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Originally published as JCO Early Release 10.1200/JCO.2005.15.602 on July 11 2005 © 2005 American Society of Clinical Oncology. Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic SyndromeFrom the Section of Hematology/Oncology and the Department of Health Studies, University of Chicago, Chicago, IL Address reprint requests to Koen van Besien, MD, Section of Hematology/Oncology, 5841 S Maryland Ave, Rm I 209, Chicago, IL 60637; e-mail: Kvbesien{at}uchicago.edu
PURPOSE: This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS: After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION: Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.
Allogeneic hematopoietic stem-cell transplantation (SCT) offers the potential for prolonged disease-free survival for patients with advanced myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who otherwise have a dismal prognosis.1-3 However, such patients are often older, have chemotherapy-resistant disease, have comorbidities, and lack related donors. With conventional total-body irradiation (TBI) or busulfan-based conditioning regimens followed by infusion of unmodified allografts, long-term survival rates range between 20% and 50%. Adverse risk factors include more advanced disease, older age, the presence of comorbidities, and use of an unrelated donor.4-9 Modification of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis have been investigated to improve outcomes in these high-risk populations. In our previous exploratory studies, we evaluated the fludarabine plus melphalan regimen originally pioneered by the M.D. Anderson group (Houston, TX) and found it to be a reasonable alternative to TBI-containing regimens.10,11 The rationale for using high-dose melphalan for conditioning in allogeneic transplantation results from its convenience, its broad antitumor activity in hematologic malignancies, and its immunosuppressive effects, initially described in animal models, but subsequently confirmed by empirical clinical observations.12,13 Fludarabine was added to this conditioning regimen because of its potent immunosuppressive effects and its potential synergism with alkylators.14 In our experience, the fludarabine and melphalan regimen allowed engraftment of matched-sibling cells, unrelated-donor cells, and even T-cell–depleted haplo-identical cells. Long-term survival of patients with advanced hematologic malignancies was similar to that after TBI-based conditioning.10 Conversely, we observed a considerable incidence of regimen-related morbidity and even mortality, with deaths as a result of mucositis, veno-occlusive disease/sinusoidal obstruction syndrome, and cardiac toxicity.11 We suspected that regimen-related toxicity was compounded by the toxic effects of methotrexate used for GVHD prophylaxis.15-18 We also observed a high incidence of severe and sometimes fatal acute GVHD as well as extensive chronic GVHD that affected long-term outcomes, consistent with other studies of unmanipulated SCT, especially in the unrelated-donor setting.19 More recently, the addition of alemtuzumab to the fludarabine and melphalan regimen has been proposed as a reduced-toxicity conditioning for patients with advanced hematologic malignancies.20,21 Alemtuzumab provides in vivo T-cell depletion and results in a low incidence of acute and chronic GVHD.22 We present outcome data for 52 consecutive patients with AML or MDS enrolled onto our phase II study of this regimen for advanced hematologic malignancies.
The protocol was approved by the Institutional Review Board of the University of Chicago (Chicago, IL). All patients and donors provided written informed consent.
Patients
Additional eligibility criteria included Eastern Cooperative Oncology Group performance status Comorbidities were assessed retrospectively using the Charlson comorbidity index, which assigns a score of 2 for a diagnosis of leukemia and tabulates additional points for a variety of comorbidities.24 A history of prior infections is not taken into account in the Charlson score. Performance status was routinely recorded for patients before transplantation.
Donors and Stem-Cell Processing
Preparative Regimen
Post-Transplantation Immunosuppression Patients received tacrolimus from day –2 until day 100. Tacrolimus was initially administered IV and switched to oral administration on engraftment, targeting a trough level of 5 to 15 ng/mL. After day 100, tacrolimus was tapered over a period of 2 to 3 weeks, unless there was evidence of acute or chronic GVHD. Early withdrawal of immunosuppression was used if disease relapse occurred.
Supportive Care and Growth Factors Patients received levofloxacin 500 mg or gatifloxacin 400 mg/d orally (PO) until resolution of neutropenia. Most patients received fluconazole 200 mg/d until day 180. Patients with a history of invasive fungal infection, or those considered at high risk for it, received voriconazole 200 mg bid PO instead. Two trimethoprim/sulfamethoxazole double-strength tablets per day twice a week were administered from engraftment until 1 year after transplantation. Antiviral prophylaxis was initially administered as previously described.25 All patients who were cytomegalovirus (CMV) positive or had a CMV-seropositive donor were given ganciclovir 5 mg/kg from day –8 until day –3. They then were given acyclovir 10 mg/kg every 8 hours IV until discharge. On discharge, acyclovir 800 mg PO tid was continued until day 180. Subsequently, the policy was changed to include valacyclovir 2,000 mg qid from discharge until day 210 for all patients who were CMV positive or had a CMV-positive donor.26 Patients were screened weekly for CMV viremia until day 120 and treated with ganciclovir on detection of CMV viremia. Antifungal, antiviral, and Pneumocystis prophylaxis and screening for CMV viremia continued indefinitely for those with active GVHD or those receiving immunosuppressive treatment. Irradiated and leukocyte-depleted blood products were administered to maintain a hemoglobin level greater than 8 g/dL and platelet count greater than 10 x 109/L. No attempt was made to provide CMV-negative blood products for CMV-negative transplant recipients; instead, CMV-negative donor/recipient pairs were screened weekly for CMV viremia.27
Post-Transplantation Evaluation
Engraftment Analysis
Statistical Methods
Univariate comparisons and multivariate analyses used Cox proportional hazards regressions. Parameters calculated in the univariate and multivariate analyses included disease status (standard risk v high risk), age, performance status at transplantation (0 v
Patients From December 2001 until October 2004, 52 consecutive patients with AML or MDS were enrolled. Their characteristics are listed in Table 1. Median age at transplantation was 52 years (range, 17 to 71 years). Twenty patients had standard-risk disease and 32 had high-risk disease. There were nine patients with AML in CR1, four with AML in CR2, and seven with MDS. Among the nine patients with AML in CR1, two had therapy-related AML, four had AML with unfavorable cytogenetics, two had normal cytogenetics but hyperleukocytosis at diagnosis (90 x109/L and 200 x 109/L, respectively), and one had a tetraploid karyotype and required two courses of chemotherapy to achieve CR1. Among the MDS patients, there were four therapy-related MDS with an international prognostic score (IPS) of 1.5 in three patients and 1 in one patient.23 Finally, three patients with transfusion-dependent refractory anemia with ring sideroblasts were included. Two of them had an IPS score of 0 and one had a score of 0.5.
Among the 28 patients with high-risk AML, one was in a third remission, and one had a hypoplastic marrow after intensive reinduction within 2 weeks before transplantation; 26 patients had blasts in the bone marrow at the time of transplantation. Nineteen of the 26 also had circulating blasts (median, 2% of WBCs; range, 1% to 40%). The four patients with high-risk MDS had more than 5% blasts in the bone marrow at transplantation and three of them also had between 1% and 4% circulating blasts. Their IPS scores were 1, 1.5, 1.5, and 2, respectively. Fifteen patients had significant comorbidities as determined by the Charlson comorbidity index, 13 had experienced disease relapse after a prior transplantation, and 21 had a poor performance status (18 patients had a moderate decline [performance score = 1] and three had a more substantial decline [performance score > 1]). Nine patients had radiologic sequelae from prior fungal infections (eight of whom also had high-risk disease). Twenty-seven patients received stem cells from related donors, including 23 HLA-identical sibling donors, three one-antigen–mismatched related donors, and one two-antigen–mismatched related donor. In the latter case, the second allele mismatch was detected only on sequencing after graft failure. Twenty-five patients had unrelated donors, of which 22 were molecularly matched at A, B, C, and DR, but three had a one-antigen or one-allele mismatch at one of these loci. In all but three patients, the donors and/or recipients were positive for CMV.
Engraftment
Treatment-Related Deaths
GVHD The cumulative probability of grade 2 to 4 acute GVHD was 33% at 1 year (95% CI, 21% to 49%). Only four patients developed grade 3 to 4 acute GVHD, for a cumulative probability of 10% (95% CI, 4% to 25%). Five patients developed chronic GVHD, extensive in all cases, for a cumulative probability of chronic GVHD of 18% at 1 year (95% CI, 8% to 40%). All five patients with extensive chronic GVHD were recipients of unrelated donor transplants (Fisher’s exact test, P = .02).
Univariate and Multivariate Analysis of Outcomes
In univariate Cox regression analyses (Table 4), disease status, age, performance score, and presence of comorbidities were significantly (P  .05) associated with one or more outcomes. The relative risks and P values of the remaining independent variables in the multivariate Cox regressions with stepwise model selection are listed in Table 5. Performance status was strongly associated with treatment-related mortality (P = .002). Prior transplantation (P = .02), age (P = .03), and having therapy-related AML (P = .05) were also associated with treatment-related mortality. Disease status (P = .004) and performance status (P = .007) were both strongly associated with risk of disease recurrence. Donor type was also associated (P = .06) with risk of disease recurrence. Both disease status (P = .001) and performance score (P < .001) were strongly associated with progression-free survival. Having an unrelated donor was also associated with decreased progression-free survival, but the association was less strong (P = .02). Disease status, performance status, presence of comorbidities, and age were all associated with overall survival, but none of the P values was significant. After relapse, many patients underwent salvage chemotherapy and sometimes second transplantations. Such interventions likely influenced overall survival and may have diluted the impact of each of these potential predictors.
Figures 2 and 3 and Table 6 illustrate the effect of disease status and performance status on outcome. Patients with high-risk disease had a 39% probability of disease recurrence, a 39% probability of treatment-related mortality, and a probability of progression-free survival at 1 year of only 25%. Similarly, patients with decreased performance status had 54% probability of treatment-related mortality, 40% probability of relapse, and probability of progression-free survival at 1 year of only 6%. In contrast, probability of progression-free survival for those with standard-risk disease or those with a normal performance score was 61% in each case.
Allogeneic transplantation is a curative treatment for patients with advanced leukemia or MDS. Complications of intensive myeloablative conditioning, relapse, and lack of donors have long limited its application to younger patients in excellent condition. Recent improvements, including better selection of unrelated donors,5 better management and prevention of infectious complications,35,36 the development of novel conditioning regimens,9,37,38 and newer methods of GVHD prophylaxis have generated considerable interest in extending the use of transplantation to older and less fit patients.1-3 In our previous studies of the fludarabine and melphalan regimen, we observed excellent engraftment, reasonable disease control, but excessive toxicity and GVHD.11 To reduce toxicity and GVHD, we omitted methotrexate in the current study and replaced it with in vivo alemtuzumab (Campath Ilex Pharmaceuticals, San Antonio, TX). Alemtuzumab is a monoclonal antibody directed against CD52, an antibody widely expressed on B cells, T cells, and natural killer cells. Immunoglobulin M antibodies, IgG antibodies, and most recently, humanized IgG antibodies (alemtuzumab) against CD52 have been used as in vitro T-cell–depleting agents with variable success rates.39 The British Cooperative Group were the first to report a combination of fludarabine, melphalan, and in vivo alemtuzumab for conditioning in allogeneic transplantation and have studied its use mainly in lymphoid malignancies.20,21 They used single-agent cyclosporine for post-transplantation GVHD prophylaxis and demonstrated a high rate of engraftment, acceptable toxicity, and in most malignancies, relatively low rates of treatment-related mortality.20-22 They also reported a low incidence of acute and in particular of chronic GVHD using both matched-related and matched-unrelated allografts. We used nearly the same conditioning regimen but substituted tacrolimus for cyclosporine. Another major difference was our use of aggressive CMV prophylaxis with pretransplantation ganciclovir and post-transplantation high-dose valacyclovir in the majority of patients.26 This resulted in a cumulative incidence of CMV reactivation of only 29% and possibly a reduction of adenovirus reactivation.40-42 Here we report our results in AML and MDS. Our patient population had many unfavorable clinical features. The majority of patients had refractory leukemia or MDS with an increased percentage of blasts. Even the so-called standard-risk patients had unfavorable types of leukemia or MDS. In addition to high-risk disease, the patients were at high risk of transplantation complications, making standard ablative transplantation a relative contraindication for the majority. More than one fourth had experienced disease relapse after a prior transplantation and others had suffered previous fungal infections, had serious comorbidities, or had a decreased performance status. More than half received transplants from unrelated donors or from mismatched related donors. Finally, the median age of 52 years was older than in most other studies of novel conditioning regimens and older than in our own previous studies. Given these many adverse features, the 1-year survival of 48% overall and progression-free survival of 38% are encouraging. Additional analysis of these data engenders several observations of interest. First, we confirm the British report on high rates of engraftment, relatively minimal regimen-related toxicity, and low incidence and severity of acute and chronic GVHD. In addition, similar to other recent reports,5,43-45 related and unrelated donor transplantation appeared to result in similar outcomes. Still, even from our preliminary experience, it is obvious that the risk for chronic GVHD remains higher after matched unrelated than after HLA-identical sibling transplantation, and in multivariate analysis, some impact of donor type on progression-free survival remained. Recipient age and Charlson comorbidity score are probably less important in predicting outcome of transplantation and were only moderately associated with outcome.9,46 Pretransplantation disease status and performance status were the major predictors for progression-free and overall survival. The outcomes for patients with standard-risk disease were excellent. Among 20 such patients, there were only three recurrences and four treatment-related deaths, resulting in a progression-free survival rate of 61% at 1 year, with no recurrences beyond 1 year. This regimen is therefore curative for a high fraction of AML/MDS patients with standard-risk disease and, because of the low risk of severe GVHD, may be preferable to non–T-cell depleted transplantation. Other studies in younger standard-risk patients with T-cell depletion and more ablative regimens have yielded similar results.47-52 In contrast, Bacigalupo et al19 showed in a randomized study that non–T-cell depleted transplantation is associated with a prolonged and persistent risk of morbidity and mortality, related to GVHD and bronchiolitis obliterans. Our data can also be compared with those of the M.D. Anderson group, which obtained (with a busulfan and fludarabine regimen) approximately 75% progression-free survival at 1 year among patients who underwent transplantation in remission, but with a more than 50% cumulative incidence of chronic GVHD.53 Our series had a much higher proportion of patients receiving unrelated-donor transplantation and a lower risk of chronic GVHD. Patients with active leukemia or MDS with increased blasts fared poorly (Fig 3). Their progression-free survival rate at 200 days after transplantation was 38% (95% CI, 21% to 55%) and at 1 year it was 25% (95% CI, 12% to 42%). In light of the extremely poor prognosis of this group, the regimen potentially provided prolonged palliation to approximately one fourth of the high-risk patients. However, few were cured; among seven high-risk patients who were still in remission 1 year after transplantation, four had a recurrence during the second year of follow-up. Classic myeloablative conditioning regimens are similarly associated with high rates of disease recurrence and treatment-related mortality in patients with high-risk disease, and do not represent a better choice.54,55 For such patients, alternative approaches including investigational therapies need to be explored, and when such patients are counseled to undergo transplantation, the limited expectation of benefit must be clarified. The most important predictor of treatment-related mortality was performance status, which was also a major predictor of progression-free survival and of overall survival.9,46 Even modest decreases in performance status led to major differences in outcome (Fig 4). It is likely that assessment of performance status captures the impact of leukemia and of certain comorbidities better than currently available scoring systems such as the Charlson score. Pending the development of better instruments, data on performance status should be routinely and ideally prospectively included in transplantation trials.
In summary, the fludarabine and melphalan regimen when combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML and MDS and low tumor burden; it demonstrates excellent disease control and high tolerability. The effective T-cell depletion greatly reduces the risk of GVHD and thus attenuates the impact of age and comorbidities on TRM. Stringent antiviral prophylaxis may have contributed to the relatively low rate of viral reactivation and opportunistic infections.42 For patients with active disease, this regimen provides modest palliation, but long-term disease control is poor. Despite the low incidence of GVHD, the management of patients with decreased performance status also poses considerable problems. In this difficult patient group, our reduced-intensity conditioning was still associated with considerable nonrelapse mortality, and other approaches need to be investigated.
Although all authors have completed the disclosure declaration, the following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank Theodore Karrison, PhD, for help in the statistical analysis.
Supported by a grant from Berlex Pharmaceuticals and by National Cancer Institute grant No. CA 101337. Authors' disclosures of potential conflicts of interest are found at the end of this article. Presented in part at the 40th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004.
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5. 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 transplant outcome. Blood 104:1923-1930, 2004
6. 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 Med 328:593-602, 1993 7. de Witte T, Hermans J, Vossen J, et al: Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:620-630, 2000[CrossRef][Medline]
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9. Sorror ML, Maris MB, Storer B, et al: Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: Influence of pretransplantation comorbidities. Blood 104:961-968, 2004 10. van Besien K, Devine S, Wickrema A, et al: Fludarabine melphalan is a suitable alternative to fludarabine-TBI based conditioning for allogeneic transplantation in patients with advanced hematologic malignancies. Hematol J 3:78a 2002 (suppl 1; abstr 580) 11. van Besien K, Devine S, Wickrema A, et al: Regimen-related toxicity after fludarabine-melphalan conditioning: A prospective study of 31 patients with hematologic malignancies. Bone Marrow Transplant 32:471-476, 2003[CrossRef][Medline] 12. Van Besien KW, Demuynck H, LeMaistre CF, et al: High dose melphalan allows durable engraftment of allogeneic bone marrow. Bone Marrow Transplant 15:321-323, 1995[Medline] 13. Singhal S, Powles R, Treleaven J, et al: Melphalan alone prior to allogeneic bone marrow transplantation from HLA-identical sibling donors for hematologic malignancies: Alloengraftment with potential preservation of fertility in women. Bone Marrow Transplant 18:1049-1055, 1996[Medline] 14. Gandhi V, Plunkett W: Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 41:93-103, 2002[CrossRef][Medline]
15. Essell JH, Thompson JM, Harman GS, et al: Marked increase in veno-occlusive disease of the liver associated with methotrexate use for graft-versus-host disease prophylaxis in patients receiving busulfan/cyclophosphamide. Blood 79:2784-2788, 1992 16. Dulley FL, Kanfer EJ, Appelbaum FR, et al: Venocclusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation. Transplantation 43:870-873, 1987[Medline] 17. Styler MJ, Crilley P, Biggs J, et al: Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: A retrospective, multicenter analysis. Bone Marrow Transplant 18:171-176, 1996[Medline] 18. Cutler C, Li S, Kim H-S, et al: Oral mucositis incidence and severity after methotrexate and non-methotrexate containing GVHD prophylaxis. Blood 104:104a, 2004 (suppl 1; abstr 351) 19. Bacigalupo A, Vignola M, Lamparelli T, et al: Long term follow up of two randomized trials on antithymocyte globulin (ATG) for GvHD prophylaxis in unrelated donor transplants: Chronic GvHD, bronchiolitis and quality of life. Blood 104:128a, 2004 (suppl 1; abstr 638)
20. Chakraverty R, Peggs K, Chopra R, et al: Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood 99:1071-1078, 2002
21. Kottaridis PD, Milligan DW, Chopra R, et al: In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 96:2419-2425, 2000
22. Morris E, Thomson K, Craddock C, et al: Outcome following alemtuzumab (CAMPATH-1H)- containing reduced intensity allogeneic transplant regimen for relapsed and refractory non-Hodgkin's lymphoma (NHL). Blood 104:3865-3871, 2004
23. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997 24. Charlson M, Szatrowski TP, Peterson J, et al: Validation of a combined comorbidity index. J Clin Epidemiol 47:1245-1251, 1994[CrossRef][Medline] 25. Verma A, Devine S, Morrow M, et al: Low incidence of CMV viremia and disease after allogeneic peripheral blood stem cell transplantation: Role of pretransplant ganciclovir and post-transplant acyclovir. Bone Marrow Transplant 31:813-816, 2003[CrossRef][Medline]
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39. Hale G, Zhang MJ, Bunjes D, et al: Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. Blood 92:4581-4590, 1998 40. Avivi I, Chakrabarti S, Milligan DW, et al: Incidence and outcome of adenovirus disease in transplant recipients after reduced-intensity conditioning with alemtuzumab. Biol Blood Marrow Transplant 10:186-194, 2004[CrossRef][Medline]
41. Chakrabarti S, Mackinnon S, Chopra R, et al: High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: Potential role of Campath-1H in delaying immune reconstitution. Blood 99:4357-4363, 2002 42. Kline J, Pollyea D, Larson RA, et al: Ganciclovir and high-dose valacyclovir prevent cytomegalovirus reactivation in patients receiving allogeneic stem cell transplants with Campath-1H based conditioning regimens. Biol Blood Marrow Transplant 11:94, 2005 (suppl 1; abstr 277) 43. Chalandon Y, Halter J, Guengoer T, et al: Impact of molecular HLA-matching for allogeneic transplantation from unrelated donors. Blood 104:280a, 2004 (abstr 979) 44. Fillion A, Loiseau P, Rocha V, et al: Decreased transplant related mortality and better survival in HLA matched (12/12 A, B, C, DRB1, DQB1, DBP1) unrelated bone marrow transplants. Blood 104:280a, 2004 (abstr 977) 45. Yakoub-Agha I, Boiron J-M, Michallet M, et al: Genoidentical donor versus A, B, Cw, Dr, DQ, HLA allelic matched unrelated donor for stem cell transplantation in patients with standard risk hematological malignancy. Blood 104:279a, 2004 (abstr 976) 46. Pollyea D, Artz AS, Stock W, et al: Clinical predictors of transplant related mortality after reduced intensity allogeneic hematopoietic transplantation. Blood 104:324a, 2004 (abstr 1145) 47. Deeg HJ, Appelbaum FR, Storer B, et al: Reduced incidence of acute and chronic graft-versus-host disease (GvHD) without increased relapse in patients with high-risk myeloid disorders given thymoglobulin (THY) as part of the transplant conditioning regimen: A dose-finding study. Blood 104:569a, 2004 (abstr 181)
48. Papadopoulos EB, Carabasi MH, Castro-Malaspina H, et al: T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: Freedom from relapse in the absence of graft-versus-host disease. Blood 91:1083-1090, 1998
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53. de Lima M, Couriel D, Thall PF, et al: Once-daily intravenous busulfan and fludarabine: Clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 104:857-864, 2004
54. Sierra J, Storer B, Hansen JA, et al: Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: The effect of leukemic burden, donor HLA matching, and marrow cell dose. Blood 89:4226-4235, 1997 55. Kebriaei P, Kline J, Stock W, et al: Impact of disease burden at time of allogeneic stem cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes. Bone Marrow Transplant 35:965-970, 2005[CrossRef][Medline] Submitted February 10, 2005; accepted April 26, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
1), disease type (AML v MDS), therapy-related leukemia versus no therapy-related leukemia, comorbidity score at transplantation (2 v > 2), prior transplantation v no prior transplantation, and donor type (HLA-identical related donor v antigen-mismatched related or unrelated donor). For the multivariate Cox models, independent variables with P > 0.1 were excluded sequentially from the models. The relative risks and the associated P values of the remaining variables are reported. All data were analyzed as of December 31, 2004. 
