| | The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Therapy of Acute Myelogenous Leukemia in Adults: An Evidence-Based ReviewReceived 8 November 2007; accepted 9 November 2007. Abstract Clinical research examining the role of hematopoietic stem cell transplantation (HSCT) in the therapy of acute myelogenous leukemia (AML) in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in Table 3, entitled Summary of Treatment Recommendations Made by the Expert Panel for Adult Acute Myelogenous Leukemia, and were reached unanimously by a panel of AML experts. The identified priority areas of needed future research in adult AML include: (1) What is the role of HSCT in treating patients with specific molecular markers (eg, FLT3, NPM1, CEBPA, BAALC, MLL, NRAS, etc.) especially in patients with normal cytogenetics? (2) What is the benefit of using HSCT to treat different cytogenetic subgroups? (3) What is the impact on survival outcomes of reduced intensity or nonmyeloablative versus conventional conditioning in older (>60 years) and intermediate (40-60 years) aged adults? (4) What is the impact on survival outcomes of unrelated donor HSCT vesus chemotherapy in younger (<40 years) adults with high risk disease? Introduction  The American Society for Blood and Marrow Transplantation (ASBMT), in 1999, began an initiative to sponsor evidence-based reviews of the scientific and medical literature for the use of blood and marrow transplantation in the therapy of selected diseases. The steering committee that was convened to oversee the projects invited an independent panel of disease-specific experts to conduct each review. Five previous reviews have been published in Biology of Blood and Marrow Transplantation: Diffuse Large B Cell Non-Hodgkin Lymphoma [1], Multiple Myeloma (MM) [2], Pediatric Acute Lymphocytic Leukemia (ALL) [3], Adult ALL [4], and Pediatric Acute Myeloid Leukemia (AML) [5]. The following is the sixth review to result from this initiative. Its goals are to assemble and critically evaluate all of the evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in the therapy of adult (≥15 years) patients with AML, make treatment recommendations based on the available evidence, and identify areas of needed research. Literature Search Methodology PubMed and Medline, the Web sites developed by the National Center of Biotechnology Information at the National Library of Medicine of the National Institutes of Health, were searched August 8, 2006, using the search terms “acute myeloid leukemia” or “acute myelogenous leukemia” and “transplant,” limited to human trials, English language, and a publication date of 1990 or later. An updated search was conducted in early May, 2007, limited to August 9, 2006, to April 30, 2007. Manuscripts were excluded if they were published before 1990, included <50 AML patients, were not peer reviewed, were editorials, letters to the editor, Phase I (dose-escalation or dose-finding) studies, reviews, consensus conference papers, practice guidelines, laboratory studies with no clinical correlates, did not focus on an aspect of therapy with HSCT for the treatment of adult AML, or if >50% of the study population was <15 years and the results were not stratified by age. In addition, for a manuscript to be included, a minimum of 70% of study subjects had to be AML patients, or study results had to be stratified by disease. Abstracts and presentations at national or international meetings were not included as evidence in this review for reasons previously described [3]. Qualitative and Quantitative Grading of the Evidence The hierarchy of evidence, including a grading system for the quality and strength of the evidence, and strength of each treatment recommendation, was established and published as an editorial policy statement in Biology of Blood and Marrow Transplantation in 2005 [6]. Table 1, Table 2 are reprinted from the policy statement and define criteria used to grade the studies included in this review and to grade the treatment recommendations. Study design, including sample size, patient selection criteria, duration of follow-up, and treatment plan also were considered in evaluating the studies. Several multicenter clinical trials were designed to biologically assign patients to a treatment arm based on the availability of a donor (“biologic allocation”). These studies of allogeneic (allo) HSCT versus chemotherapy are therefore graded as level “2” evidence, not level “1,” because they are not statistically randomized controlled trial designs. Autologous (auto) HSCT versus chemotherapy studies were graded as level “1” evidence if the study design included a statistically randomized controlled trial. Clinical studies are described with enough detail to give a concise summary of study design, sample size, and eligibility criteria. | | |  | Levels of evidence | |
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| 1++ | High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias | | | 1+ | Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias | | | 1− | Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias | | | 2++ | High-quality systematic reviews of case-controlled or cohort studies High-quality case-controlled or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal | | | 2+ | Well-conducted case-controlled or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal | | | 2− | Case-controlled or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal | | | 3 | Nonanalytic studies, for example, case reports, case series | | | 4 | Expert opinion | | | | |
All data in the text and tables were abstracted from the original manuscripts by the first author (D.O.), then double checked for accuracy and clarity by 2 other authors (T.H. and P.L.M.) and 1 additional reviewer (see Acknowledgments). In some articles there were discrepancies within the data reported and, in these cases, the data most consistent with the text of the article were presented in this review. The last author (T.H.) takes responsibility if errors remain. Appendix A lists the common abbreviations used in this review. Treatment Recommendations The strength of this review is the detail conveyed in the text about the study designs and the presentation of the outcomes in the summary tables included in each major section. Table 3 contains the summary of treatment recommendations made by the adult AML expert panel. | | | | Indication for HSCT | Treatment Recommendation Grade ∗ | Highest Level of Evidence † | | Treatment Recommendation Comments | |
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| Transplantation versus Chemotherapy | | | Autologous (Auto) SCT versus Chemotherapy (Chemo) in CR1 | | | Induction + intensive consolidation chemo (ICC), then ICC versus auto | A | 1+ | 9, 10 | Based on the survival data presented, there is no significant advantage of auto-SCT over chemotherapy. Most of the data reflect outmoded treatment strategies (i.e., BM versus PBSC; maintenance therapy pre-SCT, etc.); studies using modern technologies may effect outcomes to an unknown extent. | | | Induction + ICC, then no further Tx versus auto | B | 1− | 13, 14 | Same as above | | | Induction, then ICC versus auto | B | 1+ | [16] | Same as above | | | Allogeneic (Allo) SCT versus Chemo in CR1 | | | Myeloablative Allo-SCT versus chemo | A | 1+ | [18] | There is a survival advantage for allo-SCT versus chemotherapy for patients <55 years with high risk cytogenetics. There is insufficient evidence to routinely recommend allo-SCT for patients with intermediate risk cytogenetics, although this is a reasonable strategy. There is no survival advantage for allo-SCT in patients <55 years with low risk cytogenetics. There are insufficient data to make a recommendation on the use of myeloablative regimens for patients >55 years. | | | Reduced-intensity conditioning (RIC) Allo versus chemo | No recommendation | 2− | [26] | There are insufficient data to make a recommendation. | | | SCT versus Chemo in CR2 | | | Allo-SCT versus chemo in CR2 | D | 4 | [27] | Based on expert opinion and clinical practice, it is recommended that patients in CR2 receive an allo-SCT if there is an available donor; otherwise, an auto-SCT is recommended. | | | Transplantation Techniques | | | Allogeneic versus Autologous SCT | B | 2++ | 28, 29 | Based on data and expert opinion, an HLA-matched related donor (MRD) allo-SCT is recommended over auto-SCT, if an MRD is available. There are insufficient data to make a recommendation for matched unrelated donor (MUD) allo-SCT versus auto-SCT. These studies do not reflect modern techniques in supportive care, stem cell source, or the use of molecular HLA typing (for the MUD studies). | | | Autologous SCT | | | PBSCT versus BMT | C | 2+ | 37, 38, 39 | Based on data and clinical practice, PBSCT is recommended due to improvement in safety and early mortality. However, long-term outcomes have not been studied prospectively; therefore, the impact of PBSCT on OS is unknown. | | | Unpurged versus purged↓ | C | 2+ | 40, 41, 42 | There is no evidence of a survival advantage with purged BMT. There are insufficient data to make a recommendation for purging of PBSCT. | | | Tandem versus single | No recommendation | 2- | [43] | There are insufficient data to make a recommendation. | | | Allogeneic SCT | | | Related versus unrelated | C | 2+ | 55, 56 | MRD allo-SCT is recommended if available. If a MRD is not available, a MUD allo-SCT may provide equivalent outcomes. | | | T cell replete versus T cell depleted | B | 1+ | [57] | There is no evidence of a survival advantage with T cell-depleted grafts. | | | PBSCT versus BMT | C | 2++ | [59] | For high-risk disease, allo-PBSCT is recommended over BMT. For low-risk disease, allo-PBSCT and BMT have equivalent outcomes. There are insufficient data to make a recommendation on stem cell source for MUD allo-SCT. | | | Therapy Regimens | | | Auto-SCT— Comparison of 2 or more high-dose therapy regimens | C | 2+ | 77, 78 | There is no evidence of a survival advantage with any one high-dose therapy regimen. | | | Allo-SCT—Comparison of 2 or more myeloablative conditioning regimens | B | 1+ | 79, 80 | There is no significant survival advantage with any one myeloablative conditioning regimen. Studies of late effects may change this recommendation. If a TBI-containing conditioning regimen is used, fractionated rather than single-dose TBI is recommended. | | | Allo-SCT— Use of RIC regimens | No recommendation | 2++ | [86] | There are insufficient data to make a recommendation. The use of RIC is dependent on patient characteristics such as age, comorbidities, and cytogenetic risk. | | | | |
| ∗ Definitions: Grade of Recommendation (Table 2): (A) At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results. (B) A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+. (C) A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++; (D) Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+ †Definitions: Levels of Evidence (Table 1): 1++ High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias. 1+ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias. 1− Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias. 2++ High-quality systematic reviews of case-control or cohort studies; or High-quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal. 2+ Well-conducted case control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal; 2− Case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal. 3 Nonanalytic studies, for example, case reports, case series. 4 Expert opinion. ↨The references listed represent the highest level of evidence used to make the treatment recommendation and are not inclusive of all evidence described in the review. ↓Purging: Techniques to remove tumor, either by negative or positive selection. |
Format of the Review Evidence is taken from self-described studies of adult populations that included patients ≥15 years of age. In each section of this review, the highest quality studies are presented first; studies of equal quality are presented in descending order by sample size. The design of each study is described in the text and, unless otherwise noted, the accompanying table in each section presents the outcomes for each study. HSCT Versus Chemotherapy in Adult AML Table 4 presents a summary of the outcomes for each of the studies in this section. Of the 10 studies investigating auto-HSCT versus chemotherapy, 5 found a significant difference in disease-free survival (DFS), relapse-free survival (RFS), or leukemia-free survival (LFS), and 2 studies found a significant difference in overall survival (OS). Of the 14 studies that examined allo-HSCT versus chemotherapy ± auto-HSCT, 7 reported a statistically significant difference in DFS, LFS, or event-free survival (EFS), and 4 studies found a significant difference in OS. Table 5 presents a summary of the treatment schema used in the auto-HSCT versus chemotherapy studies. | | | | Reference [No.] | Quality and Strength of Evidence ∗ | | Number of Patients by Study Group | Upper Limit (median) Age at Diagnosis | (Interval) % Tx- Related Mortality | Median Follow-up | (Interval) % DFS/% EFS/% RFS/% LFS(Signif) | Outcome Defined | (Interval) % OS (Signif) | |
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| Autologous SCT versus Chemotherapy in CR1‡ | | | Levi et al., 2004 [7] | 1++ | Meta-analysis (6 RCT studies) 1984-1996 Recruited n = 4410 Achieved CR1 n = 3220 | Randomized n = 1044 (ITT) Auto 524 Chemo/no further TX 520 | | Not stated | Not stated | (Overall EFS) Auto versus Chemo (P signif, but not stated) | Not stated | (Not stated) RR =.94 (CI .81-1.09) (P not signif) | | | Treatment Schema I: Induction + ICC, then Auto-SCT versus Additional ICC | | | Zittoun et al., 1995 [9] (included in Levi et al., meta-analysis) | 1+ | EORTC and GIMEMA 1986-1993 Multicenter (59) Recruited n = 990 Evaluable n = 941 Achieved CR1 n = 623 | Randomized n = 254 (ITT) Auto 128 Chemo 126 | | Not stated | 3.3 yrs | (4-yr DFS) 48 ± 5 30 ± 4 (P = .05) | Time from CR1 to first relapse or death in CR | (4-yr OS) 56 ± 5 46 ± 5 (P = .43) | | | Reiffers et al., 1996 [10] (included in Levi et al. and Yanada et al., meta-analyses) | 1+ | BGMT 87 trial 1987-1990 Multicenter (4) Enrolled n = 204 Achieved CR1 n = 162 | Randomized n = 77 (ITT) Auto 39 Chemo 38 | | | Minimum Follow-up 40 months | (3-yr DFS) 51 ± 17 58 ± 16 (P not signif) | Time from CR1 to relapse, death, or last visit | (3-yr OS) 56 ± 16 55 ± 16 (P not signif) | | | Harousseau et al., 1997 [11] (included in Levi et al., meta-analysis) | 1− | GOELAM 1987-1994 Multicenter (16) Recruited n = 535 Evaluable n = 504 Achieved CR1 n = 367 | Randomized n = 164 (ITT) Auto 86 Chemo 78 | | | 62 mos | (4-yr DFS) 44 ± 5.5 40 ± 5.5 (P = .41) | Time from CR1 to relapse or death | (4-yr OS) 50 ± 6 54 ± 6 (P = .72) | | | Miggiano et al., 1996 [12] | 2+ | Retrospective Nonrandomized 1987-1994 Single center Included n = 89 | Total 89 (Actual TX) Auto 51 Chemo 38 | <60 yrs (mean age) (36) (44) | (Not stated) 0 (Not stated) | | (5-yr LFS) 69.6 41.9 (P = .008) | Not stated | Not stated | | | Treatment Schema II: Induction + ICC, then Auto-SCT versus No Further Treatment | | | Burnett et al., 1998 [13] (included in Levi et al. meta-analysis) | 1− | UK MRC AML 10 1988-1995 Multicenter (163) Recruited n = 1966 Evaluable n = 1857 Achieved CR1 n = 1509 Eligible for Randomization n = 1001 | Randomized n = 381 (ITT) Auto 190 Chemo only 191 | | Not stated | 4.8 yrs | | Time from randomization to relapse or death in CR1 | | | | Breems et al., 2004 [14] | 1− | HOVON & SAKK 1987-1995 Recruited n = 646 Achieved CR1 n = 425 Randomizable n = 344 Randomized n = 130 | Randomized n = 130 (ITT) Auto 66 No further TX 64 (Chemo only) | | Not stated | 154 mos | (5-yr DFS) 35 ± 6 44 ± 6 (P = .68) | Not stated | (5-yr OS) 39 ± 6 56 ± 6 (P = .08) | | | Rohatiner et al., 2000 [15] | 2+ | BXIII Protocol 1988-1994 Multicenter (3) Recruited n = 144 Achieved CR1 n = 106 Pre-1988 Comparison Group n = 133 | Total n = 239 (ITT) Auto 106 Chemo 133 | | Not stated | 5.5 yrs | (5-yr RFS)K-M curves only (Auto versus Chemo, P = .002) | Not stated | (5-yr OS) K-M curves only (Auto versus Chemo, P = .009) | | | Treatment Schema III: Induction, then ICC versus Auto-SCT | | | Cassileth et al., 1998 [16] (included in Levi et al., meta-analysis) | 1+ | CALGB, ECOG, SWOG 1990-1995 Intergroup, multicenter study Recruited n = 808 Evaluable n = 740 Achieved CR1 n=518 Randomized n=233 | Randomized n = 233 (ITT) Auto 116 Chemo 117 | | | 4 yrs | (4-yr DFS) 35 ± 9 35 ± 9 (P = .77) | Time from CR1 to 1st relapse or death from any cause | (4-yr OS) 43 ± 9 52 ± 9 (P = .05) | | | Bassan et al., 1998 [17] | 2− | BXIII Protocol Non-randomized 1987-1993 2 centers Enrolled n = 153 Achieved CR1 n =108 | Total n = 65 Auto BMT 41 Chemo 24 | | | Minimum 3.3 yrs | (5-yr RFS) 53 54 (P not signif) | Time from CR1 to relapse or death in CR | (5-yr OS) 60 65 (P not signif) | | | Allogeneic SCT versus Chemotherapy ± Autologous SCT in CR1 | | | Myeloablative Conditioning for Allogeneic SCT | | | Yanada et al. 2005 [18] | 1+ | Meta-analysis (5 allo-SCT studies) Published 1995-2003 Accrual 1986-1999 | Total n = 3100 Allo-SCT 1151 Alternative 1949 (Auto or chemo) | | Not stated | Not stated | Not stated | Not stated | (Not stated) (CI 1.06 - 1.30) (P = .003, Allo versus alternative) | | | Cornelissen et al. 2007 [19] | 2++ | HOVON-SAKK AML4, AML29, and AML42 trials 1987-2004 Recruited n = 2287 Evaluable n = 925 | Total n = 925 (ITT) Donor 326 No Donor 599 (Auto or chemo) | | | 63 mos | (4-yr DFS) 48 ± 3 37 ± 2 (P < .001) | Time from consolidation to relapse or death | (4-yr OS) 54 ± 3 46 ± 2 (P = .09) | | | Harousseau et al., 1997 [11] | 2++ | GOELAM 1987-1994 Multicenter (16) Recruited n = 535 Evaluable n = 504 Achieved CR1 n = 367 | Total n = 222 (ITT) Donor 88 No Donor 134 (Chemo) | | | 62 mos | (4-yr DFS) 44 ± 5.5 38 ± 4 (P = .62) | Time from CR1 to relapse or death | (4-yr OS) 53 ± 5.5 53 ± 4.5 (P = .74) | | | Reiffers et al., 1996 [10] | 2++ | BGMT 87 1987-1990 Multicenter (4) Eligible n = 204 Achieved CR1 n = 162 | Total n = 96 (ITT) Donor 36 No Donor 60 (Auto or chemo) | | | Minimum Follow-up 40 months | (3-yr DFS) 66 ± 16 56 ± 13 (P < .05) | Time from CR1 to relapse, death, or last visit | (3-yr OS) 65 ± 16 50 ± 13 (P not signif) | | | Burnett et al., 2002 [20] (Included in Yanada et al. meta-analysis) | 2+ | UK MRC AML 10 1988-1995 Multicenter (163) Recruited n = 1966 Evaluable n= 1857 Achieved CR1 n=1509 | Total n = 1287 (ITT) Donor 419 No Donor 868 (including 200 auto) | | Not stated | 80 mos | | Time from CR1 to relapse or death in CR | | | | Gale et al., 1996 [21] | 2+ | Retrospective IBMTR (transplant); GAMLCG (chemo) 1985-1993 Multicenter (40+) Included n = 1097 | Total n = 1097 (Actual TX) Allo 901 Chemo 196 | | | Not stated | (5-yr LFS) 46 (CI 42-50) 35 (CI 28-41) (P = .01) | Not stated | (5-yr OS) 48 (CI 43-53) 42 (CI 33-51) (P = .28) | | | Zittoun et al., 1995 [9] | 2+ | EORTC & GIMEMA 1986-1993 Multicenter (59) Recruited n = 990 Achieved CR1 n = 623 | Total n = 294 (ITT) Allo 168 Chemo 126 | | Not stated | 3.3 yrs | (4-yr DFS) 55 ± 4 30 ± 4 (Allo versus chemo, P < .05) | Time from CR1 to 1st relapse or death in CR | (4-yr OS) 59 ± 4 46 ± 5 (P not signif) | | | Cassileth et al., 1998 [16] | 2+ | CALGB, ECOG, SWOG 1990-1995 Intergroup, multicenter study Eligible n = 808 Achieved CR1 n = 518 | Total n = 230 (ITT) Allo 113 Chemo 117 | | | 4 yrs | (4-yr DFS) 43 ± 10 35 ± 9 (P not signif) | Time from CR1 to 1st relapse or death from any cause | (4-yr OS) 46 ± 10 52 ± 9 (Chemo versus Allo, P = .04) | | | Cassileth et al., 1992 [22] | 2+ | ECOG 1984-1988 Recruited n = 534 Evaluable n = 449 Achieved CR1 n = 305 Allo, n = 54, compared with subset of chemo pts.<41 yr, n = 50) | Total n = 104 (ITT) Allo 54 Consolidation chemo 29 Maintenance chemo 21 | | | 4 yrs | (4-yr EFS) 42 ± 13 30 ± 17 14 ± 15 (Allo versus Maint. Chemo P = .01) | Time from CR1 relapse or death | (4-yr OS) 42 ± 14 43 ± 18 19 ± 17 (Allo versus Maint. Chemo P = .047) | | | Schiller et al., 1992 [23] | 2+ | ALP 3 and 4 1982-1990 2 centers Recruited n = 103 Achieved CR1 n = 82 | Total n = 82 (Actual TX) Allo 28 Chemo 54 | | | 4 yrs | (5-yr DFS) 48 ± 21 38 ± 14 (P not signif) | Not stated | (5-yr OS) 45 ± 24 53 ± 16 (P not signif) | | | Willemze et al., 1991 [24] | 2+ | Retrospective 1983-1989 Single center Included n = 107 | Total n = 78 (Actual TX) Allo 44 Chemo 34 | | | 18 mos | (3-yr DFS) 30 (CI 19-45) 25 (CI not stated) (P = .45) | Time from CR1 to relapse or death | Not stated | | | Archimbaud et al, 1994 [25] | 2+ | LYLAM-85 1985-1990 Single center Recruited n = 172 Subset <40 yr of age n = 78 Achieved CR1 n = 58 | Total n = 58 (ITT) Donor 27 No Donor 31 (Chemo) | | | 63 mos | (7-yr LFS) 41 ± 22 27 ± 16 (P not signif) | Time from CR1 to relapse, death, or last contact | (7-yr OS) 41 ± 22 46 ± 19 (P = .10) | | | Reduced Intensity Conditioning (RIC) for Allogeneic SCT | | | Mohty et al., 2005 [26] | 2− | Retrospective 1999-2003 Single center Included n = 95 | Total n = 95 (ITT) Donor 35 No Donor 60 | | | 31 mos | | Time from DX to relapse | (4-yr OS) Data Not stated (P = .04) | | | Allogeneic SCT versus Chemotherapy in CR2 | | | Gale et al., 1996 [27] | 2+ | Retrospective MRC, ECOG, IBMTR 1980-1989 Multicenter (80+) | Total n = 501 Allo 257 Chemo 244 | | | | (3-yr LFS) 26 (CI 20-32) 17 (12-23) (P not signif) | Not stated | Not stated | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †AML indicates acute myelogenous (myeloid) leukemia; Allo, allogeneic; Auto, autologous; Chemo, chemotherapy; BMT, bone marrow transplantation; SCT, stem cell transplantation; CR, complete remission; DX, diagnosis; TX, treatment; MRC, Medical Research Council; EORTC, European Organization of Research and Treatment of Cancer; GIMEMA, Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto; CALGB, Cancer and Leukemia Group B; ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group; GOELAM, Groupe Ouest Est Leucémies Aiguës Myéloblastiques; IBMTR, International Bone Marrow Registry; GAMLCG, German AML Cooperative Group; ALP, acute leukemia protocol; HOVON, Dutch Hemato-Oncology Working Party; STT, short-term therapy; FAB, French, American, British morphology classification; ITT, intent-to-treat; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; Signif., significance (probability); OS, overall survival; WBC ct, white blood cell count; Hepato., hepatosplenomegaly; PS, performance status; RR, rate ratio; CI, 95% confidence interval. ‡Auto versus allo-SCT outcomes are presented in Table 5. §Relative Risk (RR) less than 1 indicates significant survival benefit for auto-SCT as compared to chemotherapy. ¶Hazard Ratio (HR) greater than 1 indicates allo-SCT is superior to nonallogeneic SCT. |
| | | | SCT versus Chemo Study [Strength of Evidence ∗] [Ref No.] | Induction | Intensive Consolidation | Further Treatment | |
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| Induction + ICC, then Autologous SCT versus Additional ICC | | | Zittoun et al., 1995 [1+] [9] | DNR†(45 mg/m2/day × 3) + Ara-C (200 mg/m2/day × 7); second course if partial or no CR | For patients who achieved CR after 1-2 courses: AMSA (120 mg/m2/day × 3) + Ara-C (2000 mg/m2/day × 6 for first 75 pts, then decreased to 1000 mg/m2/day × 6 for subsequent pts) | If donor available, Allo-SCT (34% of pts) using Cy (60 mg/kg/day × 2) + TBI (12 Gy) Or Bu (4 mg/kg/day × 4) + Cy (60 mg/kg/day X 2) If no donor, randomized to HiDAC (Ara-C 4 mg/m2/day × 4 + DNR 45 mg/m2/day × 3) Or Auto-SCT (55% of pts) using Bu (4 mg/kg/day X 4) + Cy (60 mg/kg/day × 2) | | | Reiffers et al., 1996 [1+] [10] | Ara-C (100 mg/m2/day × 10) + DNR (60 mg/m2/day × 3); second course if partial or no CR | For all pts who achieved CR after 1-2 courses: Ara-C (100 mg/m2/day × 7) + DNR (60 mg/m2/day × 2) | If donor available and ≤45 years, Allo-SCT using Bu (4 mg/kg/day × 4) + Mel (140/m2/day × 1) If no donor or > 45 years, randomized to 2 years maintenance using Ara-C (100 mg/m2/day × 5) + DNR (1 mg/kg i.v. × 1) administered at 1, 3, 6, 9, and 12 mos Or Auto-SCT using Bu (4 mg/kg/day × 4) + Mel (140/m2/day × 1) | | | Harousseau et al., 1997 [1+] [11] | Ara-C (200 mg/m2/day × 7) + IDR (8 mg/m2/day × 5) or RBZ (200 mg/m2/day × 4) | For pts in CR waiting for Allo-BMT: AMSA (150 mg/m2/day × 1) + Ara-C (100 mg/m2/day × 5) For all other pts in CR: HiDAC (6 g/m2/day × 4) + IDR (10 mg/m2/day × 2) Or HiDAC (6000 mg/m2/day × 4) + RBZ (200 mg/m2/day × 2) | If donor available and ≤40 years, Allo-SCT using myeloablative regimen: Bu (4 mg/kg/day × 4) + Cy (50 mg/kg/day × 4 or 60 mg/kg/day × 2) Or Cy (60 mg/kg/day × 2) + TBI (dose not stated) If no donor or >40 years, randomized to: second ICC using AMSA (150 mg/m2/day × 5) + VP-16 (100 mg/m2/day × 5) Or Auto-SCT using Bu (4 mg/kg/day × 4) + Cy (50 mg/kg/day × 4) | | | Miggiano et al., 1996 [2+] [12] | (Exact dosage not provided) DNR + Ara-C ± VP-16 Or ICE (IDR 10 mg/m2 + Ara-C + VP-16) Or IDR (10 mg/m2) ± Ara-C | For all pts who achieved CR after 1-2 courses: (Exact dosage not provided) Ara-C + AMSA Or Ara-C (conventional dose) + MITO | Auto-SCT using Bu (4mg/kg/day X 4) + Cy (50 mg/kg × 4 days or 60 mg/kg/day × 2 days) Nonrandomized control group received monthly maintenance chemotherapy (drug and dosage not stated) | | | Induction + ICC, then Autologous SCT versus No Further Treatment | | | Burnett et al., 1998 [1−] [13] | Pts randomized to: DNR (50 mg/m2/day × 3) + Ara-C (200 mg/m2/day × 10) + TG (200 mg/m2/day × 10); followed by DNR (50 mg/m2/day × 3) + Ara-C (200 mg/m2/day × 8) + TG (200 mg/m2/day × 8) whether in CR after first course or not Or Ara-C (200 mg/m2/day × 10) + DNR (50 mg/m2/day × 3) + VP-16 (100 mg/m2/day × 5); followed by Ara-C (200 mg/m2/day × 8) + DNR (50 mg/m2/day × 3) + VP-16 (100 mg/m2/day × 5) whether in CR after first course or not | All pts in CR received MACE [AMSA (100 mg/m2/day × 5) + Ara-C (200 mg/m2/day × 5) + VP-16 (100 mg/m2/day × 5)] | If donor available, pts received 1 course MidAC: MITO (10 mg/m2/day × 5) + Ara-C (2000 mg/m2/day × 3); followed by Allo-SCT using Cy (120 mg/kg/day × 2) + TBI (1200 or 1440 Gy) No donor available, pts received 1 dose MidAC, then randomized to: No further treatment Or Auto-SCT using Cy (120 mg/kg/day × 2) + TBI (1200 or 1440 Gy) | | | Breems et al., 2004 [1−] [14] | DNR (45 mg/m2/day × 3) + Ara-C (200 mg/m2/day × 7); followed by AMSA (120 mg/m2/day × 3) + Ara-C (2000 mg/m2/day × 6) whether in CR after first course or not | All pts who achieved CR received: MITO (10 mg/m2/d × 5) + VP-16 (100 mg/m2/day × 5) | If donor available, pts received Allo-SCT (regimen not stated) No donor available, pts randomized to: No further treatment Or Auto-SCT using Bu (4 mg/kg/day × 4) + Cy (1550 mg/m2/day × 4) | | | Rohatiner et al., 2000 [2+] [15] | Dox (25 mg/m2 i.v. × 3) + Ara-C (100 mg/m2 i.v. × 7) + 6-TG (100 mg/m2 po × 7); second course if partial or no CR | All pts who achieved CR received 2 additional cycles of induction regimen | Auto-SCT using Ara-C (2000 mg/m2/day × 6) + TBI (400 cGy/day × 3) Nonrandomized, historical control group received no further treatment | | | Induction, then ICC versus Autologous SCT | | | Cassileth et al., 1998 [1+] [16] | IDR (12 mg/m2/day × 3) + Ara-C (25 mg/m2 followed by 100 mg/m2/day × 7) All pts who achieved CR received another course of induction therapy at the same daily doses, but with only 2 days of IDR and 5 days of Ara-C | | If donor available, pts received Allo-SCT using Bu (4 mg/kg/day × 4) + Cy (50 mg/kg/day × 4) No donor available, pts randomized to: HiDAC (6000 mg/m2/day × 6) Or Auto-SCT using Bu (4 mg/kg/day × 4) + Cy (50 mg/kg/day × 4) | | | Bassan et al., 1998 [2−] [17] | Dox (25 mg/m2/day × 3) + Ara-C (100 mg/m2/day × 7) + 6-TG (200 mg/m2/day × 7) All pts in CR received 2 additional induction therapy courses | | Pts > 50 years received 1 course HiDAC (2000 mg/m2/day × 6) ± Dox at the physician's discretion (dose not stated) Pts 15-50 years received HiDAC (2000 mg/m2/day × 6) + TBI (400 cGy/day × 3) + Auto-SCT | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. |
Autologous SCT versus Chemotherapy in First Complete Remission (CR1) Levi et al. [7] and Nathan et al. [8] each presented the results of meta-analyses of the same 6 randomized controlled studies comparing auto bone marrow transplantation (BMT) to chemotherapy or no further treatment. The methods and results of these 2 studies were comparable; hence, only 1 study [7] is summarized here. Study requirements for potential inclusion in the Levi et al. meta-analysis were: randomization to auto-BMT in 1 arm and chemotherapy or no further treatment in the second arm, study sample aged 15-56 years, only AML patients, and data analysis based on intention-to-treat (ITT). Of 4410 recruited patients across the 6 studies, 3220 (73%) achieved CR1, and 1044 (23% of recruited patients) were randomized to receive an auto-BMT or chemotherapy only (or no further therapy). Of these, 835 (80%) received the intended treatment, 360 in the auto-BMT arm and 475 in the control arm. The reasons for nontransplant included recurrence of disease, toxicity of prior treatment, and patient refusal to have a transplant. Risk of dying (death rate) and risk of relapse or death (event rate) were determined for the auto-BMT and other arm. Relative risks (RR) and 95% confidence intervals (CI) of death and events rates were calculated for each study, from which a combined estimate of each rate was calculated across the 6 studies. Cytogenetic data from the studies were not considered in the meta-analysis. Figure 1 compares the RR of relapse or death between the auto-BMT and control groups. Treatment schema I: induction + intensive consolidation chemo (ICC), then auto-SCT versus additional ICC Zittoun et al. [9] presented the results of the European Organization for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups prospective study of 990 adult (11-59 years; >90% were ≥15 years) patients with previously untreated AML, comparing the outcomes of postremission allo-BMT, auto-BMT, and chemotherapy. Some centers from the GIMEMA group excluded patients with acute promyelocytic (M3) leukemia (APL). Of the 990 enrolled patients, 36 (4%) were ineligible (inadequate diagnosis [n = 19]; other exclusion criteria [n = 17]) and 13 (1%) had missing data, leaving a total of 941 (95%) evaluable patients. A total of 623 (66%) patients achieved CR1. A human leukocyte antigen (HLA)-matched sibling donor was available for 230 patients, and 168 (27% of CR1 patients) were assigned to allo-BMT. Of the remaining patients, 254 (41% of CR1 patients) were randomized to either auto-BMT (n = 128) or a second course of chemotherapy (n = 126). There were no significant differences among the 3 treatment groups by age, white blood cell (WBC) count at diagnosis, French-American-British (FAB) AML classification, number of induction cycles needed to reach CR1, or cytogenetic group. The median times from CR1 to the initiation of postremission therapy were 10, 14, and 15 weeks for the chemotherapy, auto-BMT, and allo-BMT groups, respectively (P < .001). Actual receipt of intended therapy was as follows: allo-BMT, n = 144 (86%), auto-BMT, n = 95 (74%), and chemotherapy, n = 104 (83%). Outcome analyses were on an ITT basis. Reiffers et al. [10] presented the outcomes of 204 adults (15-55 years) with de novo AML enrolled in the prospective, multicenter, French BGMT 87 trial comparing allo-BMT, auto-SCT, and ICC. Of 204 patients, 162 (79.4%) achieved CR1. Between CR1 and consolidation, 26 patients were excluded for the following reasons: fungal infection (n = 8), early leukemic relapse (n = 5), cardiac contraindications for anthracycline administration or intensive treatment (n = 4), encephalitis (n = 3), persistent cytopenia (n = 2), refusal of further treatment (n = 2), and hepatitis (n = 2). One patient who underwent syngeneic BMT was also excluded from the analyses. Of the remaining 135 patients, 36 were ≤45 years of age with an HLA-identical sibling donor and were assigned to allo-BMT. Of these, 33 (92%) actually received the assigned treatment. The 99 patients who did not meet the inclusion criteria for allo-BMT (39 were >45 years; 60 were ≤45 years, but with no HLA-identical sibling donor) received intensive chemotherapy, then, while still in CR (n = 77), were randomly assigned to either auto-SCT (n = 39) or maintenance chemotherapy (n = 38). ITT analyses compared the outcomes between the donor (n = 39) and no donor (n = 60) groups and the randomized auto-SCT and chemotherapy groups, in addition to a non-ITT analysis by actual treatment (allo-BMT, n = 33; auto-SCT, n = 33; and chemotherapy, n = 38). Median time from CR1 to allo-BMT was 56 days (range: 42-142 days). The patients in the donor/no donor groups were similar with regard to sex, WBC count at diagnosis, and FAB classification. The rate of high-risk cytogenetic abnormalities was higher in the donor group than the no donor group, but the difference was not statistically significant (P = .17). Of the 39 patients assigned to auto-SCT, 33 underwent either transplant with unpurged bone marrow (n = 16) or peripheral blood stem cells (PBSC). There were no significant differences in patient characteristics between the auto-SCT and maintenance chemotherapy groups. Harousseau et al. [11] reported the results of 535 adult (15-50 years) patients enrolled in the Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM) study comparing the outcomes of allo-BMT, auto-BMT, and ICC. Of the 535 patients, 18 were considered ineligible because of inadequate diagnosis (n = 9), age (n = 7), or other reasons (n = 2). In addition, 13 patients were not evaluable because of death (n = 4), major protocol violation (n = 5), or wrong randomization (n = 4). Of the 504 evaluable patients, 367 (73%) achieved CR1. Patients ≤40 years of age with an HLA-identical sibling were assigned to allo-BMT (n = 88). All other patients received a first course of ICC. The allo-BMT patients were compared to a subset of 134 patients ≤40 years of age, without an HLA-identical sibling, who had received a first course of ICC. There were no significant differences in patient characteristics between these 2 groups except in cytogenetic risk group: intermediate and unfavorable cytogenetics were less common in the allo-BMT group. The median interval between CR1 and allo-BMT was 68 days. All patients who received a first course of ICC were randomly assigned to either a second course of ICC (n = 78) or an unpurged auto-BMT (n = 86). Analyses were on an ITT basis. Of 367 patients who achieved CR1, 219 (59.5%) received the planned postremission treatment (73 allo-BMT, 75 auto-BMT, and 71 ICC). Multivariate analyses considered the impact of FAB type, WBC count at diagnosis, and cytogenetic risk group on outcomes. Miggiano et al. [12] reported the results of 89 adults (15-59 years) with AML in late CR1 treated at a single center in Italy. Three patients had antecedent myelodysplastic syndrome (MDS) and 1 patient had therapy-related AML. Of the 89 patients, 51 (57%) received an auto-BMT. Median time from CR1 to auto-BMT was 8 months. The remaining 38 patients, who served as a nonrandomized control group, were not transplanted because of poor prognostic factors (n = 23), severe toxicity after induction therapy (n = 8), patient refusal (n = 4), or logistic difficulties (n = 3). The 2 groups differed significantly in age and FAB subtype. There were no significant differences between the therapy groups by sex, type of AML (de novo versus secondary), or WBC count at diagnosis. Treatment schema II: induction + ICC, then auto-SCT versus no further treatment Burnett et al. [13] presented the results of 381 adult (74% were 15-55 years) patients enrolled in the UK Medical Research Council (MRC) AML-10 trial who were randomized to receive either auto-BMT (n = 190) or no further treatment (n = 191) after ICC. The trial was open to patients with de novo or secondary AML or refractory anemia. A total of 1966 patients were enrolled in the trial, of which 1509 (77%) achieved CR1. Of these, 508 were not eligible for randomization: 378 had a matched sibling donor, 60 relapsed, and 70 died in remission. Of the 1001 patients eligible for randomization, 620 (62%) were not randomized because of patient or physician preference for an auto-BMT (n = 79) or no further treatment (n = 481), or for unknown reasons (n = 60). The auto-BMT and no further treatment groups were similar in patient characteristics, including age, sex, WBC count, FAB type, number of cycles needed to achieve CR1, type of AML, and cytogenetic risk group. Of the 190 patients randomized to auto-BMT, 126 (66%) actually underwent the procedure, and 5 (3%) of the 191 patients randomized to no further treatment actually received an auto-BMT. Reasons for noncompliance with the allocated treatment included death (n = 7) or relapse (n= 11), patient refusal (n = 20), clinical decision (n = 16), and other (n = 7) or unknown reasons (n = 3). Outcome comparisons were by ITT, with adjustment for cytogenetic risk group. Breems et al. [14] presented the results of 646 adult (<60 years) patients with AML enrolled in the Dutch-Belgian Haemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial comparing auto-BMT versus no further treatment. Of the 646 enrolled, 425 (66%) patients achieved CR1. Eighty-one patients underwent an allo-SCT and were not included in the analysis. An additional 214 patients were deemed ineligible for randomization because of patient refusal (n = 81), early relapse (n = 54), excessive toxicity (n = 27), or not meeting inclusion criteria (n = 26), leaving 130 patients to be randomized between auto-BMT (n = 66) and no further treatment (n = 64). Of these, 36 (55%) and 38 (59%) received the assigned treatment, respectively. Analyses were on an ITT basis. The median interval between randomization and auto-BMT was 64 days. There were no significant differences in patient characteristics between the 2 groups. Rohatiner et al. [15] presented the results of a 2 sequential cohorts study comparing the outcomes of 144 adult (15-49 years) patients with AML enrolled in the BXIII protocol (Italy, England) assigned to receive an unpurged auto-BMT versus a comparison group of patients who received traditional chemotherapy. Patients with APL were excluded. Eleven patients with preceding MDS, which progressed to AML, were included in the auto-BMT group, as were 43 other patients with varying degrees of MDS concurrent with the diagnosis of AML. Of the 144 patients in the auto-BMT group, 106 achieved CR1 and, of these, 61 proceeded to the assigned transplantation. Forty-five patients did not receive the auto-BMT for the following reasons: early recurrence (n = 17), medically unfit (n = 12), patient refusal (n = 8), elective allo-BMT (n = 7), and insufficient cells (n = 1). Patients in the comparison group were from the same 3 institutions as those in the auto-BMT group and received the identical remission induction and consolidation therapy, but without the high-dose therapy and auto-BMT. Analyses were on an ITT basis. With the exception of the presence of MDS in the auto-BMT group, patient characteristics were similar in the 2 sequential cohorts. Treatment schema III: induction, then ICC versus auto-SCT Cassileth et al. [16] reported the results of an intergroup (Eastern Cooperative Oncology Group [ECOG], Southwest Oncology Group [SWOG], Cancer and Leukemia Group B [CALGB]) prospective study comparing the outcomes of chemotherapy, auto-BMT, and allo-BMT in 808 adult (16-55 years) patients with untreated AML. Of the 808 patients enrolled in the study, 36 were ineligible and 32 could not be evaluated (CR not documented [n = 19]; missing follow-up data [n = 7]; withdrew before completing therapy [n = 5]; CNS leukemia detected [n = 1]), leaving 740 (92%) patients eligible for induction therapy. Of these, 518 (70%) achieved CR1; however, 172 patients were removed from the study prior to randomization or assignment to postremission therapy, leaving 346 patients in the ITT analysis. The primary reasons for removal included patient refusal to continue, persistent medical problems after induction, and relapse before randomization. Patients with HLA-matched or single-antigen-mismatched family donors (n = 113) were biologically assigned to receive allo-BMT. The remaining 233 patients were randomized between auto-BMT (n = 116) and high-dose cytarabine-based chemotherapy (n = 117). Randomization to the 2 arms was stratified according to age (≤45 versus >45 years), FAB type (M1, M2, M3, M4 versus M0, M5, M6, M7), the number of induction courses to achieve CR (1 versus 2), and cytogenetics (favorable = t[8;21], t[15;17], or inv[16]; normal or having a single abnormality; unfavorable=5q−, −5, 7q−, abnormal chromosome 9 or 11, or 3 or more clonal abnormalities). There were no statistically significant differences among the treatment groups on any of these patient characteristics. Median times from CR1 to postremission therapy were 14.1, 14.6, and 12.4 weeks for allo-BMT, auto-BMT, and chemotherapy, respectively. Actual receipt of intended therapy was as follows: allo-BMT, n = 90 (80%); auto-BMT, n = 63 (54%); chemotherapy, n = 106 (91%). Bassan et al. [17] presented the results of 153 adult (15-60 years) patients with AML enrolled in the BXIII Protocol, a postremission, nonrandomized, collaborative study between the Bergamo/Vicenza Hospitals in Italy and St. Bartholomew Hospital in England. Patients with APL were excluded. There were 147 patients with de novo AML and 6 with secondary AML. Of the 153 patients, 108 (70%) achieved CR1; however, 1 patient refused further treatment, leaving 107 in CR1. Seventy-four patients <50 years started first consolidation, of whom 41 had an auto-BMT (55%). Seven patients with HLA-matched sibling donors underwent allo-BMT and were excluded from the analysis. Additional reasons patients did not receive an auto-BMT included relapse (n = 8), infection (n = 15), thrombocytopenia (n = 1), patient refusal (n = 1), or inadequate bone marrow harvest (n = 1). Of the 33 patients >50 years, 2 died of infection, 2 relapsed, and 10 had complications or very poor performance status, leaving 19 patients (plus 5 patients from the <50 age group) to receive the planned chemotherapy. Both groups were similar with regard to sex, FAB, blast cell count, cytogenetics, and incidence of hepatosplenomegaly. Allogeneic SCT versus Chemotherapy ± Autologous SCT in CR1 Four of the studies already described in the previous section included allo-BMT versus chemotherapy (± auto-BMT) comparisons 9, 10, 11, 16. Because allo-BMT involves biologic assignment, as opposed to randomization, comparisons of allo-BMT versus auto/chemo are graded as cohort studies and rated as level “2” evidence. Therefore, outcome results that relate to allo-BMT from these studies are presented in Table 4 under the section “Allo-BMT versus Chemotherapy ± Auto-BMT in CR1.” Following are the descriptions of several additional cohort studies of allo-BMT versus chemotherapy (± auto-BMT) in CR1, the outcomes of which are presented in the same section of Table 4. Myeloablative conditioning for allo-SCT Yanada et al. [18] presented the results of a meta-analyses of 5 studies comparing the efficacy of allo-SCT versus chemotherapy and/or auto-SCT in adult (10-55 years) patients with AML in CR1. Study requirements for potential inclusion in the meta-analysis included: published in English between 1995 and 2003, only patients with AML, offered allo-HSCT to all patients in CR1 with an HLA-matched sibling and chemotherapy or auto-SCT to all others, used ITT analyses to compare patients on the basis of donor availability, and assessed outcomes in terms of OS. Studies were excluded if they dealt exclusively with children, analyzed outcomes by actual treatment given, did not offer allo-SCT to all patients with a donor, if other articles from the same trials were eligible, or the hazard ratio (HR) and 95% CI for OS could not be assessed. A total of 3100 patients received allo-SCT (n = 1151) or alternative treatments (n = 1949) in the 5 studies. HRs were used to assess the survival advantage of allo-SCT versus alternative treatments. HRs and 95% CIs were abstracted from each study, and a general variance-based method was used to estimate the summary HR and the 95% CI for OS. Outcomes were analyzed by cytogenetic risk. Figure 2 presents a Forrest plot of the HRs and 95% CIs for OS from the 5 studies included in the meta-analysis. Cornelissen et al. [19] reported the results of a retrospective analysis of the Dutch-Belgium Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) collaborative study of 925 adult (15-55 years) patients with AML in 3 consecutive studies (AML4, AML29, and AML42) comparing donor (n = 326) versus no donor outcomes (n = 599). Patients with APL were excluded. Patients were assigned to the no donor group as a result of absence of siblings, HLA-incompatibility, or ineligibility of a potential donor. The 2 groups were comparable with respect to age, FAB type, WBC count at diagnosis, number of cycles to CR1, and cytogenetics. Of the 326 patients with an HLA-matched sibling donor, 268 (82%) underwent an allo-HSCT, 17% received a third cycle of chemotherapy, and 1% an autograft. In the no donor group, 65% underwent chemotherapy consolidation, 28% received an auto-SCT, and 8% received a mismatched related or unrelated allo-SCT. Analyses were on an ITT basis. Figure 3 compares the actuarial rates of DFS between the donor and no donor groups. Burnett et al. [20] presented a donor versus no donor analysis of 1063 HLA-typed adult (<55 years) patients in the UK MRC AML-10 trial. Of these, 419 had a matched sibling donor and 644 had no match. An additional 224 patients had no siblings and were included in the no-donor group. Of the 419 patients with a donor, 39% did not receive an allo-transplant. Of the 868 patients with no donor, 661 received chemotherapy and 207 received a transplant (auto-BMT, n = 200). Analyses were on an ITT basis and were adjusted for cytogenetic risk group. Gale et al. [21] reported the outcomes of a retrospective study of 1097 adults (16-50 years) with AML. Patients who received an allo-BMT (n = 901) and were reported in the International Bone Marrow Transplant Registry (IBMTR) were compared to 196 patients treated with chemotherapy in the German AML Cooperative Group (GAMLCG) AML86 trial. The cohorts differed significantly by sex, age, WBC count at diagnosis, and FAB types, which were adjusted for in the multivariate analysis of outcomes. Figure 4 compares the adjusted probability of LFS between the allo-BMT and chemotherapy groups. Cassileth et al. [22] compared the outcomes of allo-BMT versus chemotherapy in 534 adult (15-65 years) patients with AML enrolled in an ECOG study. Fourteen patients were cancelled and 39 deemed ineligible (inadequate pathology submission, n = 13; age >65 years, n = 2; other eligibility violations, n = 6; and erroneous diagnosis, n = 18). Another 32 patients were excluded from analysis because of major protocol violations (n = 19) or no follow-up documentation (n = 13). Of the 449 evaluable patients, 305 (68%) achieved CR1. A subset of 104 patients <41 years was assigned to allo-BMT (n = 54) if an HLA-compatible sibling donor was available, or randomly assigned to consolidation chemotherapy (n = 29) or maintenance chemotherapy (n = 21). Forty-five (83%) of the patients assigned an allo-BMT underwent the treatment. Analyses were on an ITT basis. Except for age, there were no significant differences among the groups in patient or leukemic characteristics (sex, performance status, degree of weight loss, marrow cellularity, splenic involvement, FAB types, cytogenetics, WBC count at presentation, number of circulating blasts, percentage of marrow blasts, number of induction cycles needed to achieve CR1, and time to CR1). Schiller et al. [23] reported the outcomes of 103 adult (16-45 years) patients with AML treated according to the Acute Leukemia Protocol (ALP) 3 and 4 regimens comparing allo-BMT versus chemotherapy. Eighty-two (80%) of the patients achieved CR1. Of these, 28 patients were assigned to undergo allo-BMT and were compared with 54 age-matched patients assigned to consolidation chemotherapy. The median interval from remission to allo-BMT was 44 days. Patient characteristics of the 2 groups were similar for age, sex, WBC count at diagnosis, FAB type, number of cycles needed to achieve CR1, and cytogenetics. Willemze et al. [24] presented the results of a single center, retrospective study of 107 adult (15-65 years) AML patients, comparing allo-BMT, auto-BMT, and chemotherapy postremission therapies. One patient died during the first consolidation course and was excluded from the analysis. Thirty-four patients received ICC, 28 were allocated to auto-BMT, and 44 to allo-BMT. There were no significant differences among the 3 groups by age, sex, FAB type, or mean interval (days) to reach CR1. Archimbaud et al. [25] presented the results of 78 adult (17-39 years) AML patients treated on the LYLAM-85 protocol comparing allo-BMT versus chemotherapy at a single center in France, of whom 58 (74%) achieved a CR1. Twenty-seven of these patients had an HLA-identical sibling donor and were assigned to allo-BMT (donor arm), and 20 (74%) actually underwent the procedure. The 31 patients without a matched sibling donor were assigned to the chemotherapy (no donor) arm, 24 (77%) of whom received the scheduled 3 courses of chemotherapy. Analyses were on an ITT basis. The 2 groups were similar with regard to age, sex, WBC count at diagnosis, FAB, percent blasts, platelet count, number of cycles to CR1, days to CR1, and cytogenetics. There were also no differences between the groups for the presence of hemorrhage, organomegaly, or fever at diagnosis. Reduced intensity conditioning (RIC) for allo-SCT Mohty et al. [26] presented the results of 95 adult (26-65 years) patients with AML enrolled at a single center in France. All 95 patients were considered candidates for RIC allo-BMT because of their high-risk leukemic or clinical characteristics. Patients with an HLA-identical sibling donor were assigned to the donor group (n = 35, 37%), whereas the remaining 60 patients without a donor were assigned to the no donor group and treated according to “standard institutional procedures.” In the donor group, 25 (71%) patients actually underwent allo-BMT. The reasons for not receiving an allo-BMT included patient refusal (n = 60), early relapse (n = 2), and psychiatric disorders (n = 2). Outcome analyses were on an ITT basis. There were no significant differences between the 2 groups by age, sex, type of AML, FAB, cytogenetic risk group, or number of induction cycles to achieve CR1. Allogeneic SCT versus Chemotherapy in Second Complete Remission (CR2) Gale et al. [27] presented the outcomes of 501 adult (<50 years) patients with AML in CR2 who underwent chemotherapy (n = 244) in MRC, ECOG, or single center trials, or HLA-matched sibling donor allo-HSCT (n = 257) at IBMTR centers. Allo-HSCT patients were younger, had briefer first remissions, and more had FAB M2 subtype than chemotherapy patients. The 2 groups were similar with respect to sex and WBC count at diagnosis. Outcomes were adjusted for time-to-treatment, age, and duration of CR1. Autologous Versus Allogeneic HSCT Three studies previously described in the HSCT versus Chemotherapy section 9, 16, 24 also included comparisons between allo-HSCT versus auto-HSCT outcomes, which are presented in Table 6. This section provides descriptions of additional studies focusing exclusively on the comparison of allo-HSCT versus auto-SCT, which are also presented in Table 6. The highest quality studies are presented first; studies of equal quality are presented in descending order by sample size. | | | | Reference No. | Quality and Strength of Evidence ∗ | | Number of Patients by Study Group | Upper Limit (Median) Age at Diagnosis | (Interval) % TX-Related Mortality | Median Follow-up | (Interval) %DFS/%EFS/%RFS/%LFS (Signif) | Definition of DFS/EFS/RFS/LFS | (Interval)% OS (Signif) | |
|---|
| Ringdén et al., 2000 [28] | 2++ | Retrospective EBMT 1987-1999 Included n = 6306 AML n = 4536 (72%) | Total AML n = 4536 HLA-ident. Sib allo 696 Twins allo 44 Auto 3796 | | | | (2-yr LFS) 64 ± 2 59 ± 8 51 ± 1 (Sib Allo versus Auto P < .0001) | Time from BMT to relapse or death | Not stated | | | Lazarus et al., 2006 [29] | 2++ | Retrospective CIBMTR 1989-1996 Multicenter (12) Included n = 1144 | Total n = 1144 (Actual TX) MUD Allo 476 Auto 668 | | | | (5-yr LFS) 34 (CI 29-38) 46 (CI 42-50) (P<.001) | Onset not stated; events were relapse or death | (5-yr OS) 36 (CI 31-40) 51 (CI 47-55) (P < .001) | | | Suciu et al., 2003 [30] (Included in Yanada et al. meta-analysis) | 2+ | Prospective EORTC and GIMEMA AML-10 Trial 1993-1999 Multicenter (80) Recruited n = 1198 Evaluable n = 1136 Achieved CR1 n = 822 | Total n=734 (ITT) Donor 293 No Donor 441 (Auto only) | | | 4 yrs | (4-yr DFS) 52.2 42.2 (P = .04) | Time from CR1 to first relapse or death in CR | (4-yr OS) 58.3 50.8 (P = .18) | | | Zittoun et al., 1995 [9] (Described in SCT versus Chemo section) | 2+ | Prospective EORTC and GIMEMA 1986- 1993 Multicenter (59) Recruited n = 990 Achieved CR1 n = 623 | Total n = 296 (ITT) Allo 168 Auto 128 | | Not stated | 3.3 yrs | (4-yr DFS) 55 ± 4 48 ± 5 (Not stated) | Time from CR1 to first relapse or death in CR | (4-yr OS) 59 ± 4 56 ± 5 (Not stated) | | | Cassileth et al., 1998 [16] (Described in SCT versus Chemo section) | 2+ | Prospective CALGB, ECOG, SWOG 1990-1995 Multicenter Eligible n = 808 Achieved CR1 n = 518 | Total n = 229 (ITT) Allo 113 Auto 116 | | | | (4-yr DFS) 43 ± 10 35 ± 9 (P not signif) | Time from CR1 to first relapse or death | (4-yr OS) 46 ± 10 43 ± 9 (P not signif) | | | Carella et al., 1992 [31] | 2+ | Retrospective 1983-1991 Single center Included n = 159 | Total n = 159 (Actual TX) Allo 104 Auto 55 | <46 Allo <62 Auto (26 yrs) (37 yrs) | | | Not stated | Not stated | (8-yr OS) 52 (CI 40-61) 49 (CI 33-62) (P not signif) | | | Singhal et al., 2003 [32] | 2+ | Retrospective 1984-1999 2 centers Included n = 130 AML | Total n = 130 (Actual TX) PMRDT Allo 80 Auto 50 | | | 5 yrs | | Not stated | | | | Mitus et al., 1995 [33] | 2+ | Prospective 1987-1993 Multicenter (3) Recruited n = 94 Achieved CR1 n = 84 | Total n = 84 (ITT) Allo 31 Auto 53 | | | Not stated | (5-yr EFS) 56 (CI 37-75) 45 (CI 31-67) (P = .54) | Not stated | Not stated | | | Willemze et al., 1991 [24] (Described in SCT versus Chemo section) | 2+ | Retrospective 1983-1989 Single center Included n = 107 | Total n = 72 (Actual TX) Allo 44 Auto 28 | | | 18 mos | (3-yr DFS) 30 (CI 19-45) 40 (CI 19-35) (P not signif) | Time from CR1 to relapse or death | Not stated | | | Cassileth et al., 1993 [34] | 2+ | Prospective ECOG P-C 486 No dates provided Multicenter Recruited n = 123 Evaluable n = 111 Achieved CR1 n = 83 | Total n = 58 (ITT) Allo 19 Auto 39 | | Not stated | 31 mos | (3-yr DFS) 42 ± 22 54 ± 16 (P not stated) | Not stated | Not stated | | | Löwenberg et al., 1990 [35] | 2+ | Retrospective HOVON 1984 -1987 Recruited n = 117 Achieved CR1 n = 90 | Total n = 53 (Actual Tx) Allo 21 Auto 32 | | | 30 mos | | Not stated | | | | Sierra et al., 1996 [36] | 2− | Prospective 1988-1993 Multicenter (10) Recruited n = 159 Achieved CR1 n = 120 | Total n = 115 (ITT) Allo 47 Auto 68 | | | | (4-yr LFS) 31 ± 7 50 ± 6 (P = .08) | Not stated | (4-yr OS) 32 ± 7 50 ± 6 (P = .07) | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †AML indicates acute myelogenous leukemia; Allo, allogeneic; Auto, autologous; Chemo, chemotherapy; BMT, bone marrow transplantation; SCT, stem cell transplantation; CR, complete remission; TX, treatment; URD, unrelated donor; MUD, matched-rnrelated donor; PMRDT, partially mismatched related donor transplant; PBSCT, peripheral blood stem cell transplant; EORTC, European Organization of Research and Treatment of Cancer; GIMEMA, Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto; CALGB, Cancer and Leukemia Group B; ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group; HOVON, Dutch Hemato-Oncology Working Party; EBMT, European Group for Blood and Marrow Transplantation; CIBMTR, Center for International Blood and Marrow Transplant Research; FAB, French, American, British morphology classification; ITT, intent-to-treat; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; Signif., significance (probability); OS, overall survival; CI, 95% confidence interval. |
Ringdén et al. [28] presented the results of a retrospective study of 4536 patients (75% >17 years) with AML in CR1 reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, comparing auto-BMT (n=3796), HLA-identical sibling allo-BMT (n = 696), and twins allo-BMT (n = 44). Auto-BMT patients tended to be older, the year of their transplant was later, and the interval from diagnosis to BMT was longer than for the other 2 groups. Lazarus et al. [29] presented the retrospective analysis of 1144 AML patients (≤58 years; 81% >10 years) transplanted in CR1 or CR2 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), comparing the outcomes of auto-BMT (n = 668 patients) to unrelated donor (URD) allo-BMT (n = 476 patients). Analysis of patient characteristics between the 2 groups indicated that a higher proportion of auto-BMT patients were < 10 years of age, and allo-BMT patients were more likely to be male, have a lower performance score, unfavorable cytogenetics, and require more time to achieve CR1. Median times from remission to transplantation were 102 and 104 days for auto-BMT and allo-BMT patients, respectively. Multivariate analyses considered the impact of disease status, FAB, cytogenetic risk group, and cytomegalovirus (CMV) status on outcomes. Suciu et al. [30] compared the outcomes of allo-BMT versus auto-HSCT in 1198 adult (15-46 yrs) patients with AML enrolled in the EORTC/GIMEMA AML-10 protocol. Patients with APL were excluded. Of the 1198 patients, 62 could not be evaluated because of a lack of clinical documentation. Of the remaining 1136 patients, 822 (72.4%) achieved CR1. Fifty patients were excluded from further protocol treatment because of toxicity (n = 27), poor documentation (n = 15), or other reasons (n = 8). Of the 772 patients who received consolidation, 38 were not HLA-typed because of patient refusal (n = 9), early death/toxicity (n = 20), logistic reasons (n = 5), or other reasons (n = 4). Of the remaining patients, 293 had an HLA-matched sibling donor (donor group) and were assigned to receive an allo-HSCT. The remaining 441 patients either had no siblings or no HLA-matched sibling and were assigned to receive an unpurged auto-PBSCT or BMT (no-donor group). Allo-HSCT was actually performed in 202 of 293 (68.9%) donor group patients, and 246 of 441 (55.8%) patients in the no-donor group received the assigned auto-HSCT. Eleven (2.5%) no-donor group patients received an allo-BMT with stem cells from a matched unrelated or matched related donor, while 7 (2.5%) patients with a sibling donor underwent auto-HSCT. Outcome analyses were on an ITT basis. Patient characteristics, including age, WBC count at diagnosis, FAB subtype, cytogenetics, and the CR rate after the first induction course were similar in the 2 groups. Figure 5 compares the DFS between the donor and no donor groups. Carella et al. [31] retrospectively analyzed 159 adult (≤62 years) patients with AML in CR1 who received an allo-BMT (n = 104) or unpurged auto-BMT (n = 55) at a single institution. Median times from CR1 to transplant were 150 and 144 days for allo-BMT and auto-BMT patients, respectively. Patient characteristics for the 2 groups, including sex, age, FAB, and WBC count at diagnosis, were not compared. Singhal et al. [32] presented a retrospective analysis of adult (62% >15 years) patients with AML (n = 130, 44% of sample) beyond first CR, who received either a partially mismatched related donor (PMRD) T cell-depleted allo-BMT (n = 80, 61.5%) or an unpurged auto-BMT (n = 50, 38.5%). Patients in CR1, those undergoing a second auto-BMT, and those with known secondary leukemia were excluded. Age and sex distribution were comparable between the 2 treatment groups. PMRD allo-BMT patients were less likely than auto-BMT patients to be in CR2 and more likely to have active disease at the time of transplant. Mitus et al. [33] reported the outcomes of 94 adult (17-63 years) patients with AML enrolled in a prospective, multicenter study of induction therapy followed by allo-BMT versus auto-BMT. Patients with antecedent MDS, anemia, or other cytopenia were excluded. Of the 94 patients, 84 (89%) achieved CR1. Patients <55 years with an HLA-compatible relative were assigned to allo-BMT, and those without a donor or who were age 55-65 years were assigned to auto-BMT. Median times from CR1 to transplantation were 236 and 190 days for auto-BMT and allo-BMT, respectively. One patient in each group underwent the opposite procedure. Outcome analyses were on an ITT basis. There were no significant differences between the 2 treatment groups by age, sex, FAB type, WBC count at diagnosis, or cytogenetics. Cassileth et al. [34] reported the results of 123 adult (15-55 years) patients with AML enrolled in the ECOG P-C 486 trial. Twelve (10%) patients were deemed ineligible for various reasons. Of the 111 eligible patients, 83 (75%) achieved CR1. Twenty-five (30%) patients were off-study because of infections or other disease (n = 14), patient refusal (n = 9), or other reasons (n = 2). The remaining patients were assigned to allo-BMT (n = 19) or auto-BMT (n = 39). Patient characteristics were not significantly different between the 2 groups, except that allo-BMT patients were significantly younger than auto-BMT patients. The median time from CR1 to auto-BMT was 8 weeks, and 35 of 39 patients had an auto-BMT. The median time from CR1 to allo-BMT was 9 weeks, and 17 of 19 patients underwent the procedure. Analyses were on an ITT basis. Löwenberg et al. [35] presented the outcomes of 117 adult (15-60 years) patients with AML enrolled in a Dutch Hemato-Oncology Working Party (HOVON) study comparing allo-BMT, auto-BMT, and no further treatment. Ninety (77%) patients achieved CR1 and, of these, 37 (41%) patients who were eligible for auto-BMT received no further treatment because of early relapse or death (n = 19), refusal (n = 6), insufficient graft (n = 3), chronic infection (n = 3), or other reasons (n = 6). Of the remaining 53 patients, 32 (36%) underwent an unpurged auto-BMT and 21 (23%) underwent an HLA-matched allo-BMT. Median times from CR1 to transplantation were 3.8 and 3.0 months for auto-BMT and allo-BMT, respectively. Auto-BMT patients were, on average, 10 years older than allo-BMT patients. There were no significant differences between the allo-BMT and auto-BMT groups by sex, FAB type, or time to CR1. Analyses were by actual treatment received. Sierra et al. [36] presented the outcomes of adult (79% ≥15 years) patients with AML enrolled in a prospective, multicenter study comparing allo-BMT versus auto-BMT. Patients >51 years or those having a history of MDS, previous treatment with cytotoxic drugs or radiation, or a severe concomitant disease were excluded. Of 159 patients, 120 (75%) achieved CR1, and 115 were HLA-typed. Forty-seven (41%) patients had an HLA-identical sibling donor and were assigned to allo-BMT; 26 (55%) underwent the procedure. Reasons for not receiving the assigned allo-BMT included medical contraindications (n = 13) and early relapse (n = 8). Sixty-eight patients (59%) were assigned to auto-BMT and, of these, 47 (69%) underwent the procedure. Reasons for not receiving the assigned auto-BMT included medical contraindications (n = 9), early relapse (n = 8), and patient refusal (n = 3). Outcome analyses were on an ITT basis. Median intervals from CR1 to transplantation were 166 and 147 days for auto-BMT and allo-BMT, respectively. There were no significant differences between the 2 groups on age, sex, WBC count at diagnosis, number of induction courses to CR1, or time to CR1. Autologous HSCT This section provides descriptions of auto-HSCT studies, the outcomes of which are presented in Table 7. The highest quality studies are presented first; studies of equal quality are presented in descending order by sample size. | | | | Reference No. | Quality and Strength of Evidence ∗ | | Number of Patients by Study Group | Upper Limit (Median) Age at Diagnosis | (Interval) % Tx -Related Mortality | Median Follow-up | (Interval) % DFS/% EFS/% RFS/% LFS (Signif) | Outcome Defined | (Interval) % OS (Signif) | |
|---|
| PBSCT versus BMT | | | Reiffers et al., 2000 [37] | 2+ | Retrospective EBMT Registry 1986-1994 Included n = 1393 | Total n = 1393 PB Auto 100 Unpurged BM Auto 1041 Purged BM Auto 252 | ≤64 yrs (43 yrs) (52 yrs) (52 yrs) | | Not stated | (2-yr LFS) 44 ± 6 49 ± 2 57 ± 3 (PB vs Purged BM, P = .01; PB vs Unpurged BM, P = .22) | Onset not stated; events were relapse or death | (2-yr OS) 53 ± 6 56 ± 2 66 ± 3 (PB vs Purged BM, P = .10; PB vs Unpurged BM, P = .85) | | | Sirohi et al., 2004 [38] | 2+ | Retrospective, matched 1996-2000 EBMT Registry (n = 114) and Single center (n = 57) | Total n = 171 PB Auto 114 Unpurged BM Auto 57 | | | Not stated | Not stated | Not stated | | | | Vey et al., 2004 [39] | 2+ | Retrospective 1984-1998 Single center Included n = 101 | Total n = 101 PB Auto 43 BM Auto 58 | | | 67 mos | | Time from SCT to relapse or death | | | | Purged versus Unpurged | | | Miller et al., 2001 [40] | 2+ | Retrospective ABMTR 1989-1993 Multicenter (41) Included n = 294 Subgroup CR1 w/in 6 mos n = 209 | Total CR1 w/in 6 mos n = 209 Purged BM auto 148 Unpurged BM auto 61 | | | 57 mos | (3-yr LFS) 56 (CI 47-64) 31 (CI 18-45) (P not stated) | Onset not stated; events were relapse or death | (3-yr OS) 63 (CI 52-70) 40 (CI 25-55) (P not stated) | | | Gorin et al., 1990 [41] | 2+ | Retrospective EBMT Registry 1982-1987 Multicenter (34) Included n = 263 Subgroup SR, CR1, TBI n = 107 | Total CR1, SR, TBI n = 107 Purged BM auto 30 Unpurged BM auto 77 | | Not stated | 28 mos | (4-yr LFS) 63 ± 8 34 ± 7 (P = .05) | Onset not stated; events were relapse or death | Not stated | | | Chao et al., 1993 [42] | 2+ | Retrospective 1987-1992 Single Center Included n = 50 | Total n = 50 Purged BM auto 30 Unpurged BM auto 20 | | | 31 mos | (Not stated) 57 32 (P = .36) | Not stated | Not stated | | | Tandem versus Single | | | McMillan et al., 1990 [43] | 2- | No dates stated Multicenter Rec'd first auto BMT n = 82 Eligible for second auto n = 54 Received second auto n = 26 | Total n = 51 Double auto 26 Single auto 25 | | | 31 mos | | Not stated | (3-yr OS) 73 47 (Not stated) | | | Single Arm Cohort Studies—Purging status not stated | | | Kim et al., 2004 [44] | 2++ | Retrospective 1993—not stated Single center Included n = 174 | Total CR1 n = 174 | | | 51 mos | | Time from CR1 to relapse or death in CR | | | | Molee et al., 2004 [45] | 2++ | Retrospective 1986-2001 Single center Transplanted n = 145 Transplanted in CR1 n = 117 | Total CR1 n = 117 | | | 53 mos | | Time from SCT to relapse, 2ndary AML or MDS, or death | | | | Gorin et al., 2000 [46] | 2+ | Retrospective 1984-1998 EBMT Registry Included n = 193 CR1 only n = 147 | Total CR1 n = 147 | | | 14 mos | | Onset not stated; events were relapse or death | | | | Single Arm Cohort Studies—Purged BMT | | | Gorin et al., 1999 [47] | 2+ | Retrospective 1983-1997 Single center Mafosfamide Purge AML pts. n = 165 CR1 only n = 123 | Total CR1 n = 123 | | | Not stated | | Onset not stated; events were relapse or death | | | | Linker et al., 1998 [48] | 2+ | Retrospective 1986-1993 2 Centers 4-HC Purge Included n = 165 CR1 only n = 50 | Total CR1 n = 50 | | | 6.8 yrs | | Time from BMT to relapse or TRM | | | | Isnard et al., 2001 [49] | 2- | Retrospective 1982-1994 Single center Mafosfamide Purge Included n = 108 Achieved CR n = 92 Rec'd transplant n = 61 (89% purged auto BMT; 11% allo) | Total CR1 n = 61 | | Not stated | 41 mos | | Time from CR1 to relapse or death | | | | Single Arm Cohort Studies—Unpurged BMT | | | Jourdan et al., 2005 [50] | 2+ | Prospective BGMT 95 Randomized No dates stated Multicenter Enrolled n = 437 Achieved CR1 n = 351 Randomized to HiDAC regimens n = 128 | Total n = 128 (ITT) HiDAC 1 dose 65 HiDAC 2 dose 63 | | | 73 mos | (5-yr LFS) 39 (CI 27-51) 48 (CI 36-61) (P = .12) | Time from CR1 to relapse or death | (5-yr OS) 41 (CI 29-54) 53 (CI 39-66) (P = .14) | | | Meloni et al., 1996 [51] | 2+ | Retrospective 1984-1994 Single center CR2 patients Total n = 60 (78% adults) | Total CR2 n = 60 | | Not stated | 60 mos | | Time from BMT to relapse or death | | | | Stein et al., 1996 [52] | 2+ | Prospective 1989-1993 Single center In CR1 n = 60 Rec'd Auto BMT n = 44 | Total CR1 n = 60 (ITT) | | Not stated | 37 mos | | Time from consolidation chemo to relapse or death | Not stated | | | Single Arm Cohort Studies – Unpurged PBSCT | | | Linker et al., 2000 [53] | 2+ | Prospective 1993-1998 Multicenter (6) Enrolled in CR1 n = 128 Rec'd auto PBSCT n = 117 | Total CR1 n = 128 (ITT) | | | 30 mos | | Time from start of consolidation chemo to relapse or death | Not stated | | | Pavlovsky et al., 1998 [54] | 2+ | Prospective 1991-1996 Single center Eligible in CR1 n = 56 (80% adults) Rec'd auto-PBSCT n = 54 | Total CR1 n = 56 (ITT) | | | 18 mos | | Not stated | | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †AML indicates acute myelogenous (myeloid) leukemia; Allo, allogeneic; Auto, autologous; Chemo, chemotherapy; BMT, bone marrow transplantation; SCT, stem cell transplantation; CR, complete remission; TX, treatment; PBSCT, peripheral blood stem cell transplant; ABMTR, Autologous Blood and Marrow Transplant Registry; BGMT, Bordeaux-Grenoble-Marseille-Toulouse; ITT, intent-to-treat; DFS, Disease-free survival; EFS, event-free survival; RFS, relapse-free survival; Signif., significance (probability); OS, overall survival; CI, 95% confidence interval. |
PBSCT Versus BMT Reiffers et al. [37] presented the results of a retrospective, multicenter study comparing the use of PBSC versus BM for auto-HSCT in 1393 patients (≤64 years) with AML and registered with the EBMT. Patients received an auto-PBSCT (n = 100), purged auto-BMT (n = 252), or unpurged auto-BMT (n = 1041). The significantly different patient characteristics among the groups were age (greater in PBSCT patients than purged auto-BMT patients) and FAB subtype (fewer patients with APL in the PBSCT group than in either the purged or unpurged BM groups). The interval between CR1 and HSCT was longer for purged or unpurged BMT than for PBSCT, and the proportion of patients receiving total body irradiation (TBI) was higher in the BMT groups than the PBSCT group. Sirohi et al. [38] reported the results of a retrospective matched case-control study comparing auto-BMT versus PBSCT in adult (16-66 years) patients with AML. Fifty-seven patients from a single institution who underwent an unpurged auto-BMT were matched on cytogenetics, FAB subtype, CR1 to HSCT interval, and age with 114 patients from the EBMT registry who underwent a PBSCT. Patients in the auto-BMT group were significantly older than the PBSCT patients, and WBC count at diagnosis was higher in the PBSCT patients than the auto-BMT group. Median times from CR1 to HSCT were comparable at 121 days and 119 days in the BM and PBSC groups, respectively. Vey et al. [39] retrospectively studied the outcomes of 101 adult (16-60 years) patients with AML who underwent an auto-SCT at a single center. Patients with APL (n = 4) were included. The stem cell source for patients transplanted pre-1994 was BM (n = 58); those treated after 1994 received PBSC (n = 43). HSCT was performed at a median of 3.5 months from CR1. There were no significant clinical or biologic differences between the 2 treatment groups. Purged versus Unpurged Miller et al. [40] presented the results of 209 patients (≤60 years) reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) who received either a purged (n = 148) or unpurged (n = 61) auto-BMT for AML in CR1. BM was purged with 4-hydroperoxycyclophosphamide (4-HC). Patients receiving purged BM were significantly younger, had lower performance scores, were less likely to receive consolidation chemotherapy, and were transplanted sooner after CR1 than patients receiving unpurged BM. Gorin et al. [41] presented the results of 263 patients (86% adult) with AML from the EBMT registry who underwent a purged or unpurged auto-BMT. Of the 263 patients, 231 were classified as standard risk (SR) and 32 were high risk (HR). A comparison of purged (n = 30) versus unpurged (n = 77) auto-BMT included SR patients autografted in CR1 after TBI-containing regimen(s). Marrow was purged with mafosfamide. There were no significant differences in patient characteristics between the 2 groups. Chao et al. [42] retrospectively studied the outcomes of 50 adult (96% >15 years) patients treated for AML (n = 48) or biphenotypic acute leukemia (n = 2) at a single U.S. center with purged (n = 30) or unpurged (n = 20) auto-BMT. BM was purged with 4-HC, and for the 2 biphenotypic acute leukemia patients BM purging also included etoposide. Thirty-four patients were in CR1, 12 in CR2, and 4 in first relapse at time of transplantation. Median time from CR1 to transplantation was 4 months. No significant differences in patient characteristics between the 2 groups were reported. Tandem versus Single McMillan et al. [43] presented the results of a retrospective study of 82 adult (16-57 years) patients with AML who underwent an unpurged auto-BMT. There were 4 (5%) procedure-related deaths and 9 (11%) relapses within 90 days of the first auto-BMT. Of the 69 remaining patients, 54 (78%) were eligible to proceed to a second auto-BMT. Of these, 26 (48%) underwent the second procedure. Reasons for not receiving the second BMT included patient refusal (n = 22), toxicity (n = 4), infection (n = 1), failed harvest (n = 1), and severe psychologic problems (n = 1). The outcomes of 25 patients who remained in remission at 90 days following the single auto-BMT were compared to those patients who underwent the tandem auto-BMT. The comparison single-graft group differed from the tandem BMT group in that the interval between remission and auto-BMT was significantly longer (P = .003). Single-Arm Cohort Studies The remaining 11 studies, presented only in Table 7, are single-arm, noncomparative studies examining auto-BMT or auto-PBSCT: purging status not stated (3 studies); purged auto-BMT (3 studies); unpurged auto-BMT (3 studies); and unpurged auto-PBSCT (2 studies). Allogeneic HSCT This section provides descriptions of 22 allo-HSCT studies, the outcomes of which are presented in Table 8. Seven comparative studies examined the impact on patient survival of related versus unrelated allo-HSCT (n = 2), T cell-depleted (TCD) versus T cell-replete HSCT (n = 3), and the use of BM versus PBSC (n = 2). The remaining 15 studies represent single arm, noncomparative studies of related and unrelated HSCT (n = 6) and related allo-HSCT only (n = 9). Within each subsection, the highest quality studies are presented first; studies of equal quality are presented in descending order by sample size. | | | | Reference No. | Quality and Strength of Evidence ∗ | | Number of Patients by Study Group | Upper Limit (Median) Age at Diagnosis | (Interval) % TX -Related Mortality | Median Follow-up | (Interval) % DFS/% EFS/% RFS/% LFS (Signif) | Definition of DFS/EFS/RFS/LFS | (Interval) % OS (Signif) | |
|---|
| Related versus Unrelated—Reduced-Intensity Conditioning (RIC) | | | Hegenbart et al., 2006 [55] | 2+ | Prospective 1998-2002 Multicenter (13) | Total n = 122 Related donor 58 Unrelated donor 64 | | | 44 mos | | Not stated | | | | Sayer et al., 2003 [56] | 2+ | Retrospective 1998-2000 Multicenter (10) | Total n = 113 Related donor 63 Unrelated donor 50 | | | 1 yr | (2-yr EFS) 39.9 16.7 (P = .028) | Not stated | | | | T cell Depleted versus T Cell Replete | | | Wagner et al., 2005 [57] | 1+ | Prospective Randomized 1995-2000 Multicenter (15) Total n = 405 AML n = 101 (25%) | Total AML n = 101 (ITT) T cell depleted 48 T cell replete 53 | | Not stated | 4.2 yrs | | Onset not stated; events were relapse or death | Not stated | | | Hale et al., 1998 [58] | 2++ | Retrospective Nonrandomized Case-controlled, 1984-1995 Multicenter (3) | Total n = 579 (1) in vitro and in vivo T cell depleted 70 (2) in vitro T cell depleted control 50 (3) IBMTR T cell replete control 459 | ≤56 yrs (36 yrs) (30 yrs) (32 yrs) | | | (5-yr LFS) 60 (CI 47-71) 33 (CI 21-47) 52 (CI 47-57) (P 1 versus 2 = .002; P 1 versus 3 = .24) | Not stated | (5-yr OS) 62 (CI 50-74) 35 (CI 22-49) 58 (CI 53-62) (P 1 versus 2 = .001; P 1 versus 3 = .27) | | | Marmont et al., 1991 [59] | 2+ | Retrospective IBMTR Nonrandomized 1982-1987 Multicenter (137) Total n = 3211 AML n = 1154 (62%) AML CR1 n = 717 | Total AML CR1 n = 717 T cell depleted 159 T cell replete 560 | | Not stated | Not stated | | Not stated | Not stated | | | PBSCT versus BMT | | | Garderet et al., 2003 [60] | 2++ | Retrospective EBMT Registry Nonrandomized Case-controlled 1994-1999 Total n = 213 AML n = 111 (52%) | Total AML n = 111 BM 73 PBSC 38 | Not stated 92% adult >16 yrs | | | (2-yr LFS) 42 ± 6 33 ± 8 (P = .49) | Time from SCT to relapse or death | (2-yr OS) 42 ± 6 38 ± 9 (P = .86) | | | Ringdén et al., 2002 [61] | 2+ | Retrospective EBMT Registry Nonrandomized Multicenter (224) Total n = 3465 AML n = 2294 (44%) AML CR1 n = 1532 | Total AML CR1 n = 1532 BM 1072 PBSC 460 | ≤65 yrs (Mean) (36 yrs) (38 yrs) | | | (2-yr LFS) 61 ± 2 57 ± 3 (P = .46) | Not stated | (2-yr OS) 65 ± 2 65 ± 3 (P = .94) | | | Single Arm Cohort Studies—Related and Unrelated Allo-SCT | | | Michallet et al., 2000 [62] | 2++ | Retrospective SFGM Registry 1980-1993 Advanced AML | Total n = 397 | ≤77 yrs (28 yrs) 86% adult >15 yrs | | 7.5 yrs | | Time from BMT to relapse or death | | | | Stelljes et al., 2005 [63] | 2++ | Prospective 1999-2004 Multicenter (4) RIC | Total n = 71 In CR 36 Non-CR 35 | | | 25.9 mos | (2-yr RFS) 78 (CI 63-93) 16 (CI 3-29) (P < .001) | Time from SCT to relapse or death | (2-yr OS) 81 (CI 67-95) 21 (CI 7-36) (P < .001) | | | Greinix et al., 2002 [64] | 2+ | Retrospective 1982-2000 Multicenter (4) | Total n = 172 | | (Not stated) | 5.6 yrs | | Not stated | | | | Sierra et al., 2000 [65] | 2+ | Retrospective 1985-1998 Single center | Total n = 161 | ≤55 yrs (30 yrs) 84% adult ≥18 yrs | | 2.9 yrs | (5-yr LFS) 14 ± 2 (adults) | Not stated | Not stated | | | Cook et al., 2006 [66] | 2+ | Retrospective 1989-2003 Multicenter (15) CR1 after refractory to first induction | Total n = 68 | | | > 4 yrs | | Not stated | | | | Bunjes et al., 2002 [67] | 2+ | Retrospective Dates not stated Single center High-risk AML | Total n = 57 | | | 26 mos | | Not stated | Not stated | | | Single Arm Cohort Studies—Related Allogeneic SCT | | | Rocha et al., 2002 [68] | 2+ | Retrospective EBMT Registry 1992-1999 Multicenter (450+) | Total n = 572 | | | Not stated | | Not stated | | | | Tallman et al., 2000 [69] | 2+ | Retrospective IBMTR Nonrandomized 1989-1995 Multicenter (108) | Total n = 431 Standard-dose Cy 222 High-dose Cy 147 No remission Tx 62 | ≤56 yrs (29 yrs) (28 yrs) (32 yrs) | | 61 mos | (5-yr LFS) 56 (CI 49-63) 59 (CI 50-66) 50 (CI 36-63) (P not signif.) | Onset not stated; events were relapse or death | (5-yr OS) 56 (CI 49-63) 60 (CI 51-67) 60 (CI 46-71) (P not signif.) | | | Clift et al., 1992 [70] | 2+ | Retrospective 1974-1990 Multicenter (3) Untreated first relapse | Total n = 126 | ≤61 yrs (>30 yrs) 75% adult >18 yrs | | Not stated | | Time from BMT to relapse or death | Not stated | | | Mehta et al., 2002 [71] | 2+ | Retrospective 1978-1986 Single center | Total n = 119 | | | 9 yrs | | Not stated | | | | Brown et al., 1996 [72] | 2+ | Retrospective NAMTG 1984-1992 Multicenter Resistant AML (40 in untreated first relapse) | Total n = 70 | | | Not stated | | Time from BMT to relapse or death | Not stated | | | Greinix et al., 1996 [73] | 2+ | Retrospective 1982-1995 Single center | Total n = 62 CR1 35 > CR1 27 | | | 50 mos | (10-yr LFS) 60 10 (P not stated) | Not stated | Not stated | | | Zikos et al., 1998 [74] | 2+ | Prospective 1990-1994 Single center | Total n = 60 | | | 4.4 yrs | Not stated | Not stated | | | | Bibawi et al., 2001 [75] | 2+ | Retrospective 1991-1998 Single center Total n = 62 AML n = 50 (81%) Advanced AML | Total n = 50 | | | 3 yrs | Not stated | Not stated | | | | Frassoni et al., 1991 [76] | 2− | Retrospective 1981-1989 Single center Total n = 168 AML n = 118 (63%) | Total n = 118 CR1 88 Advanced Disease 30 | Not stated | Not stated | 767 days | Not stated | Not stated | (Not stated, OS) 50 40 (P not stated) | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †AML indicates acute myelogenous leukemia; BMT, bone marrow transplantation; SCT, stem cell transplantation; CR, complete remission; EBMT, European Group for Blood and Marrow Transplantation; IBMTR, International Bone Marrow Transplant Registry; ITT, intent-to-treat; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; Signif., significance (probability); OS, overall survival; ctrl grp, control group; NAMTG, North American Marrow Transplant Group; SFGM, Société Française de Greffe de Moelle; CI, 95% confidence interval. |
Related versus Unrelated Hegenbart et al. [55] presented the results of a prospective, multicenter study comparing related versus unrelated donor allo-HSCT following reduced intensity, TBI-based conditioning in 122 adult (17-74 years) patients with AML. Patients were eligible for unrelated HSCT if they were >50 years old and for related HSCT if they were >55 years old. Younger patients were included if they had comorbid conditions that excluded them from standard conditioning for allo-HSCT. Eighteen patients had secondary AML, 51 were in CR1, 39 were in CR2, and 32 had more advanced AML. Patients received either a related (n = 58, 47.5%) or unrelated (n = 64, 52.5%) donor allo-HSCT. Median time from last chemotherapy to SCT was 76 days, with no difference between the 2 groups. Patient characteristics were comparable between the 2 groups except more related than unrelated donor allo-recipients were in CR1 (55% versus 30%), and more unrelated than related recipients had undergone a previous auto-HSCT (23% versus 3%). Sayer et al. [56] reported the results of a multicenter, retrospective analysis of 113 adult (16-67 years) patients with AML who received either a matched related donor (n = 63) or matched unrelated donor (n = 50) allo-SCT following RIC with fludarabine and busulfan (Flu + Bu, n = 93) or TBI (n = 20). Stem cell source was PBSC (n = 102), BM (n = 10), or both (n = 1). Differences in patient characteristics between the 2 groups were not reported. T Cell Depleted (TCD) versus T Cell Replete Wagner et al. [57] presented the outcomes of 103 adult (77% >18 years) patients with AML randomized to undergo an unrelated allo-BMT with either TCD marrow and cyclosporine (n = 48) or a T cell-replete BMT with methotrexate (MJX) and cyclosporine (n = 53). Two methods of TCD were used: counterflow centrifugal elutriation, a physical method of separating T cells; and T10B9, an antibody. Although prognostic factors were similar between the 2 randomized groups, there were differences by age, race, and total nucleated cell dose among centers differentiated by the 2 methods of TCD. Hale et al. [58] presented the results of a retrospective, case-controlled study of adult (14-56 years) patients with AML in CR1, comparing TCD versus T cell-replete marrow in HLA-matched sibling allo-BMT. CAMPATH-1M (CAM-IgM) was used for in vitro depletion of the graft and CAMPATH-1G (CAM-IgG) for in vivo depletion of the recipient prior to graft infusion (n = 70). The results were compared with 2 control groups: (1) a historic group of 50 patients who received CAM-IgM depleted BM, but no in vivo CAM-IgG; and (2) a matched group of concurrently treated patients (n = 459) who received T cell-replete allo-BMT and were reported to the IBMTR. No differences in patient characteristics among the groups were reported. Marmont et al. [59] analyzed the effects of TCD on the outcome of HLA-matched sibling donor BMT in a multicenter, retrospective study of 1154 adult (≤56 years) patients with AML from 137 centers that reported to the IBMTR. A total of 245 AML patients received a TCD allo-BMT. A variety of TCD techniques were used by the centers, including physical, broad antibody, anti-T and NK, and anti-T. During the same time period, 909 control group patients received a non-TCD allo-BMT. No differences in patient characteristics between the 2 groups were reported. PBSCT versus BMT Garderet et al. [60] presented the results of a retrospective, case-controlled study of 111 adult (92% >16 years) patients with AML reported to the EBMT, comparing PBSC versus BM as the stem cell source. The data from 38 AML patients who received G-CSF mobilized PBSC from a matched unrelated donor were compared with a historic control group of 73 matched unrelated allo-BMT patients computer-matched on disease status at transplant, age, year of transplant, and whether or not the graft was TCD. Ringdén et al. [61] reported the results of a retrospective comparison of BM (n = 1537) versus PBSC (n = 757) as the stem cell source in 2294 adult (16-65 years) patients with AML who underwent an HLA-matched sibling HSCT and were reported to the EBMT Registry. Patient characteristics between the 2 groups were comparable, except patients receiving PBSC were older, had older donors, received more TCD grafts, and received methotrexate (MTX) and TBI less frequently than patients receiving BM. Single-Arm Cohort Studies The remaining 15 studies, presented only in Table 8, examined the outcomes of single arm, noncomparative studies of related and unrelated allo-HSCT (n = 6) and related allo-HSCT only (n = 9). No single-arm unrelated allo-HSCT studies met the inclusion criteria for this review. Comparison of Treatment Regimens Although the term “conditioning regimen” is often applied to the treatment immediately prior to allo- or auto-HSCT, in this review it is used only in relation to allo-HSCT, as conditioning regimen implies treatment that includes facilitation of engraftment of allogeneic cells. In this review, the term “high-dose therapy regimen” is used to refer to the treatment immediately prior to auto-HSCT. This section provides descriptions of 14 studies comparing treatment regimens and their impact on HSCT outcomes, which are presented in Table 9. These studies included high-dose auto-HSCT (n = 2), myeloablative (n = 8), or RIC (n = 4) allo-SCT (n = 12), and 1 study that did not differentiate between auto-and allo-SCT (presented in text only). Within each subsection, the highest quality studies are presented first; studies of equal quality are presented in descending order by sample size. | | | | Reference No. | Quality and Strength of Evidence ∗ | | Number of Patients by Study Group | Upper Limit (median) Age at Diagnosis | (Interval) % TX -Related Mortality | Median Follow-up | (Interval) % DFS/% EFS/% RFS/% LFS (Signif) | Definition of DFS/EFS/RFS/LFS | (Interval) % OS (Signif) | |
|---|
| Autologous SCT—Comparison of 2 or More High-Dose Therapy Regimens | | | Ringdén et al., 1996 [77] | 2+ | Retrospective EBMT Registry Nonrandomized 1987-1994 Multicenter | Total n = 660 Bu + Cy 330 Cy + TBI 330 | | | Not stated | (2-yr LFS) 52 ± 3 51 ± 3 (P not signif.) | Not stated | Not stated | | | Ball et al., 2000 [78] | 2+ | Retrospective Nonrandomized 1984-1997 Multicenter (13) | Total n = 138 Bu + Cy 93 Cy + TBI 35 Bu + VP-16 10 | | Not stated | Not stated | (2-yr DFS) 42 37 20 (P not stated) | Not stated | (2-yr OS) 37 34 20 (P not stated) | | | Allogeneic SCT—Comparison of 2 or More Myeloablative Conditioning Regimens | | | Blaise et al., 1992 [79] | 1+ | Prospective GEGMO Randomized 1987-1990 Multicenter (15) | Total n = 101 Bu + Cy 51 Cy + TBI 50 | Not stated (31 yrs) (32 yrs) | | | | Not stated | | | | Ringdén et al., 1999 [80] | 1+ | Retrospective Randomized 1988-1992 Multicenter (6) AML n = 69 (41%) | Total n = 69 Bu + Cy 37 Cy + TBI 32 | | | Not stated | | Not stated | Not stated for AML only | | | Farag et al., 2005 [81] | 2++ | Retrospective Nonrandomized 1984-2001 2 centers | Total n = 237 Bu + Cy + VP-16 127 Bu + Cy 110 | | | | Not stated | Not stated | (5-yr OS) 27.3 (CI 18.9-35.6) 30.1 (CI 20.2-39.1) (P = .48) | | | Resbeut et al., 1995 [82] | 2++ | Prospective SFGM Nonrandomized 1983-1990 Multicenter (17) | Total n = 171 (ITT) Cy + Fractionated TBI 106 Cy + Single dose TBI 65 | (Not stated) (29 yrs) (25.7 yrs) | | 63 mos | (5-yr DFS) 56 (CI 44-67) 43 (CI 31-56) (P = .07) | Time from BMT to relapse or death | (5-yr OS) 64 (CI 53-72) 45 (CI 33-58) (P = .04) | | | Litzow et al., 2002 [83] | 2+ | Retrospective Nonrandomized IBMTR 1988-1996 Multicenter (350) | Total n = 581 Bu + Cy 381 Cy + TBI 200 | | | | (5-yr LFS) 54 (CI 48-59) 58 (CI 50-65) (P = .44) | Onset not stated; events were relapse or death | (5-yr OS) 55 (CI 49-60) 60 (CI 52-66) (P = .58) | | | Ringdén et al., 1996 [77] | 2+ | Retrospective EBMT Registry Nonrandomized 1987-1994 Multicenter | Total n = 446 Bu + Cy 223 Cy + TBI 223 | | | Not stated | (2-yr LFS) 64 ± 3 66 ± 3 (P not signif.) | Not stated | Not stated | | | Bacigalupo et al., 2000 [84] | 2+ | Retrospective Non-randomized 1980-1998 Single center | Total n = 150 Cy + TBI ≥ 9.9 Gy 116 Cy + TBI < 9.9 Gy 34 | | | 2467 days | Not stated | Not stated | | | | Schapp et al., 1997 [85] | 2+ | Retrospective Nonrandomized 1981-1995 Single center Total n = 181 AML n = 70 (39%) | Total AML n = 70 Cy + TBI 29 Cy + TBI + DNR or Ida 41 | ≤59 yrs (Overall) (32 yrs) (36 yrs) | | 63 mos | (5-yr LFS) 34 (CI 10-58) 51 (CI 34-68) (P = .053) | Onset not stated; events were relapse or death | (5-yr OS) 38 (CI 15-61) 51 (CI 36-66) (P = .149) | | | Allogeneic SCT—Reduced-Intensity Conditioning (RIC) Regimens | | | Shimoni et al., 2006 [86] | 2++ | Prospective Nonrandomized No dates given (5 years) Single center AML/MDS (85% AML) | Total n = 112 (ITT) Cy + Bu 45 RIC Flu + Bu2 41 Modified ablative Flu + Bu4 26 | ≤70 yrs (50 yrs) (57 yrs) (51 yrs) | | 22 mos | (2-yr DFS) 45 (CI 29-60) 43 (CI 24-62) 49 (CI 25-72) (P not signif) | Time from BMT to relapse or death | (2-yr OS) 50 (CI 34-66) 47 (CI 30-65) 49 (CI 24-74) (P not signif) | | | Aoudjhane et al., 2005 [87] | 2+ | Retrospective EBMT Registry Nonrandomized 1997-2003 Multicenter (182) | Total n = 722 Myeloablative 407 RIC 315 | | | | (2-yr LFS) 44 ± 3 40 ± 3 (P = .80) | Not stated | (2-yr OS) 46 ± 3 47 ± 3 (P = .43) | | | de Lima et al., 2004 [88] | 2+ | Retrospective Nonrandomized 1995-2000 Single center AML/MDS (72% AML) | Total n = 94 Flu + Mel 62 Flu + Cy 32 | | | 40 mos | (3-yr PFS) 32 19 (P not stated) | Not stated | (3-yr OS) 35 30 (P not signif.) | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †AML indicates acute myelogenous (myeloid) leukemia; BMT, bone marrow transplantation; SCT, stem cell transplantation; CR, complete remission; EBMT, European Group for Blood and Marrow Transplantation; IBMTR, International Blood and Marrow Transplant Research; ITT, intent-to-treat; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; Signif., significance (probability); OS, overall survival; SFGM, Société Française de Greffe de Moelle; GEGMO, Groupe d'Etude des Greffes de Moelle Osseuse; CI, 95% confidence interval. |
Autologous SCT—High-Dose Therapy Regimens Ringdén et al. [77] reported the outcomes of 660 adult (79% >20 years) patients with AML in CR1 who underwent auto-SCT after treatment with Bu + Cy (n = 330) or Cy + TBI (n = 330) and were reported to the EBMT Registry. Significantly more patients treated with Bu + Cy were in first relapse, and patients in the Cy + TBI group were more likely to be male and in CR2. Figure 6 compares the actuarial LFS between patients receiving Bu + Cy versus Cy + TBI prior to auto-SCT. Ball et al. [78] reported the results of a retrospective, nonrandomized, multicenter study of 138 adult (≤67 years) patients with AML comparing 3 high dose therapy regimens followed by auto-BMT. The treatment regimen prior to 1988 was Cy + fractionated TBI (n = 35), post-1988 it was changed to Bu + Cy (n = 93), and 10 patients at 1 center (post-1988) were treated with Bu + VP-16. No differences in patient characteristics among the 3 groups were reported. In all, 110 patients were in CR (CR1, n = 23; CR2/3, n = 87) and 28 were in first relapse at the time of transplantation. Allogeneic HSCT Myeloablative conditioning regimens Blaise et al. [79] presented the results of a prospective, randomized study by the Groupe d'Etudes de la Greffe de Moelle Osseuse (GEGMO) of 101 adult (>14 years) patients with AML in CR1 conditioned prior to an HLA-matched sibling donor allo-HSCT with either Bu + Cy (n = 51) or Cy + TBI (n = 50). Sixty three (62%) patients (Cy + TBI, n = 31; Bu + Cy, n = 32) were transplanted <120 days after diagnosis. There were no statistical differences in patient characteristics between the 2 groups. Ringdén et al. [80] reported the results of a retrospective analysis of 69 adult (≤55 years) patients with AML in CR1 (n = 51) or in ≥CR2 or early relapse (n = 18) in a randomized trial comparing Bu + Cy (n = 37) versus Cy + TBI (n = 32) followed by an HLA-matched sibling donor allo-BMT. There were no differences in patient characteristics between the 2 groups. Farag et al. [81] presented the outcomes of 237 adult (17-62 years) patients with AML in a retrospective, nonrandomized study comparing Bu + Cy + VP-16 (n = 127) versus Bu + Cy (n = 110) followed by allo-HSCT from HLA-matched related or unrelated donors. Patients who received Bu + Cy + VP-16 were significantly more likely to be older, have high-risk disease, and to receive a matched-unrelated donor allo-HSCT than the patients in the Bu + Cy group. Resbeut et al. [82] reported the results of a prospective study by the Société Française de Greffe de Moelle (SFGM) of 171 adult (median age = 27 years) patients with AML in CR1 who were nonrandomly assigned to Cy + single dose TBI (10 Gy) (n = 65) or Cy + fractionated TBI (range 10-15 Gy; 76% received 12 Gy in 6 fractions over 3 days) (n = 106) prior to undergoing an HLA-matched sibling allo-BMT. Patient characteristics were comparable between the 2 groups except for a shorter diagnosis-to-BMT interval in the fractionated TBI group. Litzow et al. [83] presented the outcomes of 581 adult (20-57 years) patients with AML in CR1 in a retrospective, nonrandomized, IBMTR study comparing Bu + Cy versus Cy + fractionated TBI (dose >11.25 Gy) conditioning regimens followed by HLA-matched sibling allo-HSCT. Significantly more patients in the Bu + Cy group were >40 years, and a higher percentage of Cy + TBI patients required more than 1 cycle of chemotherapy to achieve CR1. Ringdén et al. [77] reported the outcomes of 446 adult (79% >20 years) patients with AML in CR1 who underwent allo-HSCT following conditioning with Bu + Cy (n = 223) or Cy + TBI (n = 223) and were reported to the EBMT Registry. Significantly more patients treated with Bu + Cy were in first relapse, and patients in the Cy + TBI group were more likely to be male and in CR2. Figure 7 compares the actuarial LFS between patients receiving Bu + Cy versus Cy + TBI prior to allo-HSCT. Bacigalupo et al. [84] presented the results of a retrospective, nonrandomized study of 150 adult (≤47 years) patients with AML in CR1, comparing conditioning with Cy + low dose TBI (<9.9 Gy, n = 34) versus Cy + high dose TBI (≥9.9 Gy, n = 116) prior to HLA-matched related donor allo-BMT. There were no significant differences in patient characteristics between the 2 groups. Schapp et al. [85] reported the results of a retrospective, nonrandomized study of 70 adult (13-59 years) patients with AML in CR1 who underwent conditioning with Cy + TBI (n = 29) or Cy + TBI + DNR or Ida (n = 41) followed by an HLA-matched sibling donor allo-HSCT. No significant differences in patient characteristics between the 2 groups were reported. Reduced-intensity conditioning regimens Shimoni et al. [86] presented the outcomes of 112 adult (17-70 years) patients with AML (n = 95) or MDS (n = 17) in CR1 enrolled in a prospective, nonrandomized study comparing standard myeloablative conditioning with Cy + Bu (12.8 mg/kg) (n = 45) versus RIC with Flu + Bu (6.4 mg/kg, FluBu2, n = 41) or a modified myeloablative conditioning regimen with Flu + Bu (12.8 mg/kg, FluBu4, n = 26) followed by matched or mismatched, related or unrelated allo-SCT. Older patients (>65 years) were more likely to receive FluBu2 conditioning, patients with active disease were more likely to receive FluBu4 conditioning. Aoudjhane et al. [87] reported the results of a retrospective, nonrandomized study of 722 adult (>50 years) patients with AML reported to the EBMT Registry who underwent an HLA-matched sibling allo-SCT, comparing RIC (n = 315) with Flu + low-dose TBI (<3 Gy), Bu (≤8 mg/kg), or other nonmyeloablative drugs versus myeloablative conditioning (n = 407) with TBI (>10 Gy) or Bu (>8 mg/kg) + other myeloablative drugs. RIC patients were older and more likely to be male than patients who received a myeloablative (MA) conditioning regimen. Figure 8 compares the unadjusted cumulative incidence of LFS between the RIC and MA cohorts. de Lima et al. [88] reported the outcomes of 94 adult (22-75 years) patients with AML (n = 68) or high-risk MDS (n = 26) in a retrospective, nonrandomized study comparing a nonmyeloablative regimen of Flu + Cy + Ida (FAI, n = 32) versus a myelosuppressive, RIC regimen of Flu + Mel (FM, n = 62) prior to HLA-matched related or unrelated donor allo-SCT. Compared to patients who received FM, those treated with FAI were significantly older and more likely to be in CR1 at transplant. Kroger et al. [89] reported the results of a prospective, nonrandomized study of 90 adult (≤64 years) patients with AML comparing Bu + Cy + low dose VP-16 (30 mg/kg) (n = 60) versus Bu + Cy + high dose VP-16 (45 mg/kg) (n = 30) followed by auto-or allo-HSCT (HSCT type not differentiated; outcomes are presented only in the text, not in Table 9). Stem cell sources were allo-related BM (n = 53), allo-unrelated BM (n = 5), allo-unrelated PBSC (n = 2), syngeneic BM (n = 2), auto-purged BM (n = 9), auto-unpurged BM (n = 9), or auto-PBSC (n = 10). Differences in patient characteristics between the 2 conditioning regimens were not reported. Median follow-up was 16 months. Two-year treatment-related mortality (TRM) was 16% versus 26%, 3-year DFS was 62% versus 40% (P = .03), and 3-year OS was 63% versus 41% (P = .06) for patients receiving low-versus high-dose VP-16, respectively. Treatment for Relapse after First allo-HSCT This section presents 2 studies of treatment for relapse after an initial allo-HSCT, 1 using donor lymphocyte infusion (DLI) and the other a second allo-HSCT. Although these studies may not meet all criteria for inclusion, they were included in this review to illustrate the typical outcome of these treatments for adult AML patients. Study designs and outcomes are presented in the text. DLI Collins et al. [90] reported the results of a retrospective study of 46 adult (median age 33.5 years) patients with AML who received a DLI to treat relapse after a related (n = 44) or unrelated (n = 2) allo-BMT. Six patients were not assessable for response to DLI because of prior chemotherapy. Of the remaining 39 patients, 6 (15.4%) achieved CR. Median follow-up of survivors after DLI was 506 days. An OS value was not provided; however, a Kaplan-Meier curve indicated a 3-year OS of approximately 15%. Second Allogeneic SCT Eapen et al. [91] presented the outcomes for 125 adult (overall, 66% >21 years) AML patients from the IBMTR who received a second allo-SCT for recurrent or persistent leukemia after initial HLA-matched sibling SCT. Overall, 85% of the patients received allografts from the same donor for both transplants. Median follow-up of survivors was 93 months. The 3-year LFS and OS were both 27% (95% CI, 19%-35%). Auto-SCT as Treatment of Therapy-Related or Secondary AML The following 2 studies examined auto-SCT as treatment for secondary AML after MDS or therapy-related AML. De Witte et al. [92] reported the outcomes of 60 adult patients (median age 39 years), retrieved from the registries of the Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation, who underwent an auto-BMT in CR1 for secondary (n = 39) or therapy-related MDS/AML (n = 21). The median interval between diagnosis and auto-BMT was 7 months. Median follow-up of survivors was 10 months. For secondary AML and therapy-related MDS/AML patients, 2-year OS from BMT was 34% and 41%, DFS was 30% and 36%, and TRM was 5% and 10%, respectively. Kröger et al. [93] reported the results of 65 adult (median age 39 years) patients with therapy-related MDS/AML who underwent an auto-SCT and were reported to the EBMT. Stem cell source was BM (n = 31), PBSC (n = 30), or a combination of both (n = 4). The median time between diagnosis and transplant was 5 months. Median follow-up was not reported. Two-year TRM was 12% (95% CI, 6%-38%) and 3-year DFS and OS from BMT were 32% (95% CI, 18%-45%) and 35% (95% CI, 21%-49%), respectively. Late Effects and Quality of Life Late Effects The following studies investigated late effects in adult patients who underwent auto- or allo-SCT for treatment of AML, providing additional insight into the potential outcomes related to specific treatments. Frassoni et al. [94] investigated the occurrence of late events in patients with AML who underwent allo-HSCT (n = 1059) or auto-BMT (n = 656). They found that the incidence of late relapse continuously decreased with time. Patients with no recurrence at 2 years had an 82% chance of remaining in CR at 9 years following transplantation. The latest relapses were observed following allo-HSCT at 6.6 years for patients transplanted in CR1, as opposed to 3.7 years for patients transplanted in CR2, and following auto-HSCT at 6 years and 5.1 years, respectively. Compared to auto-SCT, patients who underwent allo-HSCT experienced a lower frequency of late relapse. Abdallah et al. [95] analyzed the long-term outcomes and toxicities of 98 high-risk AML patients in CR1 or CR2 treated with TBI and high-dose Cy prior to auto-SCT purged with mafosfamide. Long-term complications (median observation period of 11.67 years) included cataracts (44.4%), HCV infections (5%), cardiac complications (4%), MDS (4%), and renal insufficiency (2%). Wadleigh et al. [96] conducted a retrospective study of 62 patients who underwent allo-HSCT for the treatment of AML or AML arising from MDS to determine whether gemtuzumab ozogamicin (GO), a monoclonal antibody (mAb) used in the treatment of AML, increased the risk of veno-occlusive disease (VOD). Nine of 14 (64%) of patients who received GO prior to allo-SCT developed VOD compared to 4 (8%) of 48 patients without prior GO exposure (P < .0001). Toor et al. [97] investigated life-threatening bleeding associated with platelet transfusion refractoriness among 39 patients who underwent high-dose chemoradiotherapy followed by sibling donor allo-BMT (n = 12) or auto-BMT (n = 27). Increased platelet requirements in HLA alloimmunized auto-BMT patients were observed at a median of 211 platelet transfusions versus 0 transfusions in nonalloimmunized auto-BMT patients (P < .01) and 17 in allo-BMT patients. Five of 6 HLA alloimmunized auto-BMT patients experienced delayed bleeding, which contributed to their death while still in CR. Butt and Clark [98] studied the iron status of 32 adult AML patients enrolled in the MRC AML 10 and 12 trials and found that patients who underwent auto-SCT had a higher median first serum ferritin level (3245 μg/L) than patients who received chemotherapy alone (1148 μg/L) or allo-SCT (1334 μg/L) because of increased use of transfused blood. Nine of the 10 auto-SCT recipients underwent venisection, but no patient suffered end organ damage. Quality of Life (QOL) The following studies investigated the QOL reported by or observed in patients who underwent allo- or auto-SCT for the treatment of AML. Watson et al. [99] surveyed 481 patients 1 year from the end of treatment in the MRC AML 10 trial to compare QOL following allo-BMT (n = 97), auto-BMT (n = 74), or chemotherapy (n = 310). On the EORTC Quality of Life-Core 30 Questionnaire (QLQ-C30) with 5 functional scales (physical, role, cognitive, emotional, and social) and a leukemia-specific measure (QLQ-LEU) designed to assess late effects of BMT, allo-BMT was found to have a significantly adverse impact on most QOL dimensions compared to auto-BMT or chemotherapy. Zittoun et al. [100] studied the self-reported QOL of 98 patients in continued CR for 1-7.4 years after undergoing allo-BMT, auto-BMT, or ICC in the EORTC-GIMEMA AML 84 trial. On all parameters, including somatic symptoms (mouth sores, cough, hair loss, headache), repeated acute medical problems, physical functioning, role functioning, leisure activities, sexual functioning, overall physical condition, and overall QOL, there were significant differences among the 3 groups with a consistent ranking of allo-BMT lower than auto-BMT and auto-BMT lower than chemotherapy. Hsu et al. [101] used the EORTC QLQ-C30, as well as the World Health Organization QOL questionnaire (WHOQOL-BREF), to examine differences in QOL between 41 AML patients who underwent allo-BMT as consolidation or salvage therapy versus 63 patients who received traditional chemotherapy alone. The mean scores on the 2 QOL questionnaires did not differ significantly between the 2 groups; however, when comparing survival-weighted psychometric scores (SWPS), patients who underwent allo-BMT had significantly (P < .01) higher SWPS on all functioning domains and symptom items of the QLQ-C30 and all 4 domains (physical, psychologic, social, and environmental) of the WHOQOL-BREF than those who received chemotherapy only. Wellisch et al. [102] found no significant differences in QOL between AML patients who underwent BMT (n = 11) or chemotherapy only (n = 27), with regard to occurrence of depressive symptoms, multifocal psychiatric symptomatology, or on any subscale of the CARES Questionnaire, a 139-item inventory designed to evaluate the problems and rehabilitation needs of patients with cancer. Prognostic Factors Table 10 presents a summary of patient and disease prognostic factors and their reported effect on survival outcomes as determined by multivariate analysis in adult AML studies. Atlhough many of the referenced studies in Table 10 were described in the text and tables of this review, others were specifically prognostic factor studies [references in brackets] that are not presented in this evidence-based review because they did not meet the inclusion criteria. Studies were not included in this table if the study did not conduct a multivariate analysis and/or if transplantation was not an included treatment modality. The data in this table are provided for the reader's information and were not used to make treatment recommendations. | | | | | References Reporting Significant Impact of Prognostic Factor on Survival Outcome | References Reporting No Significant Impact of Prognostic Factor on Survival Outcome | |
|---|
| Patient Characteristics | | | Age | 19, 20, 27, 28, 32, 37, 40, 45, 47, 55, 57, 58, 62, 68, 69, 71, 103,‡104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 125, 127, 128, 131, 132, 133, 134, 135, 136, 135, 137, 139 | 10, 11, 12, 24, 35, 39, 41, 46, 49, 50, 51, 63, 64, 74, 75, 117, 118, 119, 129 | | | Sex | 15, 69, 104, 118 | 11, 12, 19, 24, 32, 40, 41, 45, 49, 58, 106, 113, 116, 117, 125, 129 | | | Disease Characteristics at Diagnosis | | | AML type (de novo or secondary) | 114, 126, 134, 135 | 15, 26, 55, 63 | | | WBC count | 10, 11, 19, 20, 30, 49, 50, 104, 112, 114, 116, 118, 120, 125, 127, 130, 133, 134, 137, 139 | 12, 39, 40, 45, 46, 117, 119, 125, 129 | | | FAB subtype | 30, 37, 61, 68, 105, 113, 114 | 11, 12, 15, 24, 26, 35, 40, 41, 49, 50, 106, 116 | | | Performance status | 56, 57, 69, 109, 116, 118, 121 | 11, 40 | | | Cytogenetic risk group/Karyotype | 11, 15, 18, 19, 26, 29, 30, 39, 45, 49, 50, 55, 57, 66, 68, 104, 105, 107, 110, 112, 113, 114, 116, 117, 122, 123, 124, 129, 131, 132, 134, 135, 137, 138, 141 | 10, 40, 44, 75 | | | Molecular markers (eg, FLT3,§ BAALC, CEBPA, NPM1, ERG, etc.) | 107, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 | | | | Flow cytometric cell surface expression (eg, CD2, CD34, CD36, CD56, etc.) | 131, 137, 138, 139, 140, 141 | | | | CMV status | 29, 57 | 63 | | | Hepatomegaly/Splenomegaly | 15 | [116] | | | Extramedullary disease | | 40 | | | Disease Characteristics at SCT | | | No. cycles to achieve CR1 | 10, 45, 50, 66 | 11, 12, 19, 26, 39, 117 | | | Time to CR1 | | 24, 35, 40 | | | Duration of CR1 | 27, 40, 51, 65 | | | | Time from diagnosis to CR1 | 37, 106 | 41, 46 | | | Time from diagnosis to SCT | 28, 66, 108 | 74, 117 | | | Time from CR1 to stem cell harvest | | 12, 40, 41 | | | Time from CR1 to SCT | 37, 105, 115 | 12, 19, 40, 41, 46, 51, 106 | | | Disease status at SCT | 29, 55, 60, 61, 62, 63, 64, 65, 72, 109, 114 | 32, 41, 49, 56, 74, 75, 124 | | | % BM blasts at SCT | 56, 104, 109, 121 | 15, 117 | | | Year of Transplant | 46, 49, 64, 69, 113 | 40, 41, 58, 59, 106 | | | | |
| ∗ Survival = any one or more of the following: OS, DFS, RFS, LFS, EFS, PFS (see other tables for explanation of abbreviations). †Factors were not included if the study did not conduct a multivariate analysis and/or if transplantation was not an included treatment modality. ‡Bracketed [ ] references indicate prognostic factor studies that are not described in the text of the evidence-based review. §Only FLT3-ITD has been shown to have prognostic significance, other FLT3 mutations have unknown significance. |
Future Directions Areas of Needed Research After reviewing the evidence, the panel recommended that large clinical trials be conducted to investigate the following important areas of needed research in adult onset AML: (1) What is the role of HSCT in treating patients with specific molecular markers (eg, FLT3, NPM1, CEBPA, BAALC, MLL, NRAS, etc.) especially in patients with normal cytogenetics? (2) What is the benefit of using SCT to treat different cytogenetic subgroups? (3) What is the impact on survival outcomes of reduced intensity or nonmyeloablative versus conventional conditioning in older (>60 years) and intermediate (40-60 years) aged adults? (4) What is the impact on survival outcomes of unrelated donor SCT vesus chemotherapy in younger (<40 years) adults with high risk disease? Ongoing Studies Several studies are summarized below that address areas of needed research or other critical issues that may affect the treatment recommendations made in Table 3. These studies are currently accruing patients and/or have been published in abstract form. Effect of specific molecular markers on outcome in AML patients with normal cytogenetics Schlenk et al. [142] evaluated the prognostic value of NPM1, FLT3, CEBPA, MLL, and NRAS gene mutations on RFS and OS following allo-SCT in adult (16-60 years) AML patients with normal cytogenetics. Between 1993 and 2004, 872 patients with normal cytogenetics were entered on 4 AMLSG treatment trials [AML-2/95, AML-1/99, AML HD93, AML HD98A]. In all 4 trials there was a biologic allocation to an MRD allo-SCT in CR1. The median age of patients was 48 years; median follow-up time was 49 months. Of 666 patients achieving a CR after induction therapy, 171 had a MRD and 143 (84%) of these received an allo-HSCT in CR1. Subgroup analyses were performed on an ITT basis by mutation status (NPM1+/FLT3-internal tandem duplication [ITD] versus all other combinations), which revealed a significant improvement in RFS (HR = 0.56, 95% CI 0.39-0.81) and OS (HR = 0.69 (95% CI 0.48-0.98) in the subgroup of patients without the NPM1+/FLT3-ITD marker constellation who received an allo-SCT in CR1. Dose intensity prior to auto-SCT The EORTC and GIMEMA Leukemia Cooperative Groups have sponsored a phase III randomized, international, multicenter, prospective study (Protocol ID: EORTC-1992.00) of adult (15-60 years) patients with AML, comparing high-dose versus standard dose induction therapy (Ara-C + DNR + VP-16), followed by consolidation and auto-PBSCT or BMT with or without interleukin-2. Dose intensity and in vivo purged vs unpurged auto-PBSCT The ECOG has sponsored a phase III randomized, multicenter, prospective trial (Protocol ID: ECOG-1900) in adult (16-60 years) patients with AML, comparing survival outcomes after high or standard dose DNR + Ara-C followed by in vivo purged (with gemtuzumab ozogamicin) versus unpurged auto-PBSCT. Patients with appropriate donors are biologically assigned to allo-SCT. Comparison of allo-SCT conditioning regimens The Fred Hutchinson Cancer Research Center (FHCRC) has sponsored a phase III, randomized, multicenter, prospective study (Protocol ID: FHCRC-1992.00) of adult (≤65 years) patients with AML or MDS, comparing survival outcomes after myeloablative (Flu + Bu or Cy + Bu) versus nonmyeloablative (Flu + TBI) conditioning prior to allo-PBSCT. Patients are stratified by transplant center (FHCRC versus other), diagnosis (AML versus MDS), donor (MRD versus URD), and etiology (primary versus treatment related). The Cooperative German Transplant Study Group has sponsored 2 single center, phase III, randomized, prospective studies comparing nonmyeloablative (Flu + TBI, 8 Gy) versus myeloablative (Cy + TBI, 12 Gy) conditioning prior to allo-SCT in adult (18-60 years) AML patients in CR1 (Protocol ID: 9005-2005) or in CR2 (Protocol ID: AML_CR2_Allo_HSCT). The Hôpital Saint Antoine in France has sponsored a multicenter, phase III, randomized, prospective study (Protocol ID: P040420) of adult (35-55 years) patients with AML, comparing myeloablative (Cy + TBI) versus nonmyeloablative (Flu + TBI, 2Gy) conditioning prior to allo-SCT. The Technische Universitaet Dresden, Germany, has sponsored a single center, phase III, randomized, prospective study (AML2003, Protocol ID: MK1-95) investigating standard versus intensified therapy for adult (16-60 years) AML patients prior to allo-HSCT. In the first 8 months of the trial, 107 AML patients with a median age of 48 years (17-60 years) were recruited, 57 of whom were randomized to the intensive treatment arm [143]. RIC allo-HSCT versus chemotherapy The Cooperative German Transplant Study Group (Protocol ID: TRALG1/02) has sponsored a multicenter, prospective study of older adult (51-70 years) AML patients in a donor versus no donor design comparing allo-HSCT with RIC versus traditional chemotherapy. G-CSF-mobilized PBSC versus BM allo-HSCT The National Marrow Donor Program (NMDP) and the National Institutes of Health (NIH) have sponsored a phase III randomized, multicenter, prospective trial (Protocol ID: BMTCTN-0201) of adult (≤66 years) patients with hematologic malignancies (AML, ALL, CML, MDS, myeloproliferative diseases, and therapy-related AML or MDS), comparing survival outcomes after granulocyte colony stimulating factor (G-CSF)-mobilized PBSCT versus BMT from HLA-compatible unrelated donors. Nonmyeloablative allo-HSCT in older patients The CALGB has sponsored a phase II trial (Protocol ID: CALGB-100103) studying the efficacy of a RIC regimen of Flu + Bu followed by allo-HSCT to treat older adult (60-74 years) patients with AML in CR1. Strengths/Limitations and Discussion The strengths of this systematic evidence-based review are the details conveyed in the text about each study's design, the presentation of outcomes in summary tables for each major section, and the treatment recommendations made by the adult AML expert panel. A limitation of this systematic evidence-based review is the inclusion of only published data, specifically peer-reviewed articles published since 1990. Unpublished data can represent “negative” findings that could lead to publication bias; however, the inclusion of high-quality, peer-reviewed publicly available data was of paramount importance. Also excluded were data published in abstract form because abstracts do not adequately convey the full details of the study design or patient characteristics to meet evidence-based criteria for inclusion in systematic reviews, nor for making a true assessment of the widespread applicability or impact of the treatment outside the scope of the trial. A limitation of the studies included in this review is the inability to provide level “1” evidence for allo-HSCT trials because of the low rate of patients allocated to the allo-HSCT arm who would actually receive the assigned treatment (approximately 35% of patients have a matched-related donor [144]). Therefore, trials that biologically allocate patients to allo-HSCT based on donor availability have level “2” as their highest evidence grade. Other study-specific limitations that affect the quality of this systematic evidence-based review include the variability in reporting patient characteristics pre-HSCT, changing treatment modalities over time, and the paucity of RCT data on sufficiently large patient populations. The success of most therapies is affected by cytogenetic risk, which is either not reported, not collected, or missing on too many patients. Chemotherapy regimens, HLA typing techniques, pre-HSCT treatment regimens, stem cell sources, and post-HSCT supportive care have changed considerably over the 17 years of trials included in this review. The clinical research process is lengthy, making the data from many of these studies outmoded at the time of publication. RCT data were lacking in many areas of this review, leading to several treatment recommendations based on small prospective studies and/or large retrospective registry reports. To address some of these limitations, the authors recommend methodology standardization, including use of consistent study designs, endpoint definitions, and reporting of study results. Multicenter randomized phase III comparative trials with large enrollments and high statistical power are required to advance the field more constructively than single institution phase II trials with 1 treatment arm, or retrospective multicenter or registry studies. Much of today's therapies for cancer result from the randomized clinical trial process. It is currently estimated that <5% of adult cancer patients who are eligible to participate in clinical trials actually enroll in a trial. The authors acknowledge the importance of removing barriers to participation in clinical trials, which may include patients' reluctance to be randomized, lack of patient access to clinical trials (eg, geographic, transportation, cultural), financial restraints (no or incomplete insurance coverage for trial expenses), stringent trial eligibility criteria, and reluctance of community physicians to refer patients for clinical trial participation. Acknowledgements The American Society for Blood and Marrow Transplantation and Drs. Hahn and McCarthy are indebted to the members of the AML Review Expert Panel and the ASBMT Evidence-Based Review Steering Committee, who voluntarily and enthusiastically participated in this endeavor. The authors of this review and the American Society for Blood and Marrow Transplantation thank the National Marrow Donor Program, and especially Jeffrey Chell, MD and Michael Boo, for their support of this project. The authors acknowledge Dr. C. Fred LeMaistre for pioneering and supporting this effort, Alan Leahigh and Dianne O'Rourke for their invaluable administrative assistance, and Amy Gillen for serving as the literature abstractor and additional reviewer of this manuscript. The authors are grateful to all the patients who participated in the clinical trials which led to the evidence upon which this review is based. Appendix A. Glossary of Terms - 4-HC
4-hydroperoxcyclophosphamide - ABMTR
Autologous Blood and Marrow Transplant Registry - Allo
Allogeneic - ALP
Acute leukemia protocol - AML
acute myelogenous leukemia - AMSA
Amsacrine - APL
acute promyelocytic leukemia - Ara-C
Cytarabine - Auto
autologous - BM
bone marrow - BMT
bone marrow transplantation - Bu
Busulfan - CALGB
Cancer and Leukemia Group B - CI
(95%) confidence interval - CIBMTR
Center for International Blood and Marrow Research - CMV
cytomegalovirus - CNS
central nervous system - CR
complete remission - CR1
first complete remission - CR2
second complete remission - Cy
cyclophosphamide - DFS
disease-free survival - DLI
donor lymphocyte infusion - DS
Down syndrome - DNR
Daunorubicin - DOX
Doxorubicin - EBMT
European Group for Blood and Marrow Transplant - ECOG
Eastern Cooperative Oncology Group - EFS
event-free survival - EMD
extramedullary disease - EORTC
European Organization of Research and Treatment of Cancer - FAB
French-American-Britishmorphology classification - GAMLCG
German AML Cooperative Group - GEGMO
Groupe d'Etudes de la Greffe de Moelle Ouest - GIMEMA
Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto - GOELAM
Groupe Ouest Est Leucémies Aiguës Myéloblastiques - HiDAC
high-dose Ara-C - HLA
human leukocyte antigen - HOVON
(Dutch-Belgian) Haemato-Oncology Cooperative Group - HR
high-risk and hazard ratio - HSCT
hematopoietic stem cell transplantation - IBMTR
International Bone Marrow Transplant Registry - ICC
intensive consolidation chemotherapy - IDR
Idarubicin - ITT
intention to treat - LFS
leukemia-free survival - MDS
myelodysplastic syndrome - Mel
Melphalan - MITO
Mitozantrone - MRC
Medical Research Council - MRD
matched-related donor - MUD
matched-unrelated donor - OS
overall survival - PBSC
peripheral blood stem cells - PBSCT
peripheral blood stem cell transplantation - PMRD
partially matched related donor - QOL
quality of life - RCT
randomized controlled trial - RFS
relapse-free survival - RR
relative risk - RBZ
Rubidazone - SAKK
Swiss Group for Clinical Cancer Research - SCT
stem cell transplantation - SFGM
Société Française de Greffe de Moelle - SR
standard risk - SWOG
Southwest Oncology Group - SWPS
survival-weighted psychometric scores - TBI
total body irradiation - TG
Thioguanine - TRM
treatment-related mortality - URD
unrelated donor - VP-16
Etoposide - WBC
white blood cell
Appendix B. Outline of Article Abstract Introduction Literature Search Methodology Qualitative and Quantitative Grading of the Evidence Treatment Recommendations Format of the Review SCT versus Chemotherapy in Adult AML •Autologous SCT versus Chemotherapy in CR1 •Allogeneic SCT versus Chemotherapy ± Autologous SCT in CR1 •Allogeneic SCT versus Chemotherapy in CR2 Autologous versus Allogeneic SCT Autologous SCT •PBSCT versus BMT •Purged versus Unpurged •Tandem versus Single •Single Arm Cohort Studies Allogeneic SCT •Related versus Unrelated Donor •T Cell Depleted versus T Cell Replete •PBSCT versus BMT •Single Arm Cohort Studies Comparison of Treatment Regimens •Autologous SCT •Allogeneic SCT (myeloablative; myeloablative versus RIC; nonmyeloablative versus RIC) Treatment for Relapse after First Allo-SCT Autologous SCT as Treatment for Therapy-Related AML or Secondary AML Late Effects and Quality of Life Prognostic Factors Future Directions •Areas of Needed Research •Ongoing Studies Strengths/Limitations and Discussion Acknowledgements Appendix A: Glossary of Abbreviations References References 1. 1Hahn T, Wolff SN, Czuczman M, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol Blood Marrow Transplant. 2001;7:308–331.
Full-Text PDF (2451 KB)
|
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2. 2Hahn T, Wingard JR, Anderson KC, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant. 2003;9:4–37. Abstract | Full Text |
Full-Text PDF (363 KB)
|
CrossRef
3. 3Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2005;11:823–861. Abstract | Full Text |
Full-Text PDF (627 KB)
|
CrossRef
4. 4Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant. 2006;12:1–30. Full Text |
Full-Text PDF (67 KB)
|
CrossRef
5. 5Oliansky DM, Rizzo JD, Aplan PD, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2007;13:1–25. Full Text |
Full-Text PDF (44 KB)
|
CrossRef
6. 6Jones RJ, Nieto Y, Rizzo JD, et al. The evolution of the evidence-based review: evaluating the science enhances the art of medicine-statement of the Steering Committee for Evidence-Based Reviews of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2005;11:819–822. Full Text |
Full-Text PDF (69 KB)
|
CrossRef
7. 7Levi I, Grotto I, Yerushalmi R, et al. Meta-analysis of autologous bone marrow transplantation versus chemotherapy in adult patients with acute myeloid leukemia in first remission. Leuk Res. 2004;28:605–612. Abstract | Full Text |
Full-Text PDF (92 KB)
|
CrossRef
8. 8Nathan PC, Sung L, Crump M, et al. Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst. 2004;96:38–45.
CrossRef
9. 9Zittoun 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 Med. 1995;332:217–223. MEDLINE |
CrossRef
10. 10Reiffers J, Stoppa AM, Attal M, et al. Allogeneic vs autologous stem cell transplantation vs chemotherapy in patients with acute myeloid leukemia in first remission: the BGMT 87 study. Leukemia. 1996;10:1874–1882. MEDLINE 11. 11Harousseau 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). Blood. 1997;90:2978–2986. MEDLINE 12. 12Miggiano MC, Gherlinzoni F, Rosti G, et al. Autologous bone marrow transplantation in late first complete remission improves outcome in acute myelogenous leukemia. Leukemia. 1996;10:402–409. MEDLINE 13. 13Burnett 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. Lancet. 1998;351:700–708. Abstract | Full Text |
Full-Text PDF (112 KB)
|
CrossRef
14. 14Breems DA, Boogaerts MA, Dekker AW, et al. Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: a prospective randomized Dutch-Belgian Haemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol. 2005;128:59–65. MEDLINE |
CrossRef
15. 15Rohatiner AZ, Bassan R, Raimondi R, et al. High-dose treatment with autologous bone marrow support as consolidation of first remission in younger patients with acute myelogenous leukaemia. Ann Oncol. 2000;11:1007–1015. MEDLINE |
CrossRef
16. 16Cassileth 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 Med. 1998;339:1649–1656. MEDLINE |
CrossRef
17. 17Bassan R, Raimondi R, Lerede T, et al. Outcome assessment of age group-specific (+/− 50 years) post-remission consolidation with high-dose cytarabine or bone marrow autograft for adult acute myelogenous leukemia. Haematologica. 1998;83:627–635. MEDLINE 18. 18Yanada M, Matsuo K, Emi N, et al. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission. Cancer. 2005;103:1652–1658. 19. 19Cornelissen JJ, van Putten WLJ, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom?. Blood. 2007;109:3658–3666. MEDLINE |
CrossRef
20. 20Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002;118:385–400. MEDLINE |
CrossRef
21. 21Gale RP, Buchner T, Zhang MJ, et al. HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission. Leukemia. 1996;10:1687–1691. MEDLINE 22. 22Cassileth PA, Andersen JW, Bennett JM, et al. Escalating the intensity of post-remission therapy improves the outcome in acute myeloid leukemia: the ECOG experience. The Eastern Cooperative Oncology Group. Leukemia. 1992;6(Suppl 2):116–119. MEDLINE 23. 23Schiller GJ, Nimer SD, Territo MC, et al. Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. J Clin Oncol. 1992;10:41–46. 24. 24Willemze R, Fibbe WE, Kluin-Nelemans JC, et al. Bone marrow transplantation or chemotherapy as post-remission treatment of adult acute myelogenous leukemia. Ann Hematol. 1991;62:59–63. MEDLINE |
CrossRef
25. 25Archimbaud E, Thomas X, Michallet M, et al. Prospective genetically randomized comparison between intensive postinduction chemotherapy and bone marrow transplantation in adults with newly diagnosed acute myeloid leukemia. J Clin Oncol. 1994;12:262–267. 26. 26Mohty M, de Lavallade H, Ladaique P, et al. The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia. 2005;19:916–920. MEDLINE |
CrossRef
27. 27Gale RP, Horowitz MM, Rees JKH, et al. Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia. 1996;10:13–19. MEDLINE 28. 28Ringden O, Labopin M, Gorin NC, et al. Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia?. Br J Haematol. 2000;111:1130–1137. MEDLINE |
CrossRef
29. 29Lazarus HM, Perez WS, Klein JP, et al. Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research. Br J Haematol. 2006;132:755–759. MEDLINE |
CrossRef
30. 30Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMA AML-10 trial. Blood. 2003;102:1232–1240. MEDLINE |
CrossRef
31. 31Carella AM, Frassoni F, van Lint MT, et al. Autologous and allogeneic bone marrow transplantation in acute myeloid leukemia in first complete remission: an update of the Genoa experience with 159 patients. Ann Hematol. 1992;64:128–131. MEDLINE |
CrossRef
32. 32Singhal S, Henslee-Downey PJ, Powles R, et al. Haploidentical vs autologous hematopoietic stem cell transplantation in patients with acute leukemia beyond first remission. Bone Marrow Transplant. 2003;31:889–895. MEDLINE |
CrossRef
33. 33Mitus AJ, Miller KB, Schenkein DP, et al. Improved survival for patients with acute myelogenous leukemia. J Clin Oncol. 1995;13:560–569. 34. 34Cassileth PA, Andersen J, Lazarus HM, et al. Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol. 1993;11:314–319. 35. 35Lowenberg B, Verdonck LJ, Dekker AW, et al. Autologous bone marrow transplantation in acute myeloid leukemia in first remission: results of a Dutch prospective study. J Clin Oncol. 1990;8:287–294. 36. 36Sierra J, Brunet S, Granena A, et al. Feasibility and results of bone marrow transplantation after remission induction and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group for Bone Marrow Transplantation. J Clin Oncol. 1996;14:1353–1363. 37. 37Reiffers J, Labopin M, Sanz M, et al. Autologous blood cell vs marrow transplantation for acute myeloid leukemia in complete remission: an EBMT retrospective analysis. Bone Marrow Transplant. 2000;25:1115–1119. MEDLINE |
CrossRef
38. 38Sirohi B, Powles R, Kulkarni S, et al. Reassessing autotransplantation for acute myeloid leukaemia in first remission—a matched pair analysis of autologous marrow vs peripheral blood stem cells. Bone Marrow Transplant. 2004;33:1209–1214. MEDLINE |
CrossRef
39. 39Vey N, Bouabdallah R, Stoppa A, et al. Autologous stem cell transplantation for acute myelogenous leukemia in first complete remission: a 6-year follow-up study of 101 patients from a single institution. Bone Marrow Transplant. 2004;33:177–182. MEDLINE |
CrossRef
40. 40Miller CB, Rowlings PA, Zhang MJ, et al. The effect of graft purging with 4-hydroperoxycyclophosphamide in autologous bone marrow transplantation for acute myelogenous leukemia. Exp Hematol. 2001;29:1336–1346.
CrossRef
41. 41Gorin N, 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. Blood. 1990;75:1606–1614. MEDLINE 42. 42Chao NJ, Stein A, Long GD, et al. Busulfan/Etoposide-initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood. 1993;81:319–323. MEDLINE 43. 43McMillan AK, Goldstone AH, Linch DC, et al. High-dose chemotherapy and autologous bone marrow transplantation in acute myeloid leukemia. Blood. 1990;76:480–488. MEDLINE 44. 44Kim HJ, Min WS, Eom KS, et al. Autologous stem cell transplantation using modified TAM or combination of triple-alkylating agents conditioning regimens as one of the post-remission treatments in patients with adult acute myeloid leukemia in first complete remission. Bone Marrow Transplant. 2004;34:215–220. MEDLINE |
CrossRef
45. 45Mollee P, Gupta V, Song K, et al. Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia. Bone Marrow Transplant. 2004;33:1201–2108. MEDLINE |
CrossRef
46. 46Gorin N, Labopin M, Pichard P, et al. Feasibility and recent improvement of autologous stem cell transplantation for acute myelocytic leukaemia in patients over 60 years of age: importance of the source of stem cells. Br J Haematol. 2000;110:887–893. MEDLINE |
CrossRef
47. 47Gorin N, Labopin M, Laporte JP, et al. Importance of marrow dose on posttransplant outcome in acute leukemia: models derived from patients autografted with mafosfamide-purged marrow at a single institution. Experimental Hematology. 1999;27:1822–1830.
CrossRef
48. 48Linker CA, Ries CA, Damon LE, et al. Autologous bone marrow transplantation for acute myeloid leukemia using 4-hydroperoxycyclophosphamide-purged bone marrow and the busulfan/etoposide preparative regimen: a follow-up report. Bone Marrow Transplant. 1998;22:865–872. MEDLINE 49. 49Isnard F, Guiguet M, Laporte JP, et al. Improved efficiency of remission induction facilitates autologous BMT harvesting and improves overall survival in adults with AML: 108 patients treated at a single institution. Bone Marrow Transplant. 2001;27:1045–1052. MEDLINE |
CrossRef
50. 50Jourdan E, Rigal-Huguet F, Marit G, et al. One versus 2 high-dose cytarabine-based consolidation before autologous stem cell transplantation for young acute myeloblastic leukaemia patients in first complete remission. Br J Haematol. 2005;129:403–410. MEDLINE |
CrossRef
51. 51Meloni G, Vignetti M, Avvisati G, et al. BAVC regimen and autograft for acute myelogenous leukemia in second complete remission. Bone Marrow Transplant. 1996;18:693–698. MEDLINE 52. 52Stein AS, O'Donnell MR, Chai A, et al. In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. J Clin Oncol. 1996;14:2206–2216. 53. 53Linker CA, Ries CA, Damon LE, et al. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant. 2000;6:50–57. Abstract |
Full-Text PDF (87 KB)
|
CrossRef
54. 54Pavlovsky S, Fernandez I, Milone G, et al. Autologous peripheral blood progenitor cell transplantation mobilized with high-dose cytarabine in acute myeloid leukemia in first complete remission. Ann Oncol. 1998;9:151–157. MEDLINE |
CrossRef
55. 55Hegenbart U, Niederwieser D, Sandmaier BM, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24:444–453.
CrossRef
56. 56Sayer HG, Kroger M, Beyer J, et al. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant. 2003;31:1089–1095. MEDLINE |
CrossRef
57. 57Wagner JE, Thompson JS, Carter SL, et al. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial. Lancet. 2005;366:733–741. Abstract | Full Text |
Full-Text PDF (186 KB)
|
CrossRef
58. 58Hale 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. 1998;92:4581–4590. MEDLINE 59. 59Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78:2120–2130. MEDLINE 60. 60Garderet L, Labopin M, Gorin NC, et al. Patients with acute lymphoblastic leukaemia allografted with a matched unrelated donor may have a lower survival with a peripheral blood stem cell graft compared to bone marrow. Bone Marrow Transplant. 2003;31:23–29. MEDLINE |
CrossRef
61. 61Ringden O, Labopin M, Bacigalupo A, et al. Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia. J Clin Oncol. 2002;20:4655–4664.
CrossRef
62. 62Michallet M, Thomas X, Vernant JP, et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant. 2000;26:1157–1163. MEDLINE |
CrossRef
63. 63Stelljes M, Bornhauser M, Kroger M, et al. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood. 2005;106:3314–3321. MEDLINE |
CrossRef
64. 64Greinix HT, Nachbaur D, Krieger O, et al. Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry. Br J Haematol. 2002;117:914–923. MEDLINE |
CrossRef
65. 65Sierra J, Storer B, Hansen JA, et al. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplant. 2000;26:397–404. MEDLINE |
CrossRef
66. 66Cook G, Clark RE, Crawley C, et al. The outcome of sibling and unrelated donor allogeneic stem cell transplantation in adult patients with acute myeloid leukemia in first remission who were initially refractory to first induction chemotherapy. Biol Blood Marrow Transplant. 2006;12:293–300. Abstract | Full Text |
Full-Text PDF (206 KB)
|
CrossRef
67. 67Bunjes D. Re-labeled anti-CD66 monoclonal antibody in stem cell transplantation for patients with high-risk acute myeloid leukemia. Leuk Lymphoma. 2002;43:2125–2131. MEDLINE |
CrossRef
68. 68Rocha V, Labopin M, Gluckman E, et al. Relevance of bone marrow cell dose on allogeneic transplantation outcomes for patients with acute myeloid leukemia in first complete remission: results of a European survey. J Clin Oncol. 2002;20:4324–4330.
CrossRef
69. 69Tallman MS, Rowlings PA, Milone G, et al. Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood. 2000;96:1254–1258. MEDLINE 70. 70Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol. 1992;10:1723–1729. 71. 71Mehta J, Powles R, Sirohi B, et al. Does donor-recipient ABO incompatibility protect against relapse after allogeneic bone marrow transplantation in first remission acute myeloid leukemia?. Bone Marrow Transplant. 2002;29:853–859. MEDLINE |
CrossRef
72. 72Brown RA, Wolff SN, Fay JW, et al. High-dose etoposide, cyclophosphamide and total body irradiation with allogeneic bone marrow transplantation for resistant acute myeloid leukemia: a study by the North American Marrow Transplant Group. Leuk Lymphoma. 1996;22:271–277. MEDLINE |
CrossRef
73. 73Greinix HT, Keil F, Brugger SA, et al. Long-term leukemia-free survival after allogeneic marrow transplantation in patients with acute myelogenous leukemia. Ann Hematol. 1996;72:53–59. MEDLINE |
CrossRef
74. 74Zikos P, Van Lint MT, Frassoni F, et al. Low transplant mortality in allogeneic bone marrow transplantation for acute myeloid leukemia: a randomized study of low-dose cyclosporin versus low-dose cyclosporin and low-dose methotrexate. Blood. 1998;91:3503–3508. MEDLINE 75. 75Bibawi S, Abi-Said D, Fayad L, et al. Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced myelodysplastic syndrome and acute myelogenous leukemia. Am J Hematol. 2001;67:227–233. MEDLINE |
CrossRef
76. 76Frassoni F. Eradication of leukaemic marrow and prevention of leukaemia relapse with total body irradiation and bone marrow transplantation. Med Oncol Tumor Pharmacother. 1991;8:189–201. MEDLINE 77. 77Ringden O, Labopin M, Tura S, et al. A comparison of busulphan versus total body irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol. 1996;93:637–645. MEDLINE 78. 78Ball ED, Wilson J, Phelps V, et al. Autologous bone marrow transplantation for acute myeloid leukemia in remission or first relapse using monoclonal antibody-purged marrow: results of phase II studies with long-term follow-up. Bone Marrow Transplant. 2000;25:823–829. MEDLINE |
CrossRef
79. 79Blaise D, Maraninchi D, Archimbaud E, et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse. Blood. 1992;79:2578–2582. MEDLINE 80. 80Ringden O, Remberger M, Ruutu T, et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood. 1999;93:2196–2201. MEDLINE 81. 81Farag SS, Bolwell BJ, Elder PJ, et al. High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia. Bone Marrow Transplant. 2005;35:653–661. MEDLINE |
CrossRef
82. 82Resbeut M, Cowen D, Blaise D, et al. Fractionated or single-dose total body irradiation in 171 acute myeloblastic leukemias in first complete remission: is there a best choice? SFGM. Societe Francaise de Greffe de Moelle. Int J Radiat Oncol Biol Phys. 1995;31:509–517.
Full-Text PDF (963 KB)
|
CrossRef
83. 83Litzow MR, Perez WS, Klein JP, et al. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission. Br J Haematol. 2002;119:1115–1124. MEDLINE |
CrossRef
84. 84Bacigalupo A, Vitale V, Corvo R, et al. The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on the risk of relapse in patients with acute myeloid leukaemia undergoing allogeneic bone marrow transplantation. Br J Haematol. 2000;108:99–104. MEDLINE |
CrossRef
85. 85Schaap N, Schattenberg A, Bar B, et al. Outcome of transplantation for standard-risk leukaemia with grafts depleted of lymphocytes after conditioning with an intensified regimen. Br J Haematol. 1997;98:750–759. MEDLINE 86. 86Shimoni A, Hardan I, Shem-Tov N, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablabtive versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–328. MEDLINE |
CrossRef
87. 87Aoudjhane 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). Leukemia. 2005;19:2304–2312. MEDLINE 88. 88de Lima M, Anagnostopoulos A, Munsell M, et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104:865–872. MEDLINE |
CrossRef
89. 89Kroger N, Zabelina T, Sonnenberg S, et al. Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia. Bone Marrow Transplant. 2000;26:711–716. MEDLINE |
CrossRef
90. 90Collins RH, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433–444. 91. 91Eapen M, Giralt SA, Horowitz MM, et al. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant. 2004;34:721–727. MEDLINE |
CrossRef
92. 92De Witte T, Van Biezen A, Hermans J, et al. Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Blood. 1997;90:3853–3857. MEDLINE 93. 93Kroger N, Brand R, van Biezen A, et al. Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2006;37:183–189. MEDLINE |
CrossRef
94. 94Frassoni F, Labopin M, Gluckman E, et al. Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia. 1994;8:924–948. MEDLINE 95. 95Abdallah A, Egerer G, Weber-Nordt RM, et al. Long-term outcome in acute myelogenous leukemia autografted with mafosfamide-purged marrow in a single institution: adverse events and incidence of secondary myelodysplasia. Bone Marrow Transplant. 2002;30:15–22. MEDLINE |
CrossRef
96. 96Wadleigh M, Richardson PG, Zahrieh D, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003;102:1578–1582. MEDLINE |
CrossRef
97. 97Toor AA, Choo SY, Little JA. Bleeding risk and platelet transfusion refractoriness in patients with acute myelogenous leukemia who undergo autologous stem cell transplantation. Bone Marrow Transplant. 2000;26:315–320. MEDLINE |
CrossRef
98. 98Butt NM, Clark RE. Autografting as a risk factor for persisting iron overload in long-term survivors of acute myeloid leukaemia. Bone Marrow Transplant. 2003;32:909–913. MEDLINE |
CrossRef
99. 99Watson M, Buck G, Wheatley K, et al. Adverse impact of bone marrow transplantation on quality of life in acute myeloid leukaemia patients; analysis of the UK Medical Research Council AML 10 Trial. Eur J Cancer. 2004;40:971–978. Abstract | Full Text |
Full-Text PDF (239 KB)
|
CrossRef
100. 100Zittoun R, Suciu S, Watson M, et al. Quality of life in patients with acute myelogenous leukemia in prolonged first complete remission after bone marrow transplantation (allogeneic or autologous) or chemotherapy: a cross-sectional study of the EORTC-GIMEMA AML 8A trial. Bone Marrow Transplant. 1997;20:307–315. MEDLINE 101. 101Hsu C, Wang JD, Hwang JS, et al. Survival-weighted health profile for long-term survivors of acute myelogenous leukemia. Qual Life Res. 2003;12:503–517. MEDLINE |
CrossRef
102. 102Wellisch DK, Centeno J, Guzman J, et al. Bone marrow transplantation vs. high-dose cytorabine-based consolidation chemotherapy for acute myelogenous leukemia. A long-term follow-up study of quality-of-life measures of survivors. Psychosomatics. 1996;37:144–154. MEDLINE 103. 103Delaunay J, Vey N, Leblanc T, et al. Prognosis of in(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood. 2003;102:462–469. MEDLINE |
CrossRef
104. 104Farag SS, Archer KJ, Mrozek K, et al. Isolated trisomy of chromosomes 8, 11, 13 and 21 is an adverse prognostic factor in adults with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Int J Oncol. 2002;21:1041–1051. MEDLINE 105. 105Ferrant A, Labopin F, Frassoni F, et al. Karoytype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation Study. Blood. 1997;90:2931–2938. MEDLINE 106. 106Frassoni F, Labopin M, Powles R, et al. Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 2000;355:1393–1398. Abstract | Full Text |
Full-Text PDF (91 KB)
|
CrossRef
107. 107Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005;106:3658–3665. MEDLINE |
CrossRef
108. 108Jourdan E, Maraninchi D, Reiffers J, et al. Early allogeneic transplantation favorably influences the outcome of adult patients suffering from acute myeloid leukemia. Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant. 1997;19:875–881. MEDLINE 109. 109Kebriaei 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. 2005;35:965–970. MEDLINE |
CrossRef
110. 110Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): A Cancer and Leukemia Group B Study. J Clin Oncol. 2005;23:5705–5717.
CrossRef
111. 111Ogawa H, Ikegame K, Kawakami M, et al. Impact of cytogenetics on outcome of stem cell transplantation for acute myeloid leukemia in first remission: a large-scale retrospective analysis of data from the Japan Society for Hematopoietic Cell Transplantation. Int J Hematol. 2004;79:495–500. MEDLINE |
CrossRef
112. 112Schoch C, Schnittger S, Klaus M, et al. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood. 2003;102:2395–2402. MEDLINE |
CrossRef
113. 113Wahlin A, Markevarn B, Golovleva I, et al. Improved outcome in adult acute myeloid leukemia is almost entirely restricted to young patients and associated with stem cell transplantation. Eur J Haematol. 2002;68:54–63. MEDLINE |
CrossRef
114. 114Wheatley K, Burnett A, Goldstone A, et al. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. Br J Haematol. 1999;107:69–79. MEDLINE |
CrossRef
115. 115Cahn JY, Labopin M, Mandelli F, et al. Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: a retrospective analysis of the European Bone Marrow Transplant Group. Blood. 1995;85:575–579. MEDLINE 116. 116Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–4083. MEDLINE 117. 117Fung HC, Stein A, Slovak M, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome. Biol Bone Marrow Transplant. 2003;9:766–771. 118. 118Lee KW, Choi IS, Roh EY, et al. Adult patients with t(8;21) acute myeloid leukemia had no superior treatment outcome to those without t(8;21): a single institution's experience. Ann Hematol. 2004;83:218–224. 119. 119Schlenk RF, Benner A, Hartmann F, et al. Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia. 2003;17:1521–1528. MEDLINE |
CrossRef
120. 120Nguyen S, Leblanc T, Fenaux P, et al. A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup. Blood. 2002;99:3517–3523. MEDLINE |
CrossRef
121. 121Wong R, Shahjahan M, Wang X, et al. Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant. 2005;11:108–114. Full Text |
Full-Text PDF (44 KB)
|
CrossRef
122. 122Mehta J, Powles R, Sirohi B, et al. Impact of cytogenetics on the outcome of autotransplantation for acute myeloid leukemia in first remission: is the benefit of intensive pretransplant therapy limited to patients with good karyotypes?. Bone Marrow Transplant. 2003;32:157–164. MEDLINE |
CrossRef
123. 123Slovak ML, Kopecky KJ, Wolman SR, et al. Cytogenetic correlation with disease status and treatment outcome in advanced stage leukemia post bone marrow transplantation: a Southwest Oncology Group study (SWOG-8612). Leukemia Res. 1995;19:381–388. 124. 124Gale RP, Horowitz MM, Weiner RS, et al. Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission. Bone Marrow Transplant. 1995;16:203–208. MEDLINE 125. 125Baldus CD, Tanner SM, Ruppert AS, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood. 2003;102:1613–1618. MEDLINE |
CrossRef
126. 126Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740–3746. MEDLINE |
CrossRef
127. 127Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372–4380. MEDLINE |
CrossRef
128. 128Frohling S, Schlenk RF, Stolze I, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: Prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22:624–633.
CrossRef
129. 129Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–1759. MEDLINE |
CrossRef
130. 130Marcucci G, Baldus CD, Ruppert AS, et al. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B Study. J Clin Oncol. 2005;23:9234–9242.
CrossRef
131. 131Rombouts EJC, Pavic B, Lowenberg B, et al. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood. 2004;104:550–557. MEDLINE |
CrossRef
132. 132Rombouts WJC, Lowenberg B, Van Putten WLJ, et al. Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myeloid leukemia of intermediate risk: Impact of internal tandem duplication in the Flt3 gene. Leukemia. 2001;15:1046–1053. MEDLINE |
CrossRef
133. 133Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733–3739. MEDLINE |
CrossRef
134. 134Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107:4011–4020. MEDLINE |
CrossRef
135. 135Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335. MEDLINE |
CrossRef
136. 136Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: A Cancer and Leukemia Group B Study. Cancer Res. 2001;61:7233–7239. MEDLINE 137. 137Casanovas RO, Slimane FK, Garand R, et al. Immunological classification of acute myeloblastic leukemias: relevance to patient outcome. Leukemia. 2003;17:515–527. MEDLINE |
CrossRef
138. 138Perea G, Domingo A, Villamor N, et al. Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients. Leukemia Res. 2005;29:1109–1116. 139. 139Raspadori D, Damiani D, Lenoci M, et al. CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia. 2001;15:1161–1164. MEDLINE |
CrossRef
140. 140Repp R, Schaekel U, Helm G, et al. Immunophenotyping is an independent factor for risk stratification in AML. Cytometry Part B: Clin Cytometry. 2003;53B:11–19. 141. 141Spoo AC, Lubbert M, Wierda WG, et al. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood. 2007;109:786–791. MEDLINE |
CrossRef
142. 142Schlenk RF, Corbacioglu A, Krauter J, et al. Gene mutations as predictive markers for postremission therapy in younger adults with normal karyotype AML. ASH Ann Meet Abstr. 2006;108:4. 143. 143Schaich M, Fuessel M, Bornhauser M, et al. Rapid risk-profiling including fast donor search within a multi-center trial allows for early allogeneic stem cell transplantation during aplasia in patients with high-risk acute myeloid leukemia. Blood. 2004;104:2767. MEDLINE |
CrossRef
144. 144Davies SM RN, Weisdorf DJ. Feasibility and timing of unrelated donor identification for patients with ALL. Bone Marrow Transplant. 1996;17:734-740. 1 Roswell Park Cancer Institute, Buffalo, New York 2 Fred Hutchinson Cancer Institute, Seattle, Washington 3 University of Miami Sylvester Cancer Center, Miami, Florida 4 University of Toronto, Toronto, ON, Canada 5 Excellus Blue Cross/Blue Shield, Rochester, New York 6 M.D. Anderson Cancer Center, Houston, Texas 7 BMT Infonet, Chicago, Illinois 8 Dana Farber Cancer Institute, Boston, Massachusetts 9 Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois  Correspondence and reprint requests: Theresa Hahn, PhD, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.
Major funding for this study was provided by the National Marrow Donor Program. PII: S1083-8791(07)00571-X doi:10.1016/j.bbmt.2007.11.002 © 2008 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. | |
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