first successful clinical bone marrow transplantation trials among patients with severe combined immunodeficiency disorders and advanced acute leukemias were reported in the late 1960s and early 1970s ( Fig. 32-1 ), after clinical methods to determine HLA were developed, permitting the “matching” of bone marrow donors and recipients. [1] [11] Subsequently, in the late 1970s, reports were published on the successful use of high-dose chemotherapy and autologous BMT to treat patients with advanced lymphomas.[14] Today allogeneic HSCT is a standard treatment for many immunodeficiency states, metabolic disorders (e.g., Hurler's syndrome), and defective hematopoietic states (e.g., severe aplastic anemia, thalassemia). Autologous HSCT currently is being investigated in nonmalignant diseases, including autoimmune diseases (e.g., multiple sclerosis), and the emerging field of regenerative medicine, which takes advantage of the plasticity of stem cells to repair defective or damaged tissues (e.g., cardiac muscle after a myocardial infarction). [15] [16] Both autologous and allogeneic HSCT are standard treatment options for a variety of hematologic malignancies and selected solid tumors. This chapter focuses primarily on the rationale for the application of HSCT in the treatment of malignancy.


Figure 32-1  Annual numbers of blood and marrow transplants worldwide, 1970–2003.  (Data from the Center for International Blood and Marrow Transplant Research, Milwaukee, WI.)



The type of HSCT that a patient receives—allogeneic versus syngeneic versus autologous—usually is predetermined, because very few patients have an identical twin (i.e., syngeneic), and the availability of an allogeneic donor is limited even with potential use of unrelated donors and stored cord blood units. Autologous hematopoietic stem cells are available to most patients provided that the autologous hematopoietic stem cells product, bone marrow or peripheral blood, is relatively free of contamination by malignant cells and that prior therapy has not limited the number of cells that can be collected.

Allogeneic Hematopoietic Stem Cell Transplantation

In allogeneic HSCT, stem cells are obtained from a donor other than the recipient. Donor and recipient usually are identical or “matched” for HLA, which is derived from the MHC located on chromosome 6.[17] A single set of MHC alleles, described as a haplotype, is inherited from each parent, resulting in HLA pairs. The most important HLAs include HLA-A, HLA-B, HLA-C, DR, and DQ loci. Among siblings, the genes which encode for HLA-B and HLA-C are located so close to each other in the MHC that one is rarely inherited without the other. As a result, an HLA match among siblings is referred to a “6 of 6,” as they are matched for HLA-A, B, and DR; however, in actuality they are matched for all of the HLA antigens.[3] The other antigens, such as HLA-C, become more important in alternative sources of hematopoietic stem cells, such as unrelated donors and cord blood, which are described in more detail later in this chapter. [18] [19]

The distinctive characteristics of allogeneic HSCT are that the stem cell graft (1) is free of contamination by malignant cells and (2) contains T cells that are capable of mediating an immunologic reaction against foreign antigens. This latter characteristic can be a major advantage if the immunologic response is directed against malignant cells—the graft-versus-leukemia or graft-versus-tumor effect—thus potentially eradicating disease and reducing the chance of disease relapse. However, if the immunologic response is directed against antigens present on normal tissues, it can lead to the destruction of normal organs, described clinically as GVHD. The risk of both graft rejection (host-versus-graft reaction) and GVHD rises with HLA disparity.

The graft-versus-leukemia effect first was recognized in animal models and subsequently was noted among patients undergoing allogeneic HSCT for acute and chronic leukemias. [20] [21] [22] [23] The clinical importance of the interactions between immunocompetent donor T cells and tumor cells in mediating a graft-versus-leukemia effect is supported by an increased rate of relapse in allogeneic stem cell grafts from which T cells have been removed (T-cell depletion), an inverse correlation between relapse and severity of GVHD, and increased rate of relapse after syngeneic or autologous HSCT using the same myeloablative conditioning regimen. [23] [24] These data suggested that T cells within the allograft were involved directly in eradicating leukemia. Finally, the most compelling evidence for a T-cell-mediated graft-versus-leukemia effect originates from the observation that infusion of allogeneic lymphocytes, a donor lymphocyte infusion, at a time remote from the transplant conditioning regimen, can treat leukemia relapse successfully after allogeneic HSCT. [25] [26] [27] [28] In an early report, donor lymphocyte infusion therapy was given to three patients with chronic myelogenous leukemia whose disease had recurred after an allogeneic HSCT.[25] The donor lymphocyte infusion, without any additional cytotoxic therapy, resulted in sustained cytogenetic and molecular remissions. Over time it became increasingly apparent that a significant part of the curative potential of allogeneic HSCT could be directly attributed to the graft-versus-leukemia effect. However, there is tremendous variability relative to the clinical effectiveness of the graft-versus-leukemia effect against different malignancies after allogeneic HSCT.

The choice of donor for an allogeneic HSCT takes into account several factors, including the patient's disease, disease state, and urgency in obtaining a donor. When allogeneic HSCT is being considered for a patient, a fully HLA-matched sibling is the preferred donor source, because the risk of graft rejection and GVHD is lowest with this source of allogeneic stem cells. As described earlier, a haplotype is inherited from each parent, and by simple Mendelian genetics it would be expected that the probability that two siblings would share the same haplotypes would be 1:4. The probability of having an HLA-matched sibling increases with the number of siblings within a specific family. The probability can be estimated using the following formula: The chance of having an HLA-matched sibling = 1 - (.75)n, where n is the number of potential sibling donors.[3] There is an approximately 1% chance of crossing over (i.e., genetic material switched between chromosomes during meiosis), primarily between the HLA-A and the HLA-β loci. The clinical outcomes for allogeneic HSCT using a sibling with a single HLA mismatch are similar to those with a fully HLA-matched sibling.[29]

For patients who lack a fully HLA-matched sibling donor, the preferred alternative sources for allogeneic stem cells include an unrelated fully HLA-matched donor, a partially HLA-matched cord blood unit, or a partially HLA-matched family member. [30] [31] [32] A closely HLA-matched volunteer hematopoietic stem cell donor may be identified through a bone marrow donor registry, such as the National Marrow Donor Program in the United States, which includes about 6 million potential donors. Many HLA phenotypes are possible, which sometimes makes the identification of a matched unrelated donor difficult and time consuming. [33] [34] Depending on the ethnic descent of both patient and donor, the probability of identifying an HLA-matched unrelated donor is between 50% and 80%. [8] [9] Due to advances in HLA-typing through the use of molecular typing techniques and improved supportive care over the last decade, current results of matched unrelated donor transplants for malignancy are not significantly different when compared to HSCT from matched sibling donor transplant. [19] [35]

One major disadvantage of using an unrelated donor is that the average time required to identify and procure an HLA-matched unrelated donor is approximately 2 to 3 months, which may be too long for patients with rapidly progressive malignancies.[36] The alternative stem cell source to an unrelated bone marrow donor for allogeneic HSCT is stored umbilical cord blood. [31] [36] [37] The major advantages of umbilical cord stem cells are that they can be obtained in less than 4 weeks and that even cord blood units mismatched in up to 2 of 6 HLA may be used for allogeneic HSCT. This degree of HLA mismatching is acceptable, because the overwhelming percentage of T cells within the cord blood unit are naïve, and the incidence of acute GVHD is comparable to or less than that associated with an HLA-matched unrelated bone marrow donor. The major disadvantage of umbilical cord blood units is they are associated with a relatively high degree of graft rejection, especially in adults. [31] [37]Engraftment and treatment-related mortality appear to be directly related to umbilical cord cell dose. It may be that the limitation of cell dose can be overcome by the use of more than one cord blood unit; this approach currently is under clinical investigation.[38] The other significant disadvantage is that once the cord blood unit is used, there is no way to go back and get additional cells for a donor lymphocyte infusion or in the event of graft failure.

The other alternative source of allogeneic hematopoietic stem cells is to identify among the patient's first-degree relatives individuals who share at least one haplotype (haplo-identical) with the potential recipient.[32] The major advantage with the use of a partially HLA-matched family member is that the donor is readily available for almost all patients. The major disadvantages are an increased risk of graft rejection, GVHD, and severe immune dysregulation, which rises with higher degrees of HLA-mismatching. Haplo-identical allogeneic HSCT has been limited primarily to use in children. [32] [39]

Once an allogeneic stem cell source has been identified, patients are put on regimens with the intent of “conditioning” or “preparing” them for the infusion of hematopoietic stem cells. Most conditioning or preparative regimens use a combination of radiation and chemotherapy. [1] [3] They also may contain radioimmunoconjugates and/or monoclonal antibodies that target T cells (e.g., alemtuzumab).[40] The choice of a specific conditioning regimen depends on the disease that is being treated. The earliest conditioning regimens were designed to permit the administration of maximum doses of chemotherapy and/or radiation (i.e. “high-dose” regimens) for the eradication of disease and to be adequately immunosuppressive to prevent graft rejection. The most commonly used chemotherapy agents in these regimens are alkylating agents (e.g., cyclophosphamide and/or etoposide) with or without total lymphoid or total body irradiation at doses varying between 800 to 1440cGy. The doses of chemotherapy and radiation used in these regimens are referred to as myeloablative, because they result in a degree of myelosuppression and immunosuppression that is nearly universally fatal without the infusion of hematopoietic stem cells as a rescue product.[41]

Allogeneic HSCT with myeloablative conditioning regimens has been performed successfully in patients older than 60 years of age; however, survival after these transplants declines with increasing age, limiting the application of allogeneic transplantation to a minority of patients who potentially could benefit from this procedure. However, the demonstration that an immune-mediated graft-versus-leukemia effect plays a central role in the therapeutic efficacy of allogeneic HSCT led to the hypothesis that myeloablative conditioning regimens were not essential for tumor eradication.[42] This idea subsequently led investigators to develop less intense conditioning regimens, which were adequately immunosuppressive to permit the engraftment of donor hematopoietic stem cells, decrease toxicities associated with myeloablative conditioning regimens, and serve as a platform for the administration of donor T cells as adoptive cellular therapy. A variety of nonmyeloablative and reduced-intensity conditioning regimens has been reported. [43] [44] [45] [46] These regimens are associated with decreased early post-transplant morbidity and mortality; however, the important clinical question is whether this reduction in toxicity comes at the cost of a loss of antitumor activity within the conditioning regimen.

Syngeneic Hematopoietic Stem Cell Transplantation

Syngeneic HSCT utilizes stem cells from an identical twin. [47] [48] Because the hematopoietic stem cells are genetically identical with the recipient, the major advantage of a syngeneic HSCT is that it is not associated with GVHD or graft rejection, resulting in a relatively low risk of treatment-related morbidity and mortality. Another significant advantage of syngeneic HSCT, which is shared with allogeneic HSCT, is there is no risk of contamination by malignant cells. The major disadvantage is that syngeneic HSCT does not provide the graft-versus-leukemia effect that is associated with allogeneic HSCT. The greatest disadvantage is that far fewer than 1% of patients have an identical twin, and consequently, this is not an option for most patients. However, when an identical twin is available, syngeneic HSCT is considered the preferred type of HSCT in almost all clinical situations.

Autologous Hematopoietic Stem Cell Transplantation

Autologous HSCT employs stem cells from the patient him- or herself. The principle behind autologous HSCT, as well syngeneic HSCT, is that certain malignancies, such as leukemias, have a steep dose-response curve to chemotherapy and, to a relative degree, radiation. [49] [50] [51] The major limitation to the administration of higher doses of chemotherapy or radiation is the myelosuppressive effects of these therapies. Autologous, allogeneic, and syngeneic hematopoietic stem cells permit the administration of high-dose chemotherapy and/or radiation by restoring hematopoiesis. The major advantages of autologous HSCT compared with allogeneic HSCT are that (1) the patient can serve as his or her own donor and (2) it may be performed in older patients with significantly decreased mortality, due to the absence of GVHD as a major complication. However, autologous HSCT can be associated with more morbidity than conventional doses of radiation and chemotherapy. A potential disadvantage of autologous HSCT is the possible reinfusion of viable tumor cells.[52] Numerous methods, including in vitro treatment with chemotherapeutic agents or monoclonal antibodies plus complement, have been developed to remove contaminating tumor cells from the graft, a process often referred to as purging, or to concentrate hematopoietic stem cells, a process referred to as positive selection. [53] [54] [55] [56]Retrospective analyses have suggested that purging leads to a reduced relapse rate in patients with acute myelogenous leukemia and β-cell non-Hodgkin's lymphomas. [57] [58]

Hematopoietic Stem Cell Acquisition and Processing

Hematopoietic stem cells may be obtained from the bone marrow, the peripheral blood, and umbilical cord blood. Hematopoietic stem cells from bone marrow are used in both autologous and allogeneic HSCT, although less frequently than in the past. Peripheral blood hematopoietic stem cells are used in approximately 90% of autologous HSCT and in approximately 70% of allogeneic HSCT.[59] The greater use of peripheral blood hematopoietic stem cells is related to their relative ease of attainment and moderate improvement in the rate of hematopoietic recovery after infusion as compared to hematopoietic stem cells derived from bone marrow. In steady-state, the concentration of hematopoietic stem cells and myeloid progenitor cells is quite low, and prior to collection of peripheral blood hematopoietic stem cells by apheresis, attempts are made to increase or “mobilize” the number of circulating hematopoietic stem cells by various techniques.[60] Hematopoietic stem cells may be mobilized into the peripheral blood following administration of myeloid hematopoietic growth factors (e.g., granulocyte colony-stimulating factor), during the recovery phase from exposure to chemotherapy, or by using both chemotherapy and growth factors. [61] [62] [63] [64] Collection of peripheral blood hematopoietic stem cells from a normal donor for allogeneic HSCT is performed following mobilization with myeloid hematopoietic growth factors only. In general, at least 1 × 106 CD34+ cells/kg of recipient weight are collected from the peripheral blood by apheresis. The cells are then processed with dimethylsulfoxide (DMSO) with or without hydroxyethylstarch and then stored in liquid nitrogen until needed for transplantation.[65]

Methods for collecting or “harvesting” hematopoietic stem cells from bone marrow are modifications of the technique initially reported by Thomas and Storb.[66] The bone marrow harvest usually is performed under general anesthesia and generally is well tolerated. [67] [68] Bone marrow hematopoietic stem cells usually are harvested by repeated aspirations from the posterior iliac crest until an adequate number of cells have been removed. If sufficient cells cannot be obtained from the posterior iliac crest, marrow also can be harvested from the anterior iliac crest and sternum. The minimal number of nucleated marrow cells required for long-term repopulation in humans is not precisely known. In practice, the number of nucleated marrow cells harvested is usually 1 - 3 × 108/kg of recipient weight, depending on the diagnosis (i.e., higher for aplastic anemia), the type and intensity of pretransplant conditioning, and whether the marrow graft will be modified in vitro. Marrow sometimes is treated in vitro to remove unwanted cells before it is returned to the patient. In allogeneic HSCT with major ABO incompatibility between donor and recipient, it is necessary to remove the mature erythrocytes from the graft to avoid a hemolytic transfusion reaction.[69] After collection and processing, hematopoietic stem cells from bone marrow may be directly infused or cryopreserved in an identical manner as hematopoietic stem cells from the peripheral blood.

Hematopoietic stem cells from cord blood are collected immediately after delivery. A minimally acceptable cord blood unit dose is 1.7 × 105 CD34+ cells per the patient's weight in kilograms to ensure engraftment in the allogeneic HSCT setting.[70] This criterion is a significant problem for adult patients, where the application of cord blood transplantation has been associated with delayed hematopoietic recovery, especially platelets, graft failure, and a relatively high treatment-related mortality in comparison to other sources of allogeneic hematopoietic stem cells.


Clinical evidence exists that syngeneic, autologous, and allogeneic HSCT all provide benefit—defined as response, freedom of progression, or overall survival—for most hematologic malignancies and for a minority of solid malignancies ( Fig. 32-2 ).[3] However, the beneficial effects of these various forms of HSCT vary greatly with each type of malignancy. Data indicate that due to their relative responsiveness to cytotoxic therapy, myeloablative conditioning regimens with syngeneic, autologous, or allogeneic HSCT result in higher response rates than cytotoxic or conventional agents for almost all hematologic malignancies. However, the durability of these responses and their effect on survival varies from disease to disease. Similarly, there is evidence of a clinical graft-versus-leukemia effect in almost every hematologic disease; however, the potency and clinical relevance are highly variable. Interpretation of the results of trials of HSCT always is complicated by issues of patient selection. This can lead to either underestimating the efficacy of HSCT if it is used after exhausting all other available therapies or overestimating its efficacy if only the patients with favorable prognostic characteristics are selected. The specific indications for HSCT are covered in the chapters for each respective disease. This section briefly addresses the outcomes for malignancies with different forms of HSCT.


Figure 32-2  Indications for blood and marrow transplantation in North America in 2003. ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; NHL, non-Hodgkin's lymphoma; MDS, myelodysplastic syndrome.  (Data from the Center for International Blood and Marrow Transplant Research, Milwaukee, WI.)


Acute Myelogenous Leukemia

Acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) were the first malignancies in which all forms of HSCT were demonstrated to be effective. [22] [24] [71] Initial studies of myeloablative allogeneic HSCT demonstrated that this treatment was capable of resulting in long-term survival for a minority of patients with refractory and relapsed AML.[71] Unfortunately, the cure rate in these latter cases is only about 10%. Long-term survival and an apparent cure rate of 20% to 40% have been achieved in patients treated in second or subsequent complete remission, and cure rates of 40% to 70% have been reported in patients given transplants in their first complete remission. [72] [73] [74] [75] Randomized controlled trials comparing autologous and allogeneic HSCT to conventional chemotherapy in patients with AML in first complete remission have demonstrated improved leukemia-free survival with both forms of HSCT; however, there has been no significant improvement in overall survival. [76] [77] [78] [79] The one exception has been in pediatric AML, where allogeneic HSCT has been demonstrated to improve both leukemia-free and overall survival for patients transplanted in first complete remission.[80] The lack of improvement in overall survival in adults is attributed to high rates of treatment-related mortality with allogeneic HSCT, high relapse rates with autologous HSCT, and the fact that patients could successfully undergo HSCT at first sign of relapse.[81] Because a significant proportion of patients can be cured with standard chemotherapy regimens without HSCT and because cure rates of 20% to 30% have been reported for HSCT in early first relapse, withholding HSCT until the first sign of treatment failure is an alternative treatment strategy.[82] Reduced-intensity and nonmyeloablative conditioning regimens may increase the applicability of allogeneic HSCT for older patients. The Acute Leukemia Working Party and European Group of Blood and Marrow Transplant compared the results of reduced-intensity conditioning with myeloablative regimens in patients with AML over 50 years of age undergoing allogeneic HSCT from HLA-matched siblings.[83] Transplant-related mortality was significantly decreased, but the relapse incidence was significantly higher after reduced-intensity conditioning. Leukemia-free survival was not statistically different between the two groups.

Myelodysplastic Syndrome

The only known curative treatment for myelodysplastic syndrome (MDS) is allogeneic HSCT. In this setting, long-term disease-free survival of greater than 40% has been obtained.[84] The best results have been obtained in relatively younger patients, who are earlier in their disease course and have not received any prior therapy. To identify factors influencing transplantation outcome for MDS, the International Bone Marrow Transplantation Registry (IBMTR) studied 452 recipients of HLA-identical sibling transplants for MDS.[85] Sixty percent of patients had refractory anemia with excess blasts (N= 136) or with excess blasts in transformation (N = 136). Three-year transplantation-related mortality, relapse, disease-free survival, and overall survival rates were 37%, 23%, 40%, and 42%, respectively. Multivariate analyses showed that young age and platelet counts higher than 100 at transplantation were associated with lower transplant-related mortality and higher disease-free and overall survival rates. Because the optimal timing for bone marrow transplantation for MDS is unknown, the IBMTR constructed a Markov model to examine three transplantation strategies for newly diagnosed MDS: transplantation at diagnosis; transplantation at leukemic progression; and transplantation at an interval from diagnosis but prior to leukemic progression.[86] Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all four IPSS risk groups with adjustments for quality of life. For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. There is evidence that reduced-intensity allogeneic HSCT may benefit older patients with MDS. [87] [88] The use of autologous HSCT for MDS remains investigational.[89]

Acute Lymphocytic Leukemia

The results of standard therapy in childhood acute lymphocytic leukemia (ALL) are sufficiently good with intensive chemotherapy regimens that HSCT probably should be performed as part of primary therapy only in special situations, such as in patients with childhood ALL who are Philadelphia (Ph) chromosome-positive, in whom the cure rate with standard therapy is very low.[90] However, the overall prognosis for both pediatric and adult patients with relapsed ALL is relatively poor, and the general treatment strategy is to obtain a second complete remission and then proceed to an allogeneic HSCT. [91] [92]

In light of this significantly higher relapse rate with conventional therapy, there has been strong interest in the use of both allogeneic and autologous stem cell transplantation as consolidation of adult patients with ALL who are in first complete remission. [93] [94] [95] The French protocol LALA 87 was designed to compare chemotherapy alone versus autologous or allogeneic HSCT as postinduction (i.e., consolidation) strategies in adult ALL.[93] This trial demonstrated a significant superiority of allogeneic bone marrow transplantation in high-risk patients with ALL. A trend also was detected in favor of autologous BMT over chemotherapy in those same patients. The BGMT Group performed a prospective, randomized trial in adults to compare disease-free survival after allogeneic or autologous bonemarrow transplantation in a total of 135 previously untreated adult patients with ALL.[94] The 3-year post–complete remission probability of disease-free survival was significantly higher in the allogeneic stem cell group. The authors concluded that early allogeneic transplantation was an effective consolidation treatment for adult patients with ALL in first complete remission. The French LALA-94 trial determined the benefits of a risk-adapted postremission strategy hematopoietic stem-cell transplantation in 922 adult patients with ALL.[95] The study demonstrated that allogeneic HSCT improved disease-free survival in high-risk ALL in the first complete remission, whereas autologous HSCT did not confer a significant benefit over chemotherapy for high-risk ALL.

Multiple Myeloma

Both allogeneic and autologous HSCT have been performed for multiple myeloma, because standard chemotherapy regimens rarely, if ever, cure the disease. The efficacy of high-dose chemotherapy in multiple myeloma has led to inclusion of autologous HSCT as part of its initial therapy. [96] [97] Its unique biologic characteristics have led to clinical data demonstrating that the inclusion of more than one cycle of high-dose chemotherapy with autologous HSCT may improve upon the results of a single transplant.[98] Although clear evidence exists of a graft-versus-leukemia effect against multiple myeloma, a tumor-specific antigen has not been identified. The use of myeloablative allogeneic HSCT is controversial, because it has been associated with a high mortality rate.[99] Results of allogeneic HSCT in multiple myeloma have improved with the use of nonmyeloablative conditioning regimens, and there is evidence to suggest that this approach can result in an improvement in progression-free and overall survival.[100]

Chronic Myelogenous Leukemia and Other Myeloproliferative Disorders

Chronic myelogenous leukemia (CML) is highly susceptible to the graft-versus-leukemia effect, as evidenced by the long-term, leukemia-free survival rates exceeding 70% for patients who were transplanted in early chronic phase and the response of CML to donor lymphocyte infusion. [101] [102] [103] [104] Allogeneic HSCT from an HLA-matched sibling or unrelated donor previously was the treatment of choice for patients of an appropriate age with chronic-phase CML. [101] [102] [103] However, due to the tremendous clinical success of imatinib (STI-571, Gleevec), the emerging predominant strategy is to use allogeneic HSCT in patients with more advanced CML, and it is reserved for patients who have failed or progressed on imatinib.[105] Autologous HSCT has limited efficacy in CML due to the relative lack of sensitivity of CML to cytotoxic therapy and the difficulty of obtaining a relatively tumor-free autograft.[106]

Myeloproliferative disorders usually are chronic in nature but can progress to a “spent” phase and develop myeloid metaplasia, which is characterized by bone marrow fibrosis and a generally poor prognosis with transformation into acute leukemia and a median survival of less than 3 years. [107] [108] Conventional treatment options at this state of the disease are limited, and the accepted standard of care for myeloid metaplasia/myelofibrosis is allogeneic stem cell transplantation with a myeloablative conditioning regimen. [109] [110] There have been anecdotal reports of the use of nonmyeloablative allogeneic HSCT for myelofibrosis and other myeloproliferative disorders.[111]

Chronic Lymphocytic Leukemia

Both allogeneic and autologous HSCT have been used for the treatment of chronic lymphocytic leukemia (CLL). [112] [113] [114] However, the application of allogeneic and autologous HSCT for CLL has been limited by treatment-related mortality and relapse for each type of HSCT. Considerable interest and research has been devoted to the use of nonmyeloablative and reduced-intensity conditioning regimens prior to allogeneic HSCT for CLL in hopes of reducing the treatment-related mortality. [115] [116] [117] The Chronic Leukemia Working Party of the European Blood and Marrow Transplant Group reported on 77 patients with CLL who underwent a nonmyeloablative allogeneic HSCT.[115] Treatment-related mortality after 12 months was 18%. At a median follow-up of 18 months, the 2-year probability of relapse was 31%. Event-free and overall survival rates at 24 months were 56% and 72%, respectively. The Cooperative German Transplant Study Group reported on 30 patients with advanced β-cell CLL who underwent reduced-intensity allogeneic stem cell transplantation from either related (N = 15) or unrelated (N = 15) donors.[116] The probabilities of overall survival, progression-free survival, and treatment-related mortality at 2 years were 72%, 67%, and 15%, respectively. These data indicate that allogeneic HSCT after reduced-intensity conditioning can result in relatively high, durable, complete response rates (>50%) with acceptable treatment-related mortality rates.

Non-Hodgkin's Lymphoma

Allogeneic, syngeneic, and autologous HSCT have been reported to yield long-term disease-free survival and an apparent cure for patients with intermediate and high-grade non-Hodgkin's lymphomas (NHL). [118] [119] [120] Due to its relative sensitivity to chemotherapy, there is substantial evidence that autologous HSCT is efficacious for patients with primary refractory or chemotherapy-sensitive recurrent NHL of specific histologies including “intermediate-grade” (e.g., disease-diffuse, large B-cell) NHL.[121] It is now apparent that patients who fail to achieve an initial complete remission, but who do not have other adverse prognostic factors such as poor performance status or bulky disease, also can achieve long-term disease-free survival.[122] Because of the superior results achieved in patients treated earlier in the course of the disease, a number of investigators have incorporated high-dose therapy and autologous HSCT into the primary treatment of patients with intermediate and high-grade non-Hodgkin's lymphoma. [123] [124]

Autologous HSCT also has been used to treat patients with indolent (“low-grade”) NHL (e.g., follicular center cell) with either purged bone marrow or peripheral blood stem cells, resulting in disease-free survival rates as high as 60%. [125] [126] However, the late relapses seen in this illness and long overall survival observed with conventional therapy make very long follow-up necessary to document the efficacy of this approach.

The demonstration of a potent graft-versus-leukemia effect against NHL is less clear, and the efficacy of donor lymphocyte infusion in lymphoma is anecdotal at best. [126] [127] [128] Consequently, the specific role of allogeneic HSCT has not been defined. However, there are data that myeloablative allogeneic HSCT can result in long-term survival for patients with recurrent or refractory NHL, [120] [129]and evidence exists that nonmyeloablative allogeneic HSCT may provide benefit for patients with recurrent follicular non-Hodgkin's lymphoma. Some evidence, however, indicates that this approach requires that the disease remains chemotherapy-sesitive.[130]

Hodgkin's Disease

High-dose therapy with autologous or allogeneic HSCT has been widely used in patients with recurrent Hodgkin's disease (HD; also known as Hodgkin's lymphoma). [131] [132] [133] As in NHL, patients with HD whose disease fails to respond to front-line therapy can derive benefit from high-dose therapy and autologous HSCT.[134] Allogeneic HSCT has had a limited role in the treatment of HD due to the efficacy of autologous HSCT, the treatment-related toxicities associated with myeloablative allogeneic HSCT, and lack of evidence of a graft-versus-leukemia effect against HD. However, recent data indicate that reduced-intensity allogeneic HSCT may benefit patients with recurrent HD, and a graft-versus-leukemia effect against HD may exist.[135]

Soft Tissue Sarcomas and Neuroblastoma

High-dose therapy and autologous HSCT have been used as either consolidation of primary therapy or treatment of metastatic or recurrent soft tissue sarcomas, such as Ewing's sarcoma, rhabdomyosarcoma, and osteosarcoma in children. [136] [137] Burdach and colleagues reported a 45% relapse-free survival for patients with poor-risk and recurrent Ewing's sarcoma who received high-dose therapy and autologous HSCT, as compared with 2% for a historical control group.[136] The European BMT Solid Tumor Registry reported the results from 21 European transplant centers on 50 patients with Ewing's sarcoma in first or second complete remission consolidated with high-dose chemotherapy and autologous HSCT.[137] Thirty-two patients with high-risk or metastatic disease in first complete remission achieved an actuarial event-free survival of 21% at 5 years. Results of prospective studies of high-dose therapy and autologous HSCT in soft tissue sarcomas, primarily in children, suggest a possible improvement in remission duration and possibly on overall survival. [138] [139] Autologous HSCT remains investigational in adults with sarcomas.

Autologous HSCT has been found to be beneficial for both newly diagnosed and recurrent neuroblastoma. [140] [141] [142] [143] The Children's Cancer Group assessed whether high-dose therapy and autologous bone marrow transplantation improved event-free survival as compared with chemotherapy alone.[140] All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with high-dose therapy and purged autologous bone marrow transplantation or to receive three cycles of intensive chemotherapy alone. The mean event-free survival rate was significantly better among the patients who were assigned to undergo transplantation.

Germ Cell Tumors

In patients with germ cell tumors for whom platinum-based chemotherapy regimens fail to effect a cure, the use of high-dose chemotherapy and autologous BMT has resulted in prolonged disease-free survival, including patients with refractory disease. [144] [145] Evidence exists suggesting that tandem transplant may result in improved results; however, no direct comparison of single versus tandem transplants has been performed.[146]

Other Solid Tumors

Several nonrandomized trials and retrospective analyses had suggested that high-dose chemotherapy and autologous stem cell transplantation were beneficial in regard to prolongation of survival in stage II/III breast cancer. [147] [148] Subsequently, several randomized trials addressed the role of high-dose therapy and autologous stem cell transplantation in patients with stage II/III breast cancer. [149] [150] [151] [152] [153] Most of these trials found no evidence of a survival advantage for patients randomized to receive high-dose therapy, although some of the trials suggested an improvement in event-free survival in the high-dose arm. Evidence also is lacking that high-dose chemotherapy and autologous HSCT improve survival in metastatic breast cancer.[154]

There has been considerable interest in investigating the presence of a “graft-versus-tumor” effect in a variety of solid tumors, including renal cell carcinoma and breast cancer. [155] [156] [157] Childs and colleagues[155] reported on a series of 19 patients with metastatic renal cell carcinoma who underwent nonmyeloablative allogeneic stem cell transplantation. Nine patients had responsive disease (47%), of which three were complete responses.


In addition to the acute toxicities associated with prolonged cytopenia, other organ toxicities can be associated with transplantation. A simple index, based on pretransplant comorbidities, has been developed that reliably predicts nonrelapse mortality and survival.[158] This comorbidity index is useful for patient counseling prior to HSCT. The late toxicities always must be kept in mind when choosing therapies for patients.[159]

Graft Rejection

Graft rejection occurs when immunologically competent cells of host origin destroy the transplanted cells of donor origin.[160] This complication occurs more commonly in patients who receive transplants from alternative or HLA-mismatched donors, in T cell-depleted transplants, and in patients with aplastic anemia who receive a non–total body irradiation (TBI)-containing regimen. Graft rejection is less likely to occur in nontransfused patients with aplastic anemia.

Cardiac Toxicity

Most transplant centers screen potential patients for underlying cardiac abnormalities that would place them at potential increased risk during the procedure.[161] Despite this screening, however, a small number of patients experience cardiotoxicity, either acutely during the transplant or at a later time, manifested as a cardiac arrhythmia, congestive heart failure, or cardiac ischemia due to the large volumes of fluids administered during the procedure or from the added physiologic stress.[162] Complications associated with a pericardial effusion can be seen in some patients during or after transplant and are more common in patients with disease near that area and those receiving radiation therapy in that field. An idiosyncratic cardiomyopathy associated with the administration of high doses of cyclophosphamide can be demonstrated in a small number of patients. Viral cardiomyopathies also can be seen as a late transplant complication.

Engraftment Syndrome

Engraftment syndrome occurs during neutrophil recovery following both autologous and allogeneic HSCT.[163] It consists of a constellation of symptoms and signs that may include fever, erythrodermatous skin rash, and noncardiogenic pulmonary edema, and, in its most extreme forms, acute renal failure and diffuse alveolar hemorrhage. These clinical findings reflect the manifestations of increased capillary permeability. Making a distinction from hyper-acute GVHD in the allogeneic setting has been difficult, however. Corticosteroid therapy often is dramatically effective for engraftment syndrome, particularly for the treatment of the pulmonary manifestations.

Pulmonary Toxicities

Pulmonary toxicities are common during and after transplantation. Patients who receive certain chemotherapeutic agents, such as 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU; carmustine) have an increased incidence of chemotherapy-induced lung tissue damage after transplant, which usually can be treated successfully with the prompt initiation of corticosteroid therapy.[164] In addition to these complications, patients who are undergoing allogeneic transplant are at increased risk for pneumonitis caused by cytomegalovirus, fungal infections due to the patient's increased immunosuppression, and adult respiratory distress syndrome or interstitial pneumonia of unknown etiology. Chronic GVHD also can manifest as bronchiolitis obliterans in the lung.[165]

Liver Toxicity

The most common liver complication associated with transplantation is venoocclusive disease (VOD [sinusoidal obstruction syndrome of the liver]). [166] [167] Symptoms associated with VOD include jaundice, tender hepatomegaly, ascites, and weight gain. Progressive hepatic failure and multiorgan system failure can develop in the most severe cases. Predisposing factors appear to be previous hepatic injury, use of estrogens, and high-dose intensity conditioning.[167]

Renal Toxicity

Acute renal failure requiring dialysis during the transplant occurs infrequently.[168] However, patients with underlying renal dysfunction are at risk for this complication. The judicious use of nephrotoxic agents can decrease its incidence. The need for dialysis typically is a short-term complication, because the patient's underlying problem (e.g., a septic event) either improves with time or becomes life-threatening, sometimes leading to death. An idiopathic or cyclosporine-induced hemolytic-uremic syndrome can be a serious complication after allogeneic stem cell transplantation, posing a high mortality risk or resulting in end-stage renal disease. Recently, nephrotic syndrome and membranous nephropathy have been described in long-term survivors; these complications seem to be associated more commonly with chronic GVHD and nonmyeloablative conditioning.[169]

Graft-versus-Host Disease

In the setting of allogeneic HSCT, complications associated with acute and chronic GVHD also are of concern. Previously, acute and chronic GVHD were distinguished chronologically by whether GVHD occurred before or after the fist 100 days after transplant, respectively. However, acute or chronic GVHD is a clinical diagnosis, based on the characteristic clinical manifestations and context, and neither is specifically defined by the “day 100” dichotomy any longer ( Table 32-2 ). In the evaluation of both acute and chronic GVHD, which usually includes a tissue biopsy, it is important to exclude other potential diagnoses such as infection, drug reaction, or second malignancies, which can mimic GVHD. Acute GVHD is manifested by symptoms in several organ systems, including the skin, gastrointestinal tract, and liver ( Table 32-3 ).[170] This complication typically occurs within the first 100 days after transplantation. The skin manifestations range from a maculopapular rash up to generalized erythroderma or desquamation. The severity of liver GVHD is scored on the basis of the bilirubin and the gastrointestinal severity on the quantity of diarrhea per day.

Table 32-2   -- Graft-versus-Host Disease Categories





Time of Manifestation after HSCT or DLI







Classic acute GVHD

≤100 d



Persistent, recurrent, or late-onset acute GVHD

>100 d







Classic chronic

No time limit



Overlap syndrome

No time limit



DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation.




Table 32-3   -- Classification of Patients with Acute Graft-versus-Host Disease







Rash <25% BSA

Total bilirubin 2–3 mg/dL

Diarrhea 500–1000 mL/day


Rash 25%–50% BSA

Total bilirubin 3–6 mg/dL

Diarrhea 1000–1500 mL/day


Generalized erythroderma

Total bilirubin 6–15 mg/dL

Diarrhea >1500 mL/day


Desquamation and bullae

Total bilirubin >15 mg/dL

Pain, with or without ileus









0 (none)






+ to ++





+ to +++





++ to +++

++ to +++

++ to +++



++ to ++++

++ to ++++

++ to ++++


BSA, body surface area.




Patients who receive transplants from unrelated donors are at much higher risk for GVHD, the incidence and severity of which rise with the age of the patient. Other risk factors for the development of GVHD include a female donor (particularly a multiparous donor), more advanced age, and cytomegalovirus seropositivity of the donor or patient. Patients receive prophylaxis for GVHD prevention most commonly with cyclosporine, with or without methotrexate and corticosteroids.[171] Treatment for acute GVHD includes high-dose corticosteroids, antithymocyte globulin, or various monoclonal antibodies. [172] [173] [174]

Chronic GVHD occurs most commonly between 100 days and 2 years from the transplant and has polymorphic features similar to a number of autoimmune diseases. It is most likely to develop in older patients who also had acute GVHD or received peripheral blood rather than bone marrow grafts.[175] Symptoms associated with chronic GVHD include sicca syndrome, rashes or skin thickening, diarrhea, wasting syndrome, bronchiolitis obliterans, or liver function abnormalities. [176] [177] [178] Patients also are at greatly increased risk for infectious complications, due to either the GVHD itself or the treatment administered. Adverse prognostic factors include thrombocytopenia, a progressive clinical presentation, extensive skin involvement, and an elevated bilirubin. Treatment for the chronic form of the disease includes corticosteroids, cyclosporine, thalidomide, ultraviolet light treatments, or other immunosuppressive agents. [179] [180]


Many of the preparative regimens used for transplant are associated with a high incidence of permanent sterility. The use of TBI almost always is associated with sterility. However, successful pregnancies have occurred after the use of non–TBI-containing regimens.[181] This is most likely to be the case in patients who were less heavily retreated before the transplant and were under the age of 25 years at the time of transplant.

Secondary Malignancies

With the increasing number of long-term survivors following HSCT, complications that develop years later are beginning to be recognized. One complication of the chemo-plus radiotherapy that is used to treat a malignancy is the development of a secondary malignancy. [182] [183] Several reports have now been published of the development of secondary AML or MDS after autologous transplantation. Some studies have suggested that the use of TBI may increase the risk of these complications.[183] It is unclear to what degree the transplant itself contributed to the development of the AML/MDS, because all patients received chemotherapy or radiotherapy, or both, before the transplant and, in some cases, after the transplant.


There has been tremendous success since the 1980s in the increased safety of hematopoietic stem cell transplantation and in the expanding application of this treatment to more patient populations. Areas currently under development that may further improve the use and efficacy of transplantation include continuous improvements in supportive care for transplant patients, broadened use of alternative donors, more refined graft manipulations, and further improvements in the nonmyeloablative transplantation techniques and GVHD prevention. Future progress depends on our ability to identify safer and better-targeted antitumor therapies that can be incorporated in the transplantation regimens without attenuating the graft-versus-tumor responses. This remains a challenge for future clinical research.


  1. Thomas E, Storb R, Clift RA, et al: Bone-marrow transplantation (two parts).  N Engl J Med1975; 292:832-843.895–902
  2. Quesenberry P, Levitt L: Hematopoietic stem cells (three parts).  N Engl J Med1979; 301:755-761.819–823, 868–872
  3. Armitage JO: Bone marrow transplantation.  N Engl J Med1994; 330:827-838.
  4. Weissman IL: Translating stem and progenitor cell biology to the clinic: barriers and opportunities.  Science2000; 287:1442-1446.
  5. Rafii S, Lyden D: Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration.  Nat Med2003; 9:702-712.
  6. Clark ML, Lynch FX: Clinical symptoms of radiation sickness, time to onset and duration of symptoms among Hiroshima survivors in the lethal and median lethal ranges of radiation.  Mil Surg1952; 111:360.
  7. Jacobson LO, Marks EK, Robson MJ, et al: Effect of spleen protection on mortality following X-irradiation.  J Lab Clin Med1949; 34:1538-1543.
  8. Rekers PE, Coulter MP, Warren S: Effects of transplantation of bone marrow into irradiated animals.  Arch Surg1950; 60:635.
  9. Lorenz E, Uphoff DE, Reid TR, Shelton E: Modification of irradiation injury in mice and guinea pigs by bone marrow injections.  J Natl Cancer Inst1951; 12:197-201.
  10. Dameshek W: Bone marrow transplantation; a present-day challenge.  Blood1957; 12:321-323.
  11. Groth CG, Brent LB, Calne RY, et al: Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles.  World J Surg2000; 24:834-843.
  12. Siskind GW, Thomas L: Studies on the runting syndrome in newborn mice.  J Exp Med1959; 110:511-523.
  13. Wilson RE, Henry L, Merrill JP: A model system for determining histocompatibility in man.  J Clin Invest1963; 42:1497-1503.
  14. Appelbaum FR, Herzig GP, Ziegler JC, et al: Successful engraftment of cryopreserved autologous bone marrow in patients with malignant lymphoma.  Blood1978; 52:85-95.
  15. Brenner MK: Haematopoietic stem cell transplantation for autoimmune disease: limits and future potential.  Best Pract Res Clin Haematol2004; 17:359-374.
  16. Orlic D, Kajstura J, Chimenti S, et al: Bone marrow cells regenerate infarcted myocardium.  Nature2001; 410:701-705.
  17. McCluskey J, Peh CA: The human leucocyte antigens and clinical medicine: an overview.  Rev Immunogenet1999; 1:3-20.
  18. Hurley CK, Wade JA, Oudshoorn M, et al: A special report: histocompatibility testing guidelines for hematopoietic stem cell transplantation using volunteer donors.  Tissue Antigens1999; 53:394-406.
  19. Flomenberg N, Baxter-Lowe LA, Confer D, et al: Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.  Blood2004; 104:1923-1930.
  20. Barnes DW, Loutit JF: Treatment of murine leukaemia with X-rays and homologous bone marrow.  Br J Haematol1957; 3:241-252.
  21. Mathé G, Amiel JL, Schwartzenberg L, et al: Successful allogeneic bone marrow transplantation in man: chimerism, induced specific tolerance and possible antileukemic effects.  Blood1965; 25:179-196.
  22. Weiden PL, Flournoy N, Thomas ED, et al: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts.  N Engl J Med1979; 300:1068-1073.
  23. Weiden PL, Sullivan KM, Flournoy N, et al: Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.  N Engl J Med1981; 304:1529-1533.
  24. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation.  Blood1990; 75:555-562.
  25. Kolb HJ, Mittermüller J, Clemm C, et al: Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.  Blood1990; 76:2462-2465.
  26. Porter DL, Roth MS, McGarigle C, et al: Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia.  N Engl J Med1994; 330:100-106.
  27. Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia.  Blood1995; 86:2041-2050.
  28. Collins Jr RH, Shpilberg O, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation.  J Clin Oncol1997; 15:433-444.
  29. Beatty PG, Clift RA, Mickelson EM, et al: Marrow transplantation from related donors other than HLA-identical siblings.  N Engl J Med1985; 313:765-771.
  30. Kernan NA, Bartsch G, Ash RC, et al: Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program.  N Engl J Med1993; 328:593-602.
  31. Rubinstein P, Carrier C, Scaradavou A, et al: Outcomes among 562 recipients of placental-blood transplants from unrelated donors.  N Engl J Med1998; 339:1565-1577.
  32. Aversa F, Tabilio A, Velardi A, et al: Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.  N Engl J Med1998; 339:1186-1193.
  33. Hurley CK, Baxter Lowe LA, et al: National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants.  Biol Blood Marrow Transplant2003; 9:610-615.
  34. Hurley CK, Wagner JE, Setterholm MI, Confer DL: Advances in HLA: practical implications for selecting adult donors and cord blood units.  Biol Blood Marrow Transplant2006; 12:28-33.
  35. Yakoub-Agha I, Mesnil F, Kuentz M, et al: Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy.  J Clin Oncol2006; 24:5695-5702.
  36. Grewal SS, Barker JN, Davies SM, Wagner JE: Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood?.  Blood2003; 101:4233-4244.
  37. Laughlin MJ, Eapen M, Rubinstein P, et al: Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia.  N Engl J Med2004; 351:2265-2275.
  38. Barker JN, Weisdorf DJ, Wagner JE: Creation of a double chimera after the transplantation of umbilical-cord blood from two partially matched unrelated donors.  N Engl J Med2001; 344:1870-1871.
  39. Henslee-Downey PJ, Abhyankar SH, Parrish RS, et al: Use of partially mismatched related donors extends access to allogeneic marrow transplant.  Blood1997; 89:3864-3872.
  40. Simpson D: T-cell depleting antibodies: new hope for induction of allograft tolerance in bone marrow transplantation?.  BioDrugs2003; 17:147-154.
  41. Baranov A, Gale RP, Guskova A, et al: Bone marrow transplantation after the Chernobyl nuclear accident.  N Engl J Med1989; 321:205-212.
  42. Sullivan KM, Storb R, Buckner CD, et al: Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms.  N Engl J Med1989; 320:828-834.
  43. Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy.  Blood1997; 89:4531-4536.
  44. Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.  Blood1998; 91:756-763.
  45. McSweeney PA, Niederwieser D, Shizuru JA, et al: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.  Blood2001; 97:3390-3400.
  46. Perez-Simon JA, Kottaridis PD, Martino R, et al: Spanish and United Kingdom Collaborative Groups for Nonmyeloablative Transplantation. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders.  Blood2002; 100:3121-3127.
  47. Fefer A, Cheever MA, Greenberg PD: Identical-twin (syngeneic) marrow transplantation for hematologic cancers.  J Natl Cancer Inst1986; 76:1269-1273.
  48. Gale RP, Horowitz MM, Ash RC, et al: Identical-twin bone marrow transplants for leukemia.  Ann Intern Med1994; 120:646-652.
  49. Frei 3rd E, Canellos GP: Dose: a critical factor in cancer chemotherapy.  Am J Med1980; 69:585-594.
  50. Kimler BF, Park CH, Yakar D, Mies RM: Radiation response of human normal and leukemic hemopoietic cells assayed by in vitro colony formation.  Int J Radiat Oncol Biol Phys1985; 11:809-816.
  51. Saijo N: Chemotherapy: the more the better? Overview.  Cancer Chemother Pharmacol1997; 40:S100-S106.
  52. Brenner MK, Rill DR, Moen RC, et al: Gene marking to trace origin of relapse after autologous bone-marrow transplantation.  Lancet1993; 341:85-86.
  53. Gorin NE, Aegerter P, Auvert B, et al: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging.  Blood1990; 75:1606-1614.
  54. Gribben JG, Freedman AS, Neuberg D, et al: Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for β-cell lymphoma.  N Engl J Med1991; 325:1525-1533.
  55. Chang J, Coutinho L, Morgenstern G, et al: Reconstruction of haemopoietic system with autologous marrow taken during relapse of acute myeloblastic leukaemia and grown in long-term culture.  Lancet1986; 1:294-295.
  56. Shpall EJ, Stemmer SM, Johnston CF, et al: Purging of autologous bone marrow transplantation: the protection and selection of the hematopoietic progenitor cell.  J Hematother1992; 1:45-54.
  57. Smith BD, Jones RJ, Lee SM, et al: Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10-year experience.  Br J Haematol2002; 117:907-913.
  58. Sharp JG, Joshi SS, Armitage JO, et al: Significance of detection of occult non-Hodgkin's lymphoma in histologically uninvolved bone marrow by a culture technique.  Blood1992; 79:1074-1080.
  59. Goldman JM, Horowitz MM: The International Bone Marrow Transplant Registry.  Int J Hematol2002; 76(Suppl 1):393-397.
  60. Prosper F, Stroncek D, Verfaillie CM: Phenotypic and functional characterization of long-term culture-initiating cells present in peripheral blood progenitor collections of normal donors treated with granulocyte colony-stimulating factor.  Blood1996; 88:2033-2042.
  61. Sheridan WP, Begley CG, Juttner CA, et al: Effect of peripheral-blood progenitor cells mobilized by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy.  Lancet1992; 339:640-644.
  62. Gianni AM, Bregni M, Stem AC: Granulocyte-monocyte colony stimulating factor to harvest circulating hemopoietic stem cells for autotrans-plantation.  Lancet1989; 1:580-585.
  63. To LB, Shepperd KM, Haylock DN, et al: Single high doses of cyclophosphamide enable the collection of high numbers of hemopoietic stem cells from the peripheral blood.  Exp Hematol1990; 18:442-447.
  64. Elias AD, Ayash L, Anderson KC, et al: Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer.  Blood1992; 79:3036-3044.
  65. Rowley SD, Feng Z, Chen L, et al: A randomized phase III clinical trial of autologous blood stem cell transplantation comparing cryopreservation using dimethylsulfoxide vs dimethylsulfoxide with hydroxyethylstarch.  Bone Marrow Transplant2003; 31:1043-1051.
  66. Thomas ED, Storb R: Technique for human marrow grafting.  Blood1970; 36:507-515.
  67. Buckner CD, Clift RA, Sanders JE, et al: Marrow harvesting from normal donors.  Blood1984; 64:630-634.
  68. Bortin MM, Buckner CD: Major complications of marrow harvesting for transplantation.  Exp Hematol1983; 11:916-921.
  69. Gale RP, Feig S, Ho W, et al: ABO blood group system and bone marrow transplantation.  Blood1977; 50:185-194.
  70. Wagner JE, Barker JN, DeFor TE, et al: Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.  Blood2002; 100:1611-1618.
  71. Thomas ED, Buckner CD, Banaji M, et al: One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation.  Blood1977; 49:511-533.
  72. Thomas ED, Buckner CD, Clift RA, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission.  N Engl J Med1979; 301:597-599.
  73. Blume KG, Beutler E, Bross KJ, et al: Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia.  N Engl J Med1980; 302:1041-1046.
  74. Santos GW, Tutschka PJ, Brookmeyer R, et al: Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide.  N Engl J Med1983; 309:1347-1353.
  75. Clift RA, Thomas ED: Seattle Marrow Transplant Team: follow-up 26 years after treatment for acute myelogenous leukemia.  N Engl J Med2004; 351:2456-2457.
  76. Zittoun RA, Mandelli F, Willemze R, et al: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups.  N Engl J Med1995; 332:217-223.
  77. Cassileth PA, Harrington DP, Appelbaum FR, et al: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission.  N Engl J Med1998; 339:1649-1656.
  78. Harousseau JL, Cahn JY, Pignon B, et al: Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM).  Blood1997; 90:2978-2986.
  79. Burnett AK, Goldstone AH, Stevens RM, et al: Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties.  Lancet1998; 351:700-708.
  80. Woods WG, Neudorf S, Gold S, Children's Cancer Group , et al: a comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission.  Blood2001; 97:56-62.
  81. Clift RA, Buckner CD, Applebaum FR, et al: Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia.  J Clin Oncol1992; 10:1723-1729.
  82. Appelbaum FR, Pearce SF: Hematopoietic cell transplantation in first complete remission versus early relapse.  Best Pract Res Clin Haematol2006; 19:333-339.
  83. Aoudjhane M, Labopin M, Gorin NC, et al: Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT).  Leukemia2005; 19:2304-2312.
  84. Anderson JE, Appelbaum FR, Fisher LD, et al: Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome.  Blood1993; 82:677-681.
  85. Sierra J, Perez WS, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia.  Blood2002; 100:1997-2004.
  86. Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low risk myelodysplasia is associated with improved outcome.  Blood2004; 104:579-585.
  87. Taussig DC, Davies AJ, Cavenagh JD, et al: Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting.  J Clin Oncol2003; 21:3060-3065.
  88. Tauro S, Craddock C, Peggs K, et al: Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia.  J Clin Oncol2005; 23:9387-9393.
  89. de Witte T, Brand R, van Biezen A, et al: The role of stem cell source in autologous hematopoietic stem cell transplantation for patients with myelodysplastic syndromes.  Haematologica2006; 91:750-756.
  90. Matsuzaki A, Nagatoshi Y, Inada H, et al: Prognostic factors for relapsed childhood acute lymphoblastic leukemia: impact of allogeneic stem cell transplantation—a report from the Kyushu-Yamaguchi Children's Cancer Study Group.  Pediatr Blood Cancer2005; 45:111-120.
  91. Garcia-Manero G, Thomas DA: Salvage therapy for refractory or relapsed acute lymphocytic leukemia.  Hematol Oncol Clin North Am2001; 15:163-205.
  92. Camera A, Annino L, Chiurazzi F, et al: GIMEMA ALL–Rescue 97: a salvage strategy for primary refractory or relapsed adult acute lymphoblastic leukemia.  Haematologica2004; 89:145-153.
  93. Thiebaut A, Vernant JP, Degos L, et al: Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87.  Hematol Oncol Clin North Am2000; 14:1353-1366.
  94. Attal M, Blaise D, Marit G, et al: Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group.  Blood1995; 86:1619-1628.
  95. Thomas X, Boiron JM, Huguet F, et al: Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.  J Clin Oncol2004; 22:4075-4086.
  96. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome.  N Engl J Med1996; 335:91-97.
  97. Child JA, Morgan GJ, Davies FE, et al: Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.  N Engl J Med2003; 348:1875-1883.
  98. Attal M, Harousseau JL, Facon T, et al: InterGroupe Francophone du Myelome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003;349:2495–2502.  Erratum in: N Engl J Med2004; 350:2628.
  99. Gahrton G, Tura S, Ljungman P, et al: Allogeneic bone marrow transplantation in multiple myeloma.  N Engl J Med1991; 325:1267-1273.
  100. Bruno B, Rotta M, Patriarca F, et al: A comparison of allografting with autografting for newly diagnosed myeloma.  N Engl J Med.2007; 356:1110-1120.
  101. Thomas ED, Clift RA, Fefer A, et al: Marrow transplantation for the treatment of chronic myelogenous leukemia.  Ann Intern Med1986; 104:155-163.
  102. Goldman JM, Apperley JF, Jones L, et al: Bone marrow transplantation for patients with chronic myeloid leukemia.  N Engl J Med1986; 314:202-207.
  103. Hansen JA, Gooley TA, Martin PJ, et al: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.  N Engl J Med1998; 338:962-968.
  104. Mackinnon S, Papadopoulos EB, Carabasi MH, et al: Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease.  Blood1995; 86:1261-1268.
  105. Hughes TP, Kaeda J, Branford S, et al: International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia.  N Engl J Med2003; 349:1423-1432.
  106. Bhatia R, McGlave PB: Autologous hematopoietic cell transplantation for chronic myelogenous leukemia.  Hematol Oncol Clin North Am2004; 18:715-732.
  107. Tefferi A, Solberg LA, Silverstein MN: A clinical update in polycythemia vera and essential thrombocythemia.  Am J Med2000; 109:141-149.
  108. Tefferi A: Myelofibrosis with myeloid metaplasia.  N Engl J Med2000; 342:1255-1265.
  109. Guardiola P, Anderson JE, Bandini G, et al: Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Francaise de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study.  Blood1999; 93:2831-2838.
  110. Jurado M, Deeg H, Gooley T, et al: Haemopoietic stem cell transplantation for advanced polycy-thaemia vera or essential thrombocythaemia.  Br J Haematol2001; 112:392.
  111. Rondelli D, Barosi G, Bacigalupo A, et al: Myeloproliferative Diseases-Research Consortium. Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia.  Blood2005; 105:4115-4119.
  112. Pavletic SZ, Khouri IF, Haagenson M, et al: Unrelated donor marrow transplantation for β-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research.  J Clin Oncol2005; 23:5788-5794.
  113. Khouri IF, Keating MJ, Vriesendorp HM, et al: Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results.  J Clin Oncol1994; 12:748-758.
  114. Khouri IF, Przepiorka D, van Besien K, et al: Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease.  Br J Haematol1997; 97:466-473.
  115. Dreger P, Brand R, Hansz J, et al: Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning.  Leukemia2003; 17:841-848.
  116. Schetelig J, Thiede C, Bornhauser M, et al: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group.  J Clin Oncol2003; 21:2747-2753.
  117. Delgado J, Thomson K, Russell N, et al: Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study.  Blood2006; 107:1724-1730.
  118. Phillips GL, Herzig RH, Lazarus HM, et al: Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow.  N Engl J Med1984; 310:1557-1561.
  119. Philip T, Armitage JO, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade of high-grade non-Hodgkin's lymphoma.  N Engl J Med1987; 316:1493-1498.
  120. Appelbaum FR, Sullivan KM, Buckner CD, et al: Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation.  J Clin Oncol1987; 5:1340-1347.
  121. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma.  N Engl J Med1995; 333:1540-1545.
  122. Kewalramani T, Zelenetz AD, Nimer SD, et al: Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large β-cell lymphoma.  Blood2004; 103:3684-3688.
  123. Haioun C, Lepage E, Gisselbrecht C, et al: Survival benefit of high-dose therapy in poor risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87–2 Protocol-A Groupe d'Etude des Lymphomes de l'Adulte Study.  J Clin Oncol2000; 18:3025-3030.
  124. Milpied N, Deconinck E, Gaillard F, Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang , et al: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support.  N Engl J Med2004; 350:1287-1295.
  125. Freedman AS, Ritz J, Neuberg D, et al: Autologous bone marrow transplantation in 69 patients with a history of low-grade β-cell non-Hodgkin's lymphoma.  Blood1991; 77:2524-2529.
  126. Rohatiner AZ, Johnson PW, Price CG, et al: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma.  J Clin Oncol1994; 12:1177-1184.
  127. Bierman PJ, Sweetenham JW, Loberiza Jr FR, et al: Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin's lymphoma: a comparison with allogeneic and autologous transplantation—The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation.  J Clin Oncol2003; 21:3744-3753.
  128. Grigg A, Ritchie D: Graft-versus-lymphoma effects: clinical review, policy proposals, and immunobiology.  Biol Blood Marrow Transplant2004; 10:579-590.
  129. Ratanatharathorn V, Uberti J, Karanes C, et al: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma.  Blood1994; 84:1050-1055.
  130. Robinson SP, Goldstone AH, Mackinnon S, et al: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation.  Blood2002; 100:4310-4316.
  131. Carella AM, Congiu AM, Gaozza E, et al: High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: an Italian study group report.  J Clin Oncol1988; 6:1411-1416.
  132. Armitage JO, Bierman PJ, Vose JM, et al: Autologous bone marrow transplantation for patients with relapsed Hodgkin's disease.  Am J Med1991; 91:605-611.
  133. Linch DC, Winfield D, Goldstone AH, et al: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomized trial.  Lancet1993; 341:1051-1054.
  134. Moskowitz CH, Nimer SD, Zelenetz AD, et al: A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model.  Blood2001; 97:616-623.
  135. Peggs KS, Hunter A, Chopra R, et al: Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation.  Lancet2005; 365:1934-1941.
  136. Burdach S, Jurgens H, Peters C, et al: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma.  J Clin Oncol1993; 11:1482-1488.
  137. Ladenstein R, Lasset C, Pinkerton R, et al: Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: a report from the EBMT Solid Tumour Registry.  Bone Marrow Transplant1995; 15:697-705.
  138. Craft A, Cotterill S, Malcolm A, et al: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study.  J Clin Oncol1998; 16:3628-3633.
  139. Arpaci F, Ataergin S, Ozet A, et al: The feasibility of neoadjuvant high-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with nonmetastatic high grade localized osteosarcoma: results of a phase II study.  Cancer2005; 104:1058-1065.
  140. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group.  N Engl J Med1999; 341:1165-1173.
  141. Sung KW, Yoo KH, Chung EH, et al: Double high-dose chemotherapy with autologous stem cell transplantation in patients with high-risk neuroblastoma: a pilot study in a single center.  J Korean Med Sci2002; 17:537-543.
  142. Luksch R, Podda M, Gandola L, et al: Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment.  Br J Cancer2005; 92:1984-1988.
  143. Matthay KK, Tan JC, Villablanca JG, et al: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a New Approaches to Neuroblastoma Therapy Consortium Study.  J Clin Oncol2006; 24:500-506.
  144. Broun ER, Nichols CR, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue.  Ann Intern Med1992; 117:124-128.
  145. Bhatia S, Abonour R, Porcu P, et al: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.  J Clin Oncol2000; 18:3346-3351.
  146. Schmoll HJ, Kollmannsberger C, Metzner B, et al: Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group.  J Clin Oncol2003; 21:4083-4091.
  147. Antman K, Ayash L, Elias A, et al: A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.  J Clin Oncol1992; 10:102-110.
  148. Antman KA, Rowlings PA, Vaughn WP, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.  J Clin Oncol1997; 15:1870-1879.
  149. Rodenhuis S, Richel DJ, van der Wall E, et al: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement.  Lancet1998; 352:515-521.
  150. Hortobagyi GN, Buzdar AU, Theriault RL, et al: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.  J Natl Cancer Inst2000; 92:225-233.
  151. Rodenhuis S, Bontenbal M, Beex LV, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer.  N Engl J Med2003; 349:7-16.
  152. Tallman MS, Gray R, Robert NJ, et al: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer.  N Engl J Med2003; 349:17-26.
  153. Zander AR, Kroger N, Schmoor C, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial.  J Clin Oncol2004; 22:2273-2283.
  154. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group.  N Engl J Med2000; 342:1069-1076.
  155. Childs R, Chernoff A, Contentin N, et al: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.  N Engl J Med2000; 343:750-758.
  156. Bishop MR, Fowler DH, Marchigiani D, et al: Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer.  J Clin Oncol2004; 22:3886-3892.
  157. Carella AM, Beltrami G, Corsetti MT, et al: Reduced intensity conditioning for allograft after cytoreductive autograft in metastatic breast cancer.  Lancet2005; 366:318-320.
  158. Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.  Blood2005; 106:2912-2919.
  159. Antin JH: Clinical practice. Long-term care after hematopoietic-cell transplantation in adults.  N Engl J Med2002; 347:36-42.
  160. Champlin RE, Horowitz MM, van Bekkum DW, et al: Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results.  Blood1989; 73:606-613.
  161. Cazin B, Gorin NC, Laporte JP, et al: Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations.  Cancer1986; 57:2061-2069.
  162. Hertenstein B, Stefanic M, Schmeiser T, et al: Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant.  J Clin Oncol1994; 12:998-1004.
  163. Spitzer TR: Engraftment syndrome following hematopoietic stem cell transplantation.  Bone Marrow Transplant2001; 27:893-898.
  164. Chao NJ, Duncan SR, Long GD, et al: Corticosteroid therapy for diffuse alveolar hemorrhage in autologous bone marrow transplant recipients.  Ann Intern Med1991; 114:145-146.
  165. Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ: Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes.  Biol Blood Marrow Transplant2003; 9:657-666.
  166. Bearman SI, Anderson GL, Mori M, et al: Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation.  J Clin Oncol1993; 11:1729-1736.
  167. DeLeve LD, Shulman HM, McDonald GB: Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (venoocclusive disease).  Semin Liver Dis2002; 22:27-42.
  168. Gruss E, Bernis C, Tomas JF, et al: Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.  Am J Nephrol1995; 15:473-479.
  169. Srinivasan R, Balow JE, Sabnis S, et al: Nephrotic syndrome: an under-recognised immune-mediated complication of nonmyeloablative allogeneic haematopoietic cell transplantation.  Br J Haematol2005; 131:74-79.
  170. Przepiorka D, Weisdorf D, Martin P, et al: 1994 Consensus Conference on Acute GVHD Grading.  Bone Marrow Transplant1995; 15:825-828.
  171. Storb R, Deeg HJ, Pepe M, et al: Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial.  Blood1989; 73:1729-1734.
  172. Martin PJ, Schoch G, Fisher L, et al: A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment.  Blood1990; 76:1464-1472.
  173. Kennedy MS, Deeg HJ, Storb R, et al: Treatment of acute graft-versus-host disease after allogeneic marrow transplantation: randomized study comparing corticosteroids and cyclosporine.  Am J Med1985; 78:978-983.
  174. Jacobsohn DA, Vogelsang GB: Novel pharmacotherapeutic approaches to prevention and treatment of GVHD.  Drugs2002; 62:879-889.
  175. Lee SJ, Vogelsang G, Flowers ME: Chronic graft-versus-host disease.  Biol Blood Marrow Transplant2003; 9:215-233.
  176. Shulman HM, Sullivan KM, Weiden PL, et al: Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients.  Am J Med1980; 69:204-217.
  177. Pavletic SZ, Carter SL, Kernan NA, et al: Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation.  Blood2005; 106:3308-3313.
  178. Filipovich AH, Weisdorf D, Pavletic S, et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.  Biol Blood Marrow Transplant2005; 11:945-956.
  179. Vogelsang GB: How I treat chronic graft-versus-host disease.  Blood2001; 97:1196-1201.
  180. Couriel D, Carpenter PA, Cutler C, et al: Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report.  Biol Blood Marrow Transplant2006; 12:375-396.
  181. Salooja N, Szydlo RM, Socie G, et al: Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey.  Lancet2001; 358:271-276.
  182. Curtis RE, Metayer C, Rizzo JD, et al: Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.  Blood2005; 105:3802-3811.
  183. Darrington DL, Vose JM, Anderson JR, et al: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies.  J Clin Oncol1994; 12:2527-2534.