Although allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor (MSD) is a potentially curative post-remission treatment for adults with acute myeloid leukemia (AML) in their first CR, transplant-related morbidity and mortality remains a major drawback. We retrospectively compared the outcomes of patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT; n=375) with those who underwent allogeneic bone marrow transplantation (allo-BMT; n=521) and allo-PBSCT (n=380) from MSDs for adults with AML/CR1, in which propensity score models were used to adjust selection biases among patients, primary physicians and institutions to overcome ambiguity in the patients’ background information. Both the multivariate analysis and propensity score models indicated that the leukemia-free survival rate of auto-PBSCT was not significantly different from that of allo-BMT (hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.92 to 1.66; P=0.16) and allo-PBSCT (HR, 1.13; 95% CI, 0.85–1.51; P=0.40). The current results suggest that auto-PBSCT remains a promising alternative treatment for patients with AML/CR1 in the absence of an available MSD.
Despite a CR rate as high as 70–80% for adult patients with AML, 60% of the patients in their first CR (CR1) relapsed on conventional post-remission chemotherapy, such as high-dose cytarabine.1, 2, 3, 4 Allogeneic (allo) hematopoietic stem cell transplantation (SCT) with bone marrow (BM) or peripheral blood (PB) from an HLA-matched sibling donor (MSD) is a potentially curative post-remission treatment for patients with AML/CR1. However, transplant-related morbidity and mortality due to regimen-related toxicities, severe infections and GvHD are drawbacks of allo-SCT, and there is an increased risk and severity of these adverse effects associated with using an alternative donor graft in the absence of a MSD. Autologous (auto) SCT using BM or PB is also effective for patients with AML/CR1, allowing for the intensification of chemotherapy with the expectation of a lower rate of relapse than conventional chemotherapy, and offering the advantage of the availability of a transplant graft, unlike that of allo-SCT. The major obstacle associated with auto-SCT is a higher rate of relapse because of the lack of a GvL effect by allogeneic cells, although this can be offset by a lower transplant-related mortality (TRM) after auto-SCT.1, 5, 6, 7, 8, 9, 10, 11, 12
The aim of this study was to retrospectively compare the outcomes of autologous peripheral blood stem cell transplantation (auto-PBSCT) with those of allogeneic bone marrow transplantation (allo-BMT) and allo-PBSCT from MSD for adults with AML/CR1 using the national registry-based data of the Transplant Registry Unified Management Program (TRUMP) in Japan.
Patients and methods
The data for 6884 Japanese patients with de novo AML aged ⩾16 years at the time of the transplant who underwent SCT were obtained from the TRUMP13 in Japan (Supplementary Figure 1). Inclusion was based on the following criteria: CR1 at transplant, first transplant with auto-PBSCT or MSD allo-BMT or MSD allo-PBSCT. The selection of these treatments was based on the attending physician's discretion. Patients with acute promyelocytic leukemia, AML with myelodysplasia-related changes, secondary AML from myelodysplastic syndrome, myeloid sarcoma or a previous history of malignancy, and those who received T-cell-depleted or cord blood grafts, were excluded. The study was designed by the Adult AML Working Group of the JSHCT (Japan Society for Hematopoietic Cell Transplantation), and was approved by the TRUMP Data Management Committee of the JSHCT and the Institutional Review Board of Aichi Medical University School of Medicine, where this study was organized.
End points and definitions
The primary end point was the 5-year leukemia-free survival (LFS). The secondary end points were the 5-year overall survival (OS), relapse and TRM. The classification of conditioning regimens (myeloablative vs reduced-intensity) was based on the report by the CIBMTR (Center for International Blood Marrow Transplant Research).14 Cytogenetic subgroups were classified according to the National Comprehensive Cancer Network Guidelines.15 The OS rate was defined as the number of days from transplantation to death from any cause. Relapse was defined as clinical or hematological recurrence after transplantation. TRM was defined as death without relapse. The LFS was defined as survival without disease relapse. Any patients who were alive at the last follow-up date were censored. The data regarding the causative microbes of infections, postmortem changes in the causes of death and supportive care, including prophylaxis for infections and therapy for GvHD given on an institutional basis, were not available for this cohort.
All statistical analyses were performed using the EZR software package (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0),16 as described in a previous report.17 The variables according to univariate and multivariate analyses included the recipient’s age at the time of transplantation, sex, initial performance status (PS), days from diagnosis to SCT, disease characteristics (the FAB subtypes, WBC count at diagnosis, myeloperoxidase (MPO) positivity of blasts, cytogenetic risk groups,15 presence of extramedullary disease, the number of chemotherapy cycles required to achieve CR) and the transplant characteristics (myeloablative conditioning (MAC) vs reduced-intensity and non-MCA (RIC/NMA),18 tacrolimus vs cyclosporine and the year of transplantation). The cutoff points for the continuous variables were determined according to the Japan Adult Leukemia Study Group scoring system, showing a >20 000/μL initial WBC count as unfavorable prognostic factor,4 and the National Comprehensive Cancer Network guidelines,15 and the median was used for all other data. The χ2-test and the Wilcoxon rank sum test were used to compare the data between two groups, and the Kruskal–Wallis test was also used to compare the data among three groups. The probability of LFS and OS was calculated using the Kaplan–Meier method and was compared using the log-rank test. The probabilities of TRM and relapse were compared using the Gray test19 and were analyzed using a cumulative incidence analysis,20 whereas considering relapse and death without disease relapse as respective competing risks. A multivariate analysis was then performed using the covariates that were identified as significant (P<0.1) according to a univariate analysis (Supplementary Table 1). Cox proportional models and Fine-Gray competing risk regression models were used to evaluate the hazard ratio (HR) associated with the stem cell source. The inverse probability of treatment weighting (IPTW) as the propensity score method21, 22, 23 using the same variables was performed to reduce the effects of selection biases in the stem cell source. For both the univariate and multivariate analyses, P-values were two-sided and statistical significance was considered to exist at values of P⩽0.05.
A total 1276 patients met the criteria for study inclusion, 375 of whom underwent auto-PBSCT, 521 underwent allo-BMT and 380 underwent allo-PBSCT (Table 1). With a median follow-up of the respective groups of 1568 (8–3650), 1212 (0–3650) and 942 (0–3650) days among survivors, 117 (32%), 129 (25%) and 100 (27%) patients had relapsed, and 131 (35%), 191 (37%) and 169 (45%) patients had died, respectively. The auto-PBSCT group included more patients who were older, female, had a worse PS, were M2 subtype-predominant, had reduced MPO positivity, favorable risk cytogenetics, had been less frequently treated with two or more chemotherapy cycles to attain CR, and had a longer duration from diagnosis to transplant than the allo-BMT and allo-PBSCT groups. The allo-PBSCT group comprised transplants in more recent years of the study compared with the auto-PBSCT group.
Transplant outcomes according to the stem cell source
The transplant outcomes according to the stem cell source are shown in Figure 1 and Table 2. The 5-year LFS after transplantation was 60% (95% confidence interval (CI), 54–65%; reference) in the auto-PBSCT group, 59% (95% CI, 54–63%; P=0.759) in the allo-BMT group and 51% (95% CI, 46–57%; P=0.145) in the allo-PBSCT group (Figure 1a). The 5-year OS after transplantation was 65% (95% CI, 59–70%) in the auto-PBSCT group and 62% (95% CI, 57–66%; P=0.422) in the allo-BMT group, and was significantly lower in the allo-PBSCT group (55%; 95% CI, 49–60%; P=0.004) (Figure 1b). The 5-year cumulative incidence of relapse after transplantation was 33% (95% CI, 28–38%) in the auto-PBSCT group, 26% (95% CI, 22–30%; P=0.079) in the allo-BMT group and 28% (95% CI, 24–33%; P=0.226) in the allo-PBSCT group (Figure 1c), whereas the 5-year cumulative incidence of TRM was significantly lower in the auto-PBSCT group (8%; 95% CI, 5–11%) compared with that in the allo-BMT group (15%; 95% CI, 12–18%; P=0.016) and that in the allo-PBSCT group (21%; 95% CI, 16–25%; P<0.001) (Figure 1d).
In the multivariate models adjusted for the clinical factors, the LFS did not differ significantly between the auto-PBSCT and allo-BMT groups (HR, 1.27; 95% CI, 0.94–1.72; P=0.114) or between the auto-PBSCT and allo-PBSCT groups (HR, 1.09; 95% CI, 0.80–1.47; P=0.559), which was also true of the OS for auto-PBSCT compared with the allo-BMT (HR, 1.02; 95% CI, 0.74–1.41; P=0.886) and with allo-PBSCT (HR, 0.86; 95% CI, 0.62–1.20; P=0.383) (Table 2). In multivariate models, auto-PBSCT was associated with a significantly higher incidence of relapse compared with allo-BMT (HR, 1.83; 95% CI, 1.29–2.58; P<0.001) and allo-PBSCT (HR, 2.11; 95% CI, 1.46–3.05; P<0.001), which was offset by the significantly lower TRM compared with allo-BMT (HR, 0.53; 95% CI, 0.29–0.96; P=0.036) and allo-PBSCT (HR, 0.29; 95% CI, 0.16–0.53; P<0.001). When an adjustment analysis based on IPTW using the propensity score was performed to reduce the selection biases of patients, the effects of auto-PB on the LFS and OS were not significantly different from those of allo-BMT and allo-PBSCT.
Although it is outside the scope of the present study, when the allo-BMT and allo-PBSCT groups were compared by the same multivariate models, no significant difference was found in either the LFS or OS, irrespective of whether IPTW adjustment was used (Supplementary Table 2).
Figure 2 shows a forest plot comparing the relative effects of auto-PBSCT with allo-BMT and allo-PBSCT on the LFS in each subgroup. Of note, the patients with a PS of 2–4 benefited from auto-PBSCT more than allo-BMT in terms of the LFS (P for interaction=0.015). Conversely, auto-PBSCT was associated with a worse LFS compared with allo-BMT in patients with a >20 000/μL initial WBC count (P for interaction=0.020). In all other groups of patients, such as those of an older age, with a high-risk FAB subtype, extramedullary disease or who required two or more chemotherapy cycles to attain CR, auto-PBSCT did not show a significantly different LFS to allo-BMT (Figure 2a). Auto-PBSCT showed no inferior effects on the LFS compared with allo-PBSCT in any subgroups, and instead, auto-PBSCT exhibited a better LFS than allo-PBSCT in patients with an initial WBC count ⩽20 000/μL (P for interaction=0.026) or >50% MPO-positive blasts (P for interaction=0.033) (Figure 2b). The CD34-positive cell count did not significantly influence LFS in patients who received auto-PBSCT (Supplementary Figure 2). The conditioning regimen (MAC vs RIC/NMA) did not significantly influence LFS in patients who received allo-BMT or allo-PBSCT (Supplementary Figure 3).
The main disadvantages of auto-PBSCT are the possibility of greater contamination of leukemic cells in the stem cell product, as suggested by a study from the European Group Blood and Marrow Transplantation,24 and the absence of a GvL effect, which is considered to lead to a lower curative potential compared with allo-SCT. Contrary to expectation, the current nation-wide study showed that the 5-year LFS after auto-PBSCT for adult patients with AML/CR1 was as high as 60%, which was not significantly different from those after allo-BMT and allo-PBSCT using MSD. These findings were confirmed by a multivariate analysis and IPTW analyses after adjusting for any patient selection bias using the propensity score models. Auto-PBSCT was associated with a 5-year relapse rate of 33%, which was compensated for by a 5-year TRM of 8%, thus suggesting that, in addition to allo-BMT/PBSCT from a MSD, auto-PBSCT can also be a curative option as post-remission treatment in many adult patients with AML/CR1.
These findings are in contrast to those of previous non-randomized prospective trials conducted in the 1990 s,1, 11, 12, 25 in which auto-SCT offered a lower survival benefit to patients with AML/CR1 than allo-SCT. One potential explanation for these differences is that the previous studies primarily used auto-BM grafts rather than auto-PB grafts for transplantation, resulting in a TRM of 10–20%. However, the stem cell source has since shifted from BM to PB for both auto- and allo-SCT. Engraftment using a PB graft may be beneficial for preventing fatal infections, resulting in TRM in as low as 5–10% of patients after auto-PBSCT,9, 26, 27 as observed in the present study. However, these beneficial effects may be counterbalanced by the increased risk and severity of GVHD after allo-PBSCT, as observed in previous studies.23, 28, 29, 30 This may result in a comparable survival outcome among auto-PBSCT, allo-BMT and allo-PBSCT.
This hypothesis may be supported by a recent report5 in which auto-PBSCT for AML/CR1 showed a 5-year TRM of 8%. The preferred use of BM in the past may also account for the lack of a clear survival advantage of auto-SCT for AML/CR1 over intensive chemotherapy in trials conducted until the early 2000 s.1, 31, 32, 33 Indeed, in recent reports,34, 35, 36, 37 auto-PBSCT showed a better long-term LFS compared with chemotherapy in patients with AML/CR1 having favorable or intermediate cytogenetics.
The subgroup analyses showed that the LFS rate after auto-PBSCT was not inferior to the rates after allo-BMT or allo-PBSCT, with the exception of allo-BMT in patients with an initial WBC count of >20 000/μL. Furthermore, the LFS after auto-PBSCT was found to be superior to that after allo-BMT in patients with a PS of 2–4 and the LFS after allo-PBSCT in patients with an initial WBC count of ⩽20 000/μL or >50% MPO-positive blasts. These findings may differ from those in previous studies from the Haemato Oncology Foundation for Adults in the Netherlands and CIBMTR,5, 35 in which a similar OS, but worse LFS, was observed between auto-SCT and allo-BMT/PBSCT using patient cohorts predominantly comprising patients with AML/CR1 with intermediate-risk cytogenetics. The risk cytogenetics category of AML blasts is a key prognostic factor that determines the post-remission therapy.15, 38 The subgroup analyses showed that the LFS rates after auto-PBSCT and allo-BMT were not significantly different in patients with favorable or intermediate-risk cytogenetics, but were significantly different in patients with poor-risk cytogenetics. A difference in the LFS was not observed between auto-PBSCT and allo-PBSCT in any of the cytogenetic risk categories. Nevertheless, the preferred post-remission treatment for AML/CR1 as indicated by the cytogenetic risk category might change over time or vary among institutions, potentially due to institutional experience, and inherent limitations in the patient selection are suggested of previously reported comparisons between auto-SCT and allo-SCT. We herein attempted to overcome such selection biases by using risk stratification IPTW models with the propensity scores, in addition to the conventional multivariate analysis, to reduce the effects of preferences among institutions in selecting a stem cell source. A propensity scoring system and IPTW model was devised to estimate the effects of treatments by comparing the outcomes of those subjects who were not randomly assigned to experimental or control groups in an observational study, and thus has the benefit of overcoming such selection biases through risk stratification to adjust for preferences among institutions.21, 22, 23 However, the propensity score model used in the present study does not take into account information regarding donor availability, depth of remission or the molecular aberrations of AML because these data were unavailable in the present cohort. This is one of limitations of the present study. For the purpose of overcoming such limitations and strengthening our conclusions, we added an analysis using the receiver operating characteristic curve to determine the extent to which the variables used in the IPTW analysis reflect the LFS, the primary end point (Supplementary Figure 4). The area under the curve surpassed 0.7 for both comparisons of auto-PB vs allo-BM and auto-PB vs allo-PB, indicating that the variables used in the IPTW analysis adequately reflected the LFS in the present study with minimal effects of other factors, including donor availability, depth of remission and the molecular aberrations of AML. The IPTW model can only be applied to statistics using two-valued variables, such as the survival and death, and does not accommodate for an analysis of competing risks such as the relapse rate and TRM. First, the effects of the conditioning regimen used for auto-PBSCT could also account for the favorable LFS, considering that 274 (76%) patients who received a conditioning regimen containing high-dose cytarabine followed by auto-PBSCT showed a 5-year LFS of 62%, which showed a slight improvement compared with the 5-year LFS of 54% (P=0.131) in the remaining 86 (24%) patients with auto-PBSCT. Evidence can also be observed in previous reports showing a favorable long-term LFS of 61–71% after auto-SCT using a high-dose cytarabine-containing regimen.39, 40 Second, the use of consolidation chemotherapy prior to auto-PBSCT could have positively affected the outcome. Although this possibility is highly speculative due to the lack of information on the type and cycle number of consolidation chemotherapy, a longer duration from the diagnosis to transplant in the present auto-PBSCT group compared with those in the allo-BMT and allo-PBSCT groups may imply that patients with auto-PBSCT received more cycles of consolidation chemotherapy prior to transplantation. Although the possibility of patient selection biases remains unclear, this hypothesis may be supported by previous studies40, 41, 42 in which two or more consolidation chemotherapy cycles prior to transplantation was the most favorable factor for the LFS and relapse after auto-SCT, but not after allo-SCT. This is in addition to the current finding that a longer duration from the diagnosis to transplant showed a trend toward improving the LFS after auto-PBSCT.
The use of auto-PBSCT as a post-remission treatment for AML/CR1 may compromise the safety and effectiveness of subsequent allo-SCT in patients who relapse and are candidates for this procedure.43, 44 However, unlike the case of salvage by MAC allo-SCT,44, 45 RIC/NMA allo-SCT using a MSD or alternative donors has been suggested to be effective in rescuing patients with AML who relapse following auto-ACT.35, 46, 47 In a study published by the CIBMTR,46 unrelated donor allo-SCT using RIC/NMA after auto-SCT relapse resulted in a 5-year OS of 37% and a 1-year TRM of 28%, contrary to the 5-year OS of 19% and 1-year TRM of 48% following that with MAC. This suggests that the failure of previous auto-SCT could be overcome by allo-SCT using RIC/NMA. One important fact related to this issue is that the treatment success for AML relapse after initial allo-SCT is limited, with a 3-year OS of 10–20% in previous studies,17, 48, 49 indicating that the counter-measure used for post-transplant relapse remains critical, regardless of whether an auto-graft had been used for initial transplantation.
A previous study50 showed that AML patients with a PS of 2–4, comparable with a Karnofsky PS of 70 or lower, had a lower probability of achieving an event-free survival after allo-SCT mainly due to a higher TRM compared with those with a PS of 0–1 (event-free survival 9% vs 33%; P<0.0001), and were thus considered to be poor candidates for allo-SCT. Auto-PBSCT may be available for such patients ineligible for allo-SCT, as suggested in the present study. As another aspect of the present findings, allo-PBSCT could be considered to be overtreatment for patients with an initial WBC ⩽20 000/μL or >50% MPO-positive blasts as they are expected to have a low relapse rate,4 and auto-PBSCT may be prioritized over allo-PBSCT for the long-term LFS.
The nature of a retrospective, registry-based analysis leads to several limitations. First, there was no available information regarding the chemotherapeutic agents used in induction and consolidation chemotherapy, the number of cycles of consolidation chemotherapy, the quantification of minimal-residual disease (MRD) or the molecular markers. Previous studies have demonstrated that MRD at the time of auto- or allo-SCT is a significant, independent predictor of subsequent relapse and a shorter survival for AML/CR1.51, 52, 53, 54, 55, 56, 57 The presence of adverse-risk molecular markers, such as internal tandem duplications of the fms-related tyrosine kinase 3 gene (flt3-ITD), could compromise the outcome of auto-SCT, although the predictive values of the molecular markers with regard to the outcome of auto- and allo-SCT have varied among studies and thus remain unclear.58, 59, 60, 61, 62 Accordingly, there is a possibility that in the present cohort auto-PBSCT was not favored for high-risk patients with AML/CR1 due to the presence of MRD and molecular markers, leading to the artificial appearance of an improved outcome after auto-PBSCT. However, the present findings in which the LFS of auto-PBSCT was not significantly different from that of allo-BMT and allo-PBSCT, regardless of the year of the transplant, in the subgroup analysis may discount this possibility, as the detection of MRD and molecular markers for leukemic cells became popular as predictors of the prognosis in the early 2000 s in Japan. The collection of data on the MRD and gene mutation profiles is outside the scope of the present study, and further studies are warranted to determine the importance of these factors. Another limitation is that the present study did not adjust for multiple testing because the analyses were conducted in an exploratory context; thus, the interpretation of the analyses in the subgroups should be carefully considered.
The present data suggest that in the absence of an available MSD, auto-PBSCT remains a promising alternative for AML patients. The present findings may also raise questions about whether, in the absence of a MSD, allo-BMT or allo-PBSCT from alternative donors should be prioritized over auto-PBSCT. However, care should be taken before drawing any conclusions because validation studies, including the collection of information regarding previous consolidation chemotherapy, the MRD status at transplant and molecular markers, are required to confirm the efficacy of auto-PBSCT for AML/CR1. Further studies are also warranted to ascertain whether the findings of this study can be extended to auto-PBSCT vs alternative donor transplantation.
Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E 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.
Stone RM . Acute myeloid leukemia in first remission: to choose transplantation or not? J Clin Oncol 2013; 31: 1262–1266.
Burnett AK, Goldstone A, Hills RK, Milligan D, Prentice A, Yin J et al. Curabilityof patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol 2013; 31: 1293–1301.
Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood 2011; 117: 2358–2365.
Keating A, DaSilva G, Pérez WS, Gupta V, Cutler CS, Ballen KK et al. Autologous blood cell transplantation versus HLA-identical sibling transplantation for acute myeloid leukemia in first complete remission: a registry study from the Center for International Blood and Marrow Transplantation Research. Haematologica 2013; 98: 185–192.
de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G et al. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial. Haematologica 2010; 95: 1754–1761.
Nakasone H, Izutsu K, Wakita S, Yamaguchi H, Muramatsu-Kida M, Usuki K . Autologous stem cell transplantation with PCR-negative graft would be associated with a favorable outcome in core-binding factor acute myeloid leukemia. Biol Blood Marrow Transplant 2008; 14: 1262–1269.
Loh YSM, Koh LP, Tai BC, Hwang WYK, Linn YC, Goh YT et al. Long-term follow-up of Asian patients younger than 46 years with acute myeloid leukemia in first complete remission: comparison of allogeneic vs. autologous hematopoietic stem cell transplantation. Leuk Lymphoma 2007; 48: 72–79.
Herr AL, Labopin M, Blaise D, Milpied N, Potter M, Michallet M et al. HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia. Leukemia 2006; 21: 129–135.
Yoshimoto G, Nagafuji K, Miyamoto T, Kinukawa N, Takase K, Eto T et al. FLT3 mutations in normal karyotype acute myeloid leukemia in first complete remission treated with autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2005; 36: 977–983.
Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B 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/GIMEMAAML-10 trial. Blood 2003; 102: 1232–1240.
Reiffers J, Stoppa AM, Attal M, Michallet M, Marit G, Blaise D 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.
Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 2007; 86: 269–274.
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15: 367–369.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology Amlv. Available from http://williams.medicine.wisc.edu/aml.pdf. Accessed 1 December 2014.
Kanda Y . Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.
Takami A, Yano S, Yokoyama H, Kuwatsuka Y, Yamaguchi T, Kanda Y et al. Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2014; 20: 1785–1790.
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15: 367–369.
Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.
Scrucca L, Santucci A, Aversa F . Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 2007; 40: 381–387.
Austin PC . The performance of different propensity score methods for estimating marginal hazard ratios. Stat Med 2013; 32: 2837–2849.
Joffe MM, Rosenbaum PR . Invited commentary: propensity scores. Am J Epidemiol 1999; 150: 327–333.
Nagafuji K, Matsuo K, Teshima T, Mori S, Sakamaki H, Hidaka M et al. Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia: a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry. Int J Hematol 2010; 91: 855–864.
Gorin NC, Labopin M, Blaise D, Reiffers J, Meloni G, Michallet M et al. Higher incidence of relapse with peripheral blood rather than marrow as a source of stem cells in adults with acute myelocytic leukemia autografted during the first remission. J Clin Oncol 2009; 27: 3987–3993.
Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L 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.
Linker CA, Ries CA, Damon LE, Sayre P, Navarro W, Rugo HS et al. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant 2000; 6: 50–57.
Vellenga E, van Putten WL, Boogaerts MA, Daenen SM, Verhoef GE, Hagenbeek A et al. Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia? Bone Marrow Transplant 1999; 23: 1279–1282.
Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367: 1487–1496.
Holtick U, Albrecht M, Chemnitz JM, Theurich S, Shimabukuro-Vornhagen A, Skoetz N et al. Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults-a systematic review and meta-analysis. Crit Rev Oncol Hematol 2014; 94: 179–188.
Holtick U, Albrecht M, Chemnitz JM, Theurich S, Skoetz N, Scheid C et al. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2014; 4: Cd010189.
Harousseau JL, Cahn JY, Pignon B, Witz F, Milpied N, Delain M 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.
Levi I, Grotto I, Yerushalmi R, Ben-Bassat I, Shpilberg O . 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.
Nathan PC, Sung L, Crump M, Beyene J . Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst 2004; 96: 38–45.
Usuki K, Kurosawa S, Uchida N, Yakushiji K, Waki F, Matsuishi E et al. Comparison of autologous hematopoietic cell transplantation and chemotherapy as postremission treatment in non-M3 acute myeloid leukemia in first complete remission. Clin Lymphoma Myeloma Leuk 2012; 12: 444–451.
Cornelissen JJ, Versluis J, Passweg JR, van Putten WL, Manz MG, Maertens J et al. Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years. Leukemia 2014; 29: 1041–1050.
Fernandez HF, Sun Z, Litzow MR, Luger SM, Paietta EM, Racevskis J et al. Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin. Blood 2011; 117: 5306–5313.
Pfirrmann M, Ehninger G, Thiede C, Bornhauser M, Kramer M, Rollig C et al. Prediction of post-remission survival in acute myeloid leukaemia: a post-hoc analysis of the AML96 trial. Lancet Oncol 2012; 13: 207–214.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A 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.
Stein AS, O'Donnell MR, Chai A, Schmidt GM, Nademanee A, Parker PM 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.
Gondo H, Harada M, Miyamoto T, Takenaka K, Tanimoto K, Mizuno S et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant 1997; 20: 821–826.
Mehta J, Powles R, Singhal S, Horton C, Tait D, Milan S et al. Autologous bone marrow transplantation for acute myeloid leukemia in first remission: identification of modifiable prognostic factors. Bone Marrow Transplant 1995; 16: 499–506.
Tallman MS, Rowlings PA, Milone G, Zhang M-J, Perez WS, Weisdorf D 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.
Breems DA, Van Putten WLJ, Huijgens PC, Ossenkoppele GJ, Verhoef GEG, Verdonck LF et al. Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse. J Clin Oncol 2005; 23: 1969–1978.
Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG 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.
Breems DA, Boogaerts MA, Dekker AW, Van Putten WL, Sonneveld P, Huijgens PC 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.
Foran JM, Pavletic SZ, Logan BR, Agovi-Johnson MA, Perez WS, Bolwell BJ et al. Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research. Biol Blood Marrow Transplant 2013; 19: 1102–1108.
Gorin NC, Labopin M, Piemontese S, Arcese W, Santarone S, Huang H et al. T replete haploidentical versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis. Haematologica 2015; 100: 558–564.
Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25: 4938–4945.
Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012; 119: 1599–1606.
Sayer HG, Kroger M, Beyer J, Kiehl M, Klein SA, Schaefer-Eckart K 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.
Schlenk RF . Post-remission therapy for acute myeloid leukemia. Haematologica 2014; 99: 1663–1670.
Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 2013; 122: 1813–1821.
Buckley SA, Appelbaum FR, Walter RB . Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia. Bone Marrow Transplant 2013; 48: 630–641.
Venditti A, Maurillo L, Buccisano F, Del Poeta G, Mazzone C, Tamburini A et al. Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation. Leukemia 2003; 17: 2178–2182.
Buccisano F, Maurillo L, Del Poeta G, Gattei V, Amadori S, Venditti A . Optimal post-remission therapy for flow-cytometry minimal residual disease positive adult patients with acute myeloid leukemia. Haematologica 2006; 91: ELT14 author reply ELT15.
Maurillo L, Buccisano F, Del Principe MI, Del Poeta G, Spagnoli A, Panetta P et al. Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia. J Clin Oncol 2008; 26: 4944–4951.
Campana D, Leung W . Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol 2013; 162: 147–161.
Gorin NC, Labopin M, Frassoni F, Milpied N, Attal M, Blaise D et al. Identical outcome after autologous or allogeneic genoidentical hematopoietic stem-cell transplantation in first remission of acute myelocytic leukemia carrying inversion 16 or t(8;21): a retrospective study from the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2008; 26: 3183–3188.
Schlenk RF, Taskesen E, van Norden Y, Krauter J, Ganser A, Bullinger L et al. The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA. Blood 2013; 122: 1576–1582.
Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.
Shayegi N, Kramer M, Bornhauser M, Schaich M, Schetelig J, Platzbecker U et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 2013; 122: 83–92.
Guieze R, Cornillet-Lefebvre P, Lioure B, Blanchet O, Pigneux A, Recher C et al. Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3-ITD molecular status for cytogenetically normal AML patients: a GOELAMS study. Am J Hematol 2012; 87: 1052–1056.
We are grateful to Professor Yoshihisa Kodera at Aichi Medical University for his helpful advice and support on advancing the study over an entire period. We are indebted to Professor Yoshinobu Kanda at Jichi Medical University for kindly suggesting how to use the EZR software program. We thank all of the physicians and data managers who provided valuable transplantation data to the JSHCT, the Japan Marrow Donor Program and the TRUMP. We also thank the members of the Data Management Committees of JSHCT, Japan Marrow Donor Program and TRUMP for their assistance. This study was supported by grants from the Ministry of Education, Culture, Sports and Technology of Japan, a Research on Allergic Disease and Immunology (H26–106) in Health and Labor Science Grant from the Ministry of Health, Labour and Welfare of Japan, the SENSHIN Medical Research Foundation (Osaka, Japan), the Aichi Cancer Research Foundation (Nagoya, Japan), and the 24th General Assembly of the Japanese Association of Medical Sciences (Nagoya, Japan). The funders had no role in the study design, data collection and analysis, the decision to publish or the preparation of the manuscript. The aim of this study was to retrospectively compare the outcomes of auto-PBSCT to those of allo-BMT and allo-PBSCT from MSD for adults with AML/CR1. The LFS of auto-PBSCT was not significantly different from that of allo-BMT and allo-PBSCT as post-transplant treatment for AML/CR1.
Akiyoshi Takami, Motonori Mizutani and Masahiko Hara designed the research and wrote the manuscript. Motonori Mizutani, Masahiko Hara and Akiyoshi Takami analyzed the data. Motonori Mizutani and Masahiko Hara performed the statistical analyses. All the authors contributed to the collection of the data and samples and critically reviewed and approved the final manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
About this article
Cite this article
Mizutani, M., Hara, M., Fujita, H. et al. Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR. Bone Marrow Transplant 51, 645–653 (2016). https://doi.org/10.1038/bmt.2015.349
Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25 years of experience in Japan
International Journal of Hematology (2020)
Outcomes of Autologous Hematopoietic Cell Transplantation Compared With Chemotherapy Consolidation Alone for Non–High-Risk Acute Myeloid Leukemia in First Complete Remission in a Minority-Rich Inner-City Cohort With Limited Access to Allografts
Clinical Lymphoma Myeloma and Leukemia (2019)
Autologous hematopoietic cell transplantation for AML in first remission – An abandoned practice or promising approach?
Seminars in Hematology (2019)
Biology of Blood and Marrow Transplantation (2019)
International Journal of Hematology (2018)