The Oncologist, Vol. 5, No. 6, 487-496,
December 2000
© 2000 AlphaMed Press
NCI All Ireland Cancer Conference Proceedings |
Nonmyeloablative Allogeneic Stem Cell Transplantation: Early Promise and Limitations
Nicole J. McCarthy,
Michael R. Bishop
Department of Experimental Transplantation and Immunology, National Cancer Institute, Medicine Branch, Bethesda, Maryland, USA
Correspondence: Michael R. Bishop, M.D., Department of Experimental Transplantation and Immunology, National Cancer Institute, Medicine Branch, Bethesda, Maryland 20892, USA. Telephone: 301-435-2754; Fax: 301-480-4354; e-mail: mbishop{at}mail.nih.gov
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ABSTRACT
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Allogeneic stem cell transplantation is used to treat a variety of malignant and nonmalignant hematologic diseases. Conventionally, high-dose chemoradiotherapy-based preparative regimens were considered essential both for tumor eradication and facilitation of donor stem cell engraftment. It is now apparent that an immune-mediated graft-versus-tumor effect has a pivotal role in the curative potential of allogeneic stem cell transplantation. This has prompted the development of less toxic, nonmyeloablative but profoundly immunosuppressive preparative regimens, often fludarabine- or radiation-based. Full donor engraftment can be achieved; however, a significant number of patients achieve a mixed chimeric state. Mixed hematopoietic chimerism provides a platform for the use of adoptive immunotherapy using donor lymphocyte infusions to maximize the immune-mediated antitumor effect, but the optimal usage has yet to be determined. Immediate procedure-related mortality with nonmyeloablative regimens has been low, but graft-versus-host disease remains a major clinical concern and treatment challenge. Major tumor responses have been seen in many hematologic malignancies primarily including patients with highly chemorefractory disease. Follow-up data have been short and additional time is needed to determine the efficacy and toxicities of this immunotherapy. This approach has potential for widespread clinical application including HLA mismatched and matched unrelated donor transplantation, exploration of a graft-versus-solid tumor effect, and correction of phenotypic expression in nonmalignant disorders.
Key Words. Graft-versus-host reaction • Hematopoietic stem cell transplantation • Hematologic neoplasms • Human • Nonmyeloablative • Transplantation conditioning • Transplantation immunology
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INTRODUCTION
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Allogeneic stem cell transplantation (alloSCT) is used to treat a variety of hematologic malignancies and an increasing spectrum of nonmalignant diseases. This treatment traditionally has consisted of a conditioning regimen with myeloablative doses of chemoradiotherapy to eradicate the underlying malignancy and suppress the patient's immune system in preparation for the allogeneic graft, which functioned primarily as a marrow rescue product. Unacceptable nonhematologic toxicity and significant procedural morbidity and mortality have limited intensification of preparative regimens to increase tumor kill and improve disease-free survival. The impact of such toxicity restricts the use of allogeneic transplantation to younger patients without comorbid medical conditions. Despite the use of high-dose chemoradiotherapy in these regimens, tumor relapse is an important cause of treatment failure.
It has become increasingly apparent that a significant part of the curative potential of alloSCT is due to alloreactivity of donor immune cells against host tumor cells referred to as the graft-versus-tumor (GVT) effect. The importance of the interactions between donor immunocompetent T lymphocytes and host-type tumor cells is supported by an increased rate of relapse in T cell-depleted allografts [1], an inverse correlation between relapse and severity of graft-versus-host disease (GVHD) [1-3] and increased rate of relapse after syngeneic or autologous stem cell transplants using the same conditioning regimen [4-6]. The most compelling evidence for GVT effect is the reinduction of remission in certain diseases that relapse post-alloSCT with donor lymphocyte infusion (DLI) [7-9]. The effectiveness of DLI in the eradication of recurrent malignancy after conventional allogeneic transplantation has been demonstrated for almost all hematologic malignancies, although it is not equally potent across tumor subtypes [10].
This demonstration that an immune-mediated GVT effect plays a central role in the therapeutic efficacy of alloSCT and that a myeloablative preparative regimen is not essential for stem cell engraftment has led to the development of less toxic nonmyeloablative conditioning regimens [11-13]. These lower intensity regimens are associated with less toxicity and do not fully ablate recipient immunity. This may produce a state of mixed chimerism in which both donor and recipient lineages maintain hematopoietic output. Stable mixed hematopoietic chimerism implies a state of mutual donor-host tolerance and thus control of graft-versus-host and host-versus-graft reactions [14]. However, a state of mixed chimerism may not allow an immune mediated antitumor effect [15]. Thus, prompt establishment of 100% donor engraftment would appear necessary to maximize the GVT effect and the therapeutic benefits of this treatment modality. This is usually achieved either by withdrawal of post-transplant immunosuppression or the use of adoptive immunotherapy using DLI.
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PREPARATIVE REGIMENS
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Nonmyeloablative preparative regimens are designed not to eradicate the underlying malignancy, but to provide sufficient immunosuppression to achieve donor engraftment of an allogeneic graft while minimizing toxicity (Table 1
) [16]. This has the potential advantage of decreasing immediate treatment-related morbidity and mortality. The question posed is just how immunosuppressed the patient needs to be to overcome the increased risk of graft rejection and reliably accept an allogeneic graft. This question has not been definitively answered; however, some results have provided insight. Porter et al. administered DLI without using a preparative regimen or stem cell rescue to answer the question as to whether a state of mixed chimerism could be achieved without prior conditioning [17]. Mixed chimerism could only be achieved in patients who had undergone prior autologous stem cell transplantation, implying that the level of immunosuppression achieved post-autologous transplant is sufficient to prevent rejection and permit some degree of allogeneic engraftment. Hence prior immunosuppressive therapy is required to sustain engraftment of HLA identical lymphocytes.
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ROLE IN HEMATOLOGIC MALIGNANCIES
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Fludarabine-Based Regimens
The purine analogue, fludarabine, has been widely incorporated into nonmyeloablative conditioning regimens. It is highly immunosuppressive, producing profound lymphopenia, which has been shown to facilitate allogeneic stem cell engraftment [18]. It has the additional advantages of having antitumor activity in hematologic malignancies and a low nonhematologic toxicity profile [19-21].
Slavin et al. used a preparative regimen consisting of fludarabine 30 mg/m2 for five days, busulphan 4 mg/kg for two days and antithymocyte globulin in a series of 26 patients eligible for alloSCT with a variety of hematologic diseases, including four patients with nonmalignant diseases [22]. This regimen was well tolerated with minimal mucositis and no pulmonary toxicity reported; however, 13 patients had mild-severe veno-occlusive disease of the liver. All patients engrafted with nine patients having a transient mixed chimerism and the remaining 17 patients having complete chimerism. The definitions and timing of chimerism assessments were not stated. GVHD was the single major complication with 
grade II acute GVHD occurring in 12 patients. Six patients had grade III acute GVHD, which was the cause of death in four patients early after discontinuation of cyclosporine. With a median follow-up of eight months, 85% of patients are alive and 81% disease-free. DLI reversed relapse in two of three cases. This series was updated in abstract to include a group of 48 patients with engraftment and toxicity data expanded and trends remaining similar [23]. All eight patients treated with nonmalignant conditions are alive and well one year after transplantation. Although this regimen is referred to as nonmyeloablative, there are insufficient data to confirm this.
Investigators in Houston have used fludarabine in combination with other cytotoxic drugs that have activity in the disease being treated. Giralt et al. treated patients with poor prognosis acute myelogenous leukemia or myelodysplastic syndrome with fludarabine, idarubicin and cytosine arabinoside or 2-chloro-deoxyadenosine (2CDA) and cytosine arabinoside with HLA-matched related donors [24]. Fifteen patients ineligible for myeloablative therapy, including 12 patients with either refractory disease or disease beyond first relapse, were treated with this approach. Eight of the 12 assessable patients had donor cell engraftment within 30 days of transplantation with six patients having 90% donor cell engraftment. Eight patients achieved remission criteria. Grade II or higher acute GVHD only occurred in three responding patients, although an accurate assessment of GVHD was difficult due to the frequent, rapid progression of disease relapse post-transplant. Overall survival was poor with only one long-term patient remaining in remission at 174+ days. However, this study did provide proof of the principle that donor engraftment could be achieved using a nonmyeloablative regimen.
Khouri et al. used fludarabine in combination with cyclophosphamide or cytarabine and cisplatin to treat 15 patients with lymphoid malignancies [25]. Five patients received fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for three days, and four patients received fludarabine 30 mg/m2 for five days and cyclophosphamide 1,000 mg/m2 for two days. Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Three of the five patients who received the lower dose fludarabine and cyclophosphamide combination failed to engraft. Eight of the engrafted patients achieved a complete response, two of whom had acute and four had chronic GVHD. Three patients had tumor responses after DLI. At a median follow-up of 180 days, five of six patients (83.3%) with sensitive disease are alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry.
Childs et al. have used fludarabine 25 mg/m2 for five days and cyclophosphamide 60 mg/kg for two days given sequentially as the conditioning regimen for 25 hematologic and 25 solid tumor patients with HLA-matched sibling donors [26]. Cyclosporine was used as GVHD prophylaxis and tapered after day 30 to enhance donor engraftment and a GVT effect. Patients with mixed T cell chimerism or disease progression following cyclosporine withdrawal received monthly escalating doses of DLI until 100% donor T cell chimerism, GVHD or disease regression. This regimen was well tolerated and early donor engraftment was detected in 49 patients, with all patients surviving greater than 100 days achieving 100% donor T cell chimerism. Two patients rejected their graft and had autologous hematopoietic recovery. Grade I-II acute GVHD occurred in 14 patients, and grade III-IV acute GVHD occurred in seven patients with two patient deaths from GVHD. Mild to moderate chronic GVHD occurred in 5 of 26 surviving patients. Treatment-related mortality at day 100 and 200 was 7.6% and 11.8%, respectively. At a median follow-up of 126 days, the overall actuarial survival was 70.2% and tumor responses were seen in all disease categories (Table 2).
Investigators in Genova have combined high-dose chemotherapy and autologous stem cell rescue followed 30 to 90 days later by a nonmyeloablative allogeneic transplant [27]. This strategy attempts to achieve both maximal tumor reduction with autografting and immune-mediated control of minimal residual disease with allografting. The high-dose chemotherapy induces significant host immunosuppression, which should contribute to the enhancement of donor engraftment during the allogeneic transplant procedure. Nine patients with advanced hematologic malignancies received fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 concurrently for three days as the preparative regimen and GVHD prophylaxis consisted of cyclosporine and methotrexate. The regimen was well tolerated with no mucositis and no patient requiring intravenous nutrition. Six patients achieved complete donor engraftment, two had mixed chimerism and one patient had autologous hematopoietic recovery. Three patients had acute GVHD, and there were no treatment-related deaths. Seven of eight patients treated with autografting followed by allografting (one patient with refractory anemia with excess blasts did not undergo autografting) were alive at a median follow-up of four months (range 2-10 months) four of whom had achieved a complete remission. This study demonstrated that the strategy of combined transplant procedures could be performed safely.
It appears that the acute toxicity associated with these fludarabine-based regimens is decreased when compared with conventional myeloablative regimens. However, it should be emphasized that these preparative regimens, although nonmyeloablative, are still of moderate intensity and require close monitoring for toxicities.
Regimens Including Radiation Therapy
Investigators in Boston were able to show in murine models that a mixed chimeric state could be induced with a nonmyeloablative preparative regimen consisting of cyclophosphamide, anti-T cell antibody therapy and thymic irradiation. These mixed chimeras could be converted to full chimeras by administration of DLI without the development of GVHD [28-30]. These observations led to the initiation of a clinical trial in patients with HLA-matched related donors using the preparative regimen consisting of cyclophosphamide 50 mg/kg for either three or four days, peri-transplant antithymocyte globulin and 700 cGy thymic irradiation if no prior mediastinal radiation had been received [31]. Twenty-one patients with chemorefractory hematologic malignancies, including 11 patients with non-Hodgkin's lymphoma, were treated and had a median age of 44 years (22-62 years). Eighteen of 20 evaluable patients showed mixed chimerism, defined as >1% donor peripheral white blood cells, at day +35 post-transplant. Fourteen patients had a tumor response including eight complete responses. Ten patients received prophylactic DLI for conversion of mixed to full chimerism and to optimize the GVT effect. Five evaluable DLI patients achieved a complete response. The incidence of GVHD was reported to have increased with the number of DLI received; however, no details regarding the overall incidence or grade of GVHD were provided. The overall treatment-related mortality was 10% and it was stated that tumor responses were seen in the absence of GVHD.
Based on results in canine studies, investigators in Seattle have developed a nonmyeloablative allogeneic transplant clinical protocol using a limited amount of total body irradiation (TBI) in combination with post-transplant cyclosporine and mycophenylate mofetil [32, 33]. Preclinical data showed this therapy to result in stable mixed chimerism with no evidence of GVHD. Based on this model, a regimen consisting of 200 cGy TBI pretransplant and short-term 35 or 56 days of cyclosporine and mycophenylate mofetil post-transplant has been brought to a clinical trial [34]. This low intensity, low toxicity conditioning regimen is given solely to permit allogeneic engraftment and not for tumor cytoreduction, which allows a clearer assessment of graft-mediated tumor responses. DLIs were given post-transplant for persistent mixed chimerism and/or to eradicate persistent disease. Forty-four patients with hematologic malignancies and HLA identical sibling donors, who were ineligible for conventional allogeneic transplantation on the basis of age or organ dysfunction, with a median age of 56 years (range 31-72 years) were treated. This conditioning regimen was well tolerated with no mucositis, minimal gastrointestinal symptoms and no new alopecia. Forty-two evaluable patients had persistent donor engraftment at two months, but nonfatal graft rejection subsequently occurred in nine patients (20%). Grade II or greater acute GVHD occurred in 39% of patients with one death. Treatment-related mortality was 6.8%. At a median follow-up of 190 days (range 60-480 days), major tumor responses occurred in 16 of 23 patients with measurable disease and sustained engraftment. This approach is being conducted in an outpatient setting with some patients. To address the high nonfatal graft rejection rate, the investigators plan to add fludarabine to the current TBI regimen in patients who have received minimal prior therapy to increase the level of recipient immunosuppression to promote engraftment.
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NONMYELOABLATIVE TRANSPLANTATION IN OTHER MALIGNANCIES
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Whether a clinically meaningful immune-mediated GVT effect can occur in solid tumors is a question still to be addressed. Diseases such as renal cell carcinoma and melanoma, in which responses to immune therapies such as interferon and interleukin-2 have been shown [35-38], provide an interesting setting in which to assess the role of the immune system and allogeneic transplantation. Using a nonmyeloablative regimen with agents that have no known efficacy in the disease may allow for a purer assessment of tumor response to immunotherapy. Childs et al. have treated patients with metastatic renal cell cancer with a fludarabine and cyclophosphamide preparative regimen, as described previously [39]. Cyclosporine was withdrawn after 30 days to achieve 100% donor chimerism and maximize the GVT effect with DLI planned for optimization of donor engraftment or treatment of persistent disease. Nineteen patients with widely metastatic and progressive renal cell cancer were treated. Six patients developed grade II acute GVHD with one associated death. Of 10 patients evaluable for response, six patients had disease regression with two patients achieving a complete response. A further three patients had stable disease. Complete responses have remained durable at 19 and 16 months. Seventeen patients survive with a median of 104 days follow-up (14-571 days).
The published data on nonmyeloablative alloSCT in metastatic melanoma include only very small patient numbers and thus no conclusions can be made [15]. There is anecdotal evidence of a graft versus adenocarcinoma effect in breast cancer in a myeloablative setting, but this requires formal study ideally in the nonmyeloablative transplant setting [40, 41].
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MATCHED UNRELATED AND HLA-MISMATCHED DONORS
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Studies using nonmyeloablative preparative regimens using matched unrelated donors as a source of stem cells are underway. Giralt et al. used a preparative regimen consisting of fludarabine 25 mg/m2 for five days or 2CDA 12 mg/m2 continuous infusion for five days in combination with melphalan 90 mg/m2 for two days to treat eight patients with hematologic malignancies with a six of six antigen serologically HLA-matched unrelated donors [42]. GVHD prophylaxis consisted of combinations of cyclosporine, tacrolimus with methotrexate or steroids. The authors stated that these preparative regimens enabled engraftment of stem cells from matched unrelated donors although patient details were not presented. Researchers in Seattle are currently investigating the addition of fludarabine to their 200 cGy TBI-based preparative regimen prior to HLA-matched unrelated donor transplantation to more effectively immunosuppress the host and decrease the risk of rejection [14].
Sykes et al. have used the same regimen of cyclophosphamide, antithymocyte globulin before and after transplantation and thymic irradiation to treat five patients with refractory non-Hodgkin's lymphoma with haploidentical related donors sharing at least one HLA A, B or DR allele on the mismatched haplotype [43]. Four of five patients were evaluable and had established multilineage mixed hematopoietic chimerism across these more extensive HLA barriers using this nonmyeloablative regimen. All evaluable patients had grade II acute GVHD, which was amenable to corticosteriod therapy. Two patients were in complete or partial clinical remission at 460 and 103 days, respectively, after bone marrow transplantation. The authors hypothesized that the tumor responses in this highly chemorefractory group reflected a very potent form of immune therapy that may be more marked given major histocompatability complex disparities rather than only minor histocompatability antigen differences.
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ROLE OF NONMYELOABLATIVE TRANSPLANTATION IN NONMALIGNANT DISORDERS
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Regimens designed to result in a state of stable mixed chimerism may have their greatest application in the setting of nonmalignant disorders. An optimal strategy may consist of a nontoxic nonmyeloablative regimen, which would allow establishment of mixed hematopoietic chimerism associated with a state of mutual donor-host tolerance without the need for long-term immunosuppressive therapy. This may have clinical application in the setting of a number of diseases including thalassemia, sickle cell anemia, primary immunodeficiency syndromes, inborn errors of metabolism, certain autoimmune diseases, and may also prove beneficial in solid organ transplantation.
Chronic granulomatous disease (CGD) is a disorder in which a stable mixed chimeric state in myeloid cells, resulting in 15% donor neutrophils, may be sufficient to ameliorate the disease. Horowitz et al. used a preparative regimen consisting of fludarabine, cyclosporine, and antithymocyte globulin followed by a T-cell-depleted graft from an HLA-identical sibling donor and cyclosporine to GVHD in eight CGD patients [44]. The median patient age was 11 years (range 5-34 years). Seven patients had mixed myeloid chimerism at the time of neutrophil recovery; one highly alloimmunized patient failed to engraft and had rapid autologous recovery. Follow-up on three patients beyond 100 days post-transplant showed greater than 15% donor neutrophils, and the four patients at less than 100 days after transplant had a median of 14.1% donor neutrophils. One patient had grade III acute GVHD of skin. Thus, engraftment can occur in the setting of a T-cell-depleted graft with a nonmyeloablative regimen followed by DLI as needed, with a low incidence of GVHD. Mixed chimerism may not be stable however, and only represent a state of flux between complete conversion to full donor chimerism or rejection of the allograft.
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DISCUSSION
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The experience to date confirms that full engraftment does not require myeloablation and that nonmyeloablative conditioning regimens can secure engraftment of allogeneic stem cells across HLA and immunological barriers with the advantage of significantly less procedure-related toxicity. However, before embracing this modality using immune-mediated GVT effect as "standard of care," even for patients for whom conventional alloSCT is prohibitive, a number of issues need to be addressed.
Nonmyeloablative alloSCT has been predominantly used to treat hematological diseases. The absolute numbers of individuals that have been treated are small with the largest reported single series consisting of 50 patients, and hence the number of patients in specific disease type is even smaller. This approach has largely been applied to older patients who would have been excluded from alloSCT on the basis of age, poor performance status, or comorbid disease. The median age of patients entering onto these protocols ranges from 31 years to 56 years of age, with patients up to the age of 72 being treated. Most of these patients represent a poor prognostic group with either relapsed chemo-resistant or primary refractory hematologic diseases (Table 1
).
The primary objective of achieving donor engraftment using a nonmyeloablative regimen has been achieved in all studies reviewed (Table 3). The optimal regimen for achieving this goal is still to be determined. Moderate intensity, nonmyeloablative fludarabine, and/or cyclophosphamide-based regimens have consistently shown proof of chimerism with the lowest intensity, the nonmyeloablative 200 cGy TBI regimen showing the lowest rate of engraftment. The highest rates of nonfatal graft rejection with autologous recovery were also seen in patients who had not been heavily pretreated. This is a major advantage over the almost universally fatal course that occurs with graft rejection and myeloablative conditioning regimens.
Hematologic toxicity has been mild in most studies, with greater myelosuppression occurring in the regimens containing multiple chemotherapeutic agents. The median day to achieving an absolute neutrophil count of greater than 0.5 x 109/l ranged from 11 to 15 days and a platelet count of greater than 20 x 109/l from 8 to 13 days post-transplant (Table 4). The shorter duration of neutropenia may help in decreasing the incidence of serious infections, and not all patients required additional platelet support.
The importance of cytoreduction either prior to alloSCT or as part of the preparative regimen is also controversial. Extrapolating from the chronic myelogenous leukemia experience [9, 10, 45, 46], durable responses from DLI are more frequent in the setting of less advanced disease. It has been shown that a state of minimal residual disease can be induced with high-dose chemotherapy and autologous stem cell rescue followed safely by immune therapy with a nonmyeloablative alloSCT. However, other investigators use the preparative regimen only as a mechanism for establishment of a mixed chimeric state, which is then the platform for adoptive immunotherapy with DLI.
Given the tumor responses observed in patients with chemorefractory disease, alloreactive donor T cells provide a potent and promising therapeutic tool. The problem with this therapeutic intervention is that an effective antitumor response can take too many months to manifest. This is evidenced by the reduced success in a number of diseases including acute leukemia where the rapidity of tumor growth outpaces the development of an effective GVT response. Indolent malignancies for which the urgency to treat is reduced or patients with disease who are at high risk for relapse or those with nonmalignant diseases may be the treatment groups where the most significant benefits are seen.
Future studies need to clearly outline definitions and management of mixed chimerism. The measurement of donor chimerism is a prerequisite for manipulating engraftment by either altering patient immunosuppression or the administration of DLI. Standardized definitions of chimerism may make studies more readily comparable. Studies to date have used a variety of methods to assess chimerism from conventional cytogenetics analysis through to more sensitive methods using polymerase chain reaction-based assays of polymorphic mini- or microsatellite markers.
There are also a number of questions still to be answered about DLI including optimal timing of delivery, most effective and least toxic dose and durability of tumor response in the nonmyeloablative transplant setting. The maximum GVT effect appears to most consistently occur in the setting of 100% donor chimerism, and thus DLI should probably be continued until this goal is reached. The exact timing and need for ongoing DLI administration poses a difficult problem as it can take several months to see an antitumor effect. Infused T cells are not selected on the basis of preferential recognition of tumor cells, hence DLI is frequently associated with GVHD. Some diseases seem to require higher doses of DLI to demonstrate a tumor response.
Despite the lower toxicity of the preparative regimen and decrease in toxicity and associated cytokine release in normal tissues, GVHD remains a major limiting toxicity of this procedure. Post-transplant immunosuppression is used to help prevent allograft rejection and suppress GVHD. In most studies, these goals can be achieved by using single-agent immunosuppression of a relatively short duration, thus further reducing toxicity. It remains to be seen if this manifests as an increased incidence of GVHD.
Although the incidence of acute GVHD may appear lower than in conventional myeloablative transplantation, this is yet to be proven. Nonmyeloablative allogeneic transplants may only result in delayed treatment-related complications. No statement can be made regarding chronic GVHD as the data are too immature and numbers are small (Table 5). It may become apparent that nonmyeloablative alloSCT and subsequent DLI are changing the time frames in which acute and chronic GVHD manifests, hence the standard GVHD definitions may be less applicable. The mortality from GVHD remains significant and approaches to reduce the incidence need to be explored further. These efforts may include T cell depletion, prolonged doses of cyclosporine, modification of donor T cells through incorporation of suicide genes (for example, herpes simplex virus—thymidine kinase gene [47]), or the isolation of tumor-specific T cell clones. These or similar approaches may be particularly relevant to the success of this treatment modality in the setting of matched unrelated donors and possibly in haploidentical transplantation.
The median follow-up for the majority of these studies is less than one year, hence the evidence for a sustained antitumor effect is very limited. Response rates seen in these highly chemo-resistant patients are encouraging and provide the impetus to use this modality to treat patients with a more favorable prognosis (Table 2). Since relapse continues to be an important cause of treatment failure after conventional alloSCT, it seems unlikely that a nonmyeloablative alloSCT will cure more patients. Early results from these studies provide encouraging results, with lower treatment-related toxicity and mortality. As efforts in nonmyeloablative alloSCT mature, it may be necessary to carry out randomized trials in order to compare efficacy and toxicities with conventional myeloablative alloSCT. If efficacious and less toxic, the hope of more widespread application of alloSCT therapy may be realized.
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ACKNOWLEDGMENT
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This is a work of the U.S. government. There are no restrictions on its use.
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Received August 15, 2000;
accepted for publication August 15, 2000.
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Abstract
Introduction
