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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

The choice of postremission therapy for acute myeloid leukemia (AML) patients is now based on the blasts' cytogenetic and molecular profile. However, the potential benefit of autologous hematopoietic stem cell transplantation (auto-HSCT) according to the NPM1/FLT3-ITD status has been poorly studied in AML patients with a normal karyotype (NK). Therefore, we evaluated the NPM1/FLT3-ITD molecular status in 135 NK-AML patients treated by allogeneic HSCT (allo-HSCT), auto-HSCT, or chemotherapy as consolidation therapy within the GOELAMS LAM-2001 trial. In univariate analyzes, 4-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher for NPM1+/FLT3-ITD− patients compared with patients presenting another molecular profile (61 vs. 43% and 72 vs. 48%, P = 0.02 and P = 0.01, respectively). In the NPM1+/FLT3-ITD− subgroup, there was no benefit for allo-HSCT or auto-HSCT vs. chemotherapy (4-year LFS: 71, 56, and 60%; 4-year OS: 73, 71, and 60%, respectively; P = NS). For patients with other NPM1/FLT3-ITD molecular profiles, allo-HSCT was found to be the best consolidation therapy, whereas auto-HSCT was associated with a better outcome when compared with chemotherapy (allo-HSCT-, auto-HSCT-, and chemotherapy-related 4-year LFS: 68, 44, and 36%, P = 0.004; 4-year OS: 68, 52, and 29%, respectively, P = 0.02). Our study indicates that allo-HSCT and auto-HSCT provide similar outcomes compared with chemotherapy as consolidation for NPM1+/FLT3-ITD− NK-AML patients. For NK-AML patients with an adverse molecular profile, auto-HSCT could represent an alternative therapeutic approach when no human leukocyte antigen–matched allogeneic donor is available. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

During the recent years, considerable progress has been made in deciphering the cytogenetic abnormalities and molecular genetic events occurring in acute myeloid leukemia (AML) cells. These data allowed for the assessment of new diagnostic and prognostic markers in AML, especially in normal karyotype AML (NK-AML) patients, considered as intermediate risk. Thus, it has been shown that mutations occur frequently in several genes in NK-AML cells, and two of them are now especially relevant in clinical practice for the prediction of relapse and the subsequent indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). The nucleophosmin gene (NPM1) has been shown to be mutated in almost half of NK-AML patients [1, 2], whereas ∼30% of these same patients carry a fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) [3]. Multiple studies have shown that the genotype “mutated NPM1 without FLT3-ITD” represents a favorable prognostic marker, with higher CR rates, and better relapse-free survival and overall survival (OS), reminiscent of what is seen in patients with favorable cytogenetics (i.e., inv(16)/t(16;16) or t(8;21) AML) [4–7]. Thus, an international expert panel of the European LeukemiaNet (ELN) has recently proposed to include mutant NPM1 (NPM1+) without FLT3-ITD NK-AML patients in the subset of favorable prognostic patients [8]. Allo-HSCT would thus no longer be recommended for such patients although there is accumulating evidence that allo-HSCT is an attractive option for patients with NK-AML and unfavorable molecular markers (i.e., NPM1+/FLT3-ITD+, NPM1-/FLT3-ITD+, and NPM1-/FLT3-ITD−) [8]. According to the ELN, autologous HSCT (auto-HSCT) represents a good alternativeoption for AML patients eligible for an allograft but lacking a human leukocyte antigen (HLA)-compatible donor and may offer an advantage in specific subsets compared with chemotherapy [8]. However, the impact of auto-HSCT according to the NPM1/FLT3-ITD status has been poorly studied so far in NK-AML. This is what was evaluated here retrospectively in a cohort of 135 NK-AML patients treated by allo-HSCT, auto-HSCT, or chemotherapy alone as consolidation within the Groupe d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) LAM-2001 trial.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

Patients

For the present analyses, we screened all the NK-AML patients of the phase III GOELAMS LAM 2001 trial who achieved CR1 and for whom samples at diagnosis were available to assess the NPM1/FLT3-ITD molecular status. The multicenter prospective randomized Phase III GOELAMS LAM-2001 trial (http://clinical.trials.gov#NCT01015196) was initiated to assess the potential benefit of adding a second auto-HSCT in non-M3-AML adults less than 60 years of age in CR1 lacking an HLA-identical sibling donor [9, 10]. This study included 832 patients (median age: 48 years old, range: 17–60). The trial received approval from the IRB of Nantes University Hospital, France. All patients provided informed consent in accordance with the Declaration of Helsinki. The design of the study is summarized in Fig. 1. Briefly, patients were first randomized at diagnosis to receive, at induction and later in the treatment course, either idarubicin (IDA) or daunorubicin (DNR) as anthracyclin. Induction chemotherapy consisted in DNR (60 mg/m2 on days 1–3) or IDA (8 mg/m2 on days 1–5) associated with continuous infusion of cytosine arabinoside (Ara-C) (200 mg/m2 on days 1–7). If there were >5% bone marrow (BM) blasts at day 15, a second induction course was given including DNR 35 mg/m2 or IDA 8 mg/m2 on days 17 and 18, according to initial randomization, and Ara-C 1000 mg/m2 bid on days 17–20. After induction therapy, all patients received a miniconsolidation (IDA 12 mg/m2 or DNR 60 mg/m2 on days 1–2 and Ara-C 50 mg/m2 bid SC on days 1–7).

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Figure 1. Design of the GOELAMS LAM-2001 trial. Abbreviations: IDA, idarubicin; DNR, daunorubicin; Ara-C, aracytine; BM, bone marrow; Allo-HSCT, allogeneic hematopoietic stem cell transplantation; MAC, myeloablative conditioning regimen (total body irradiation 12 grays over 3 days and cyclophosphamide 60 mg/kg/day for 2 days); RIC, reduced intensity conditioning regimen (fludarabine 30 mg/m2/day for 4 days, oral busulfan 2 mg/m2/day for 2 days, and anti-thymoglobulin 2.5 mg/kg/day for 2 days); HiDAC, high-dose aracytine (3 g/m2 every 12 hr); Auto-HSCT, autologous hematopoietic stem cell transplantation; BU, oral busulfan 4 mg/kg/day for 4 days; HDM, high-dose melphalan (140 or 200 mg/m2).

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Search for an HLA identical sibling donor was performed for each patient at diagnosis and was pursued up to the documentation of CR1 after induction. Unrelated HLA-matched donors were not considered in this study. Patients with a sibling donor were programmed to receive allo-HSCT. Patients up to 50 years of age were planned to receive a BM allo-HSCT with a myeloablative conditioning regimen (MAC), whereas patients over 50 years of age received a peripheral blood stem cells (PBSC) allo-HSCT with a reduced intensity conditioning regimen (RIC). Patients lacking a donor were secondly randomized to receive either one auto-HSCT or two auto-HSCTs. When transplantation (auto or allo-HSCT) was not feasible after this randomization, patients underwent the chemotherapy-based consolidation therapy planned by the protocol (one course of high-dose Ara-C 3 g/m2 bid over 4 days and one course of amsacrine 150 mg/m2 per day and etoposide 150 mg/m2 per day both over 5 days if included in the two auto-HSCTs arm).

Molecular analyses

For this study, available diagnosis samples from patients included in the GOELAMS LAM-2001 trial were screened for NPM1 mutations and FLT3 internal tandem duplication. CEBPA mutations were not considered in this study. Two central reference molecular laboratories of the GOELAMS (at Reims and Angers) analyzed these samples according to the reported methods [11, 12].

Statistical analyses

Descriptive statistics were reported as frequencies, or medians and range. Normality of samples' distribution was checked with the Kolmogorov–Smirnov test. Comparisons of median values were performed using the Mann–Whitney rank sum test. The chi-squared test or Fisher's exact test was used to test for differences between groups.

OS and leukemia-free survival (LFS) were calculated from the date of the first randomization until the date of death from any cause and from the date of CR1 until the date of relapse or death of any cause, respectively, censoring other patients at the date of last follow-up. Estimates of LFS and OS were calculated by the Kaplan–Meier method, and comparisons of survivals were achieved with the log rank test. A multivariate analysis was performed according to the Cox proportional-hazards regression model. All statistical analyses were performed with the MedCalc® software (Mariakerke, Belgium). Final analyses were performed in December 2011.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

Although molecular studies for NPM1 or FLT3 had not been planned initially, BM or peripheral blood samples collected at diagnosis from 135 of the 337 NK-AML patients of the multicenter prospective randomized Phase III GOELAMS LAM-2001 trial could be retrieved retrospectively. We did not note any discrepancies in terms of clinical or biological features nor outcome between these 135 patients analyzed here and the whole NK-AML cohort (data not shown). Forty-one patients received chemotherapy alone as consolidation therapy according to the design of the trial. Fifty-seven patients received one (n = 40) or 2 (n = 17) autografts. As recently reported, we did not see any advantage to perform a double over a single autograft in our series [9]. Consequently, the whole auto-HSCT cohort was tested as one group for the significance of the molecular status. Thirty-seven patients received an allo-HSCT (MAC: n = 27; RIC: n = 10). The outcome of allo-HSCT patients was also not different in this trial whatever they received a RIC or a MAC regimen, and the whole allo-HSCT cohort was therefore also tested as one group [10].

In line with the ELN classification [8], the impact of the favorable NPM1+/FLT3-ITD− status was compared to all other molecular combinations. The characteristics of patients are summarized in Table I. A total of 46 patients presented the NPM1+/FLT3-ITD− profile, whereas 89 patients presented one of the other combinations (NPM1+/FLT3-ITD+ in 25, NPM1-/FLT3-ITD− in 49, and NPM1-/FLT3-ITD+ in 15). There was no significant difference between the two groups regarding the characteristics of patients. Both molecular subgroups appeared also well balanced concerning the type of consolidation treatment received (i.e., chemotherapy, auto-HSCT, or allo-HSCT). According to initial randomization, 44% of patients with the NPM1+/FLT3-ITD− profile received IDA as induction compared with 35% for the other profiles (P = 0.025). However, as we have previously shown, the CR rate was not significantly different between the two induction treatment arms [9].

Table I. Characteristics of the 135 NK-AML Patients
Patients, N = 135NPM1+/FLT3-ITD− molecular profile, N = 46Other molecular profiles, N = 89P
  1. WBC, white blood cells count; FAB, French-American-British classification; CR, complete remission; Auto-HSCT, autologous hematopoietic stem cell transplantation; Allo-HSCT, allogeneic hematopoietic stem cell transplantation.

Median age (range)47 (18–60)46 (19–61)0.73
Male gender18 (39%)47 (53%)0.15
Median initial WBC count (range) ×109 L−112.2 (0.04–149)19.3 (1.3–351)0.2
FAB  0.052
 (0/1/2/4/5,6, or 7)0/5/6/9/95/26/21/15/10
 Unclassified/unavailable1712
First randomization  0.025
 Idarubicin2058
 Daunorubicin2631
Complete remission  0.79
 CR in one course39 (85%)76 (86%)
 CR in two courses7 (15%)12 (14%)
Chemotherapy10 (22%)31 (35%)0.13
Auto-HSCT21 (45.5%)36 (40.5%)
Allo-HSCT15 (32.5%)22 (24.5%)

Median follow-up was 86 months for alive patients (range: 16–118) in the whole cohort. In univariate analysis, 4-year LFS and 4-year OS were significantly higher for NPM1+/FLT3-ITD− patients compared with patients presenting another molecular profile (NPM1+/FLT3-ITD+, NPM1-/FLT3-ITD−, or NPM1-/FLT3-ITD) [(4-year LFS: 61 vs. 43% and 4-year OS: 72 vs. 48%, P = 0.02 and P = 0.01, respectively].

Outcomes according to the type of consolidation therapy received were then analyzed in each molecular profile subgroup. In the NPM1+/FLT3-ITD− subgroup, the chemotherapy, the auto-HSCT, or the allo-HSCT received as consolidation provided similar outcome for the patients [4-year LFS: 60, 56, and 71% (P = 0.77) and 4-year OS: 60, 71, and 73% (P = 0.73), respectively] (Fig. 2). For patients with other NPM1/FLT3-ITD molecular profiles, chemotherapy alone provided a clearly worse outcome than allo-HSCT but also than auto-HSCT. In this adverse molecular subgroup, 4-year LFS was 36, 44, and 68% (P = 0.004) and 4-year OS was 29, 52, and 68% (P = 0.02), respectively, for the chemotherapy, auto-HSCT, and allo-HSCT subgroups (Fig. 3).

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Figure 2. Outcome of NPM1+/FLT3-ITD− AML patients according to consolidation therapy strategy. A: LFS and B: OS. Abbreviations: AML, acute myeloid leukemia; LFS, leukemia-free survival; OS, overall survival; Chemotherapy, chemotherapy alone as consolidation therapy; Auto-HSCT, autologous hematopoietic stem cell transplantation; Allo-HSCT, allogeneic hematopoietic stem cell transplantation. Estimates of LFS and OS were calculated by the Kaplan–Meier method and compared using the log rank test.

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thumbnail image

Figure 3. Outcome of adverse molecular profiles (NPM1-/FLT3-ITD−, NPM1-/FLT3-ITD+, and NPM1+/FLT3-ITD+) of AML patients according to consolidation therapy strategy. A: LFS and B: OS. Abbreviations: AML, acute myeloid leukemia; LFS, leukemia-free survival; OS, overall survival; Chemotherapy, chemotherapy alone as consolidation therapy; Auto-HSCT, autologous hematopoietic stem cell transplantation; Allo-HSCT, allogeneic hematopoietic stem cell transplantation. Estimates of LFS and OS were calculated by the Kaplan–Meier method and compared using the log rank test.

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In multivariate analysis including age, white blood count, consolidation therapy (chemotherapy, auto-HSCT, or allo-HSCT), and mutational status (NPM1+/FLT3-ITD− or others), only the type of consolidation strategy showed a significant prognostic impact on LFS (HR: 1.89, 95% confidence interval: 1.28–2.57; P = 0.0006) and OS (HR: 1.68, 95% confidence interval: 1.17–2.42; P = 0.004).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

This study took advantage of an existing retrospective cohort of NK-AML patients in CR1, treated in an original trial that started in 2001 and aimed at comparing one vs. two auto-HSCT(s) in cases without sibling donor for allo-HSCT. Molecular studies for NPM1 or FLT3 could be performed on 135 of the 337 NK-AML patients initially included in the Phase III GOELAMS LAM-2001 trial. We could check beforehand that the series of patients for whom we could use stored material was astonishingly matching the whole group for all clinical and biological features. Moreover, skipping molecular profiles, survival curves in this subgroup exactly matched those of the whole series (data not shown).

On the basis of the rationale of this specific protocol, our data confirm the favorable prognostic impact of the NPM1+/FLT3-ITD− molecular profile in a homogeneous population of de novo NK-AML patients below 65 years of age in CR1. Indeed, the impact of the NPM1/FLT3-ITD molecular status is now well established [1–5, 8]. It was recently evaluated in 99 autografted NK-AML patients showing significantly longer OS and LFS in the subgroup of 19 patients with a favorable molecular status (OS: not reached vs. 25 months, P = 0.02; LFS: not reached vs. 16 months, P = 0.007) [13].

So far, one German team has compared outcomes after allo-HSCT vs. other consolidation strategies in NK-AML patients according to their molecular profile [5]. This donor vs. no donor analysis showed a benefit for allo-HSCT in the adverse molecular subgroup but none in the favorable NPM1+/FLT3-ITD− subgroup. Nevertheless, it appears that no clear comparison between chemotherapy, auto-HSCT, and allo-HSCT was assessed in this series as reported here. Our analyses showed that patients with the favorable NPM1+/FLT3-ITD− molecular profile had a similar outcome whether they received chemotherapy, autologous transplantation, or allogeneic transplantation as consolidation therapy. The demonstration of a very good outcome and the lack of benefit for allo-HSCT in the favorable molecular subgroup is of course a strong argument to include these patients in the non-M3 AML subgroup with favorable cytogenetics, as recommended recently [8]. Indeed, it is now well demonstrated that non-M3 AML patients in CR1 with favorable cytogenetics have a favorable outcome and do not benefit from allo-HSCT as consolidation. Moreover, comparison of auto-HSCT vs. allo-HSCT in this favorable population showed no significant differences in terms of survival [14, 15]. Currently, high-dose Ara-C stands as the consolidation of choice in these patients, although the results of auto-HSCT are very good, reaching, for example, a 5-year LFS of 66% in the study of Gorin et al. [14] and a 4-year LFS of 72% in our own LAM-2001 trial [9]. These data raise the question of the role of auto-HSCT vs. chemotherapy alone as consolidation therapy either for NPM1+/FLT3-ITD− patients or non-M3 AML patients with favorable cytogenetics in prospective studies.

Considering NK-AML patients with no favorable molecular profile, and as already reported [5, 8], it is clear from our results that they benefit from allo-HSCT as consolidation. Such patients have therefore to be still considered as belonging to the intermediate-risk subgroup where allo-HSCT is indicated if an HLA-matched donor is available [8]. Conversely, auto-HSCT may still represent a good alternative therapy compared with chemotherapy alone as consolidation, as suggested here. In published AML randomized studies, all using BM as stem cell support so far, auto-HSCT failed to demonstrate a clear advantage compared with intensive chemotherapy with OS ranging from 43 to 56% and DFS between 38 and 53% at 3–7 years [16–21]. Indeed, although two meta-analyses [22, 23] have suggested a modest advantage for auto-HSCT, because of a higher relapse rate after intensive chemotherapy (55–68% vs. 31–52%), the higher toxicity of the auto-HSCT procedure explains the lack of significantly different outcomes between these two schedules. Reducing the toxicity of auto-HSCT would therefore be of crucial importance to improve this strategy and patients' outcome. One option could be to use PBSC instead of BM, as PBSC allow for a faster hematologic recovery with a transplant-related mortality of less than 10% [24–26]. An alternative means would be to use granulocyte colony-stimulating factor as it can also shorten significantly the duration of neutropenia and hospitalization after intensive consolidation therapy and might permit the delivery of chemotherapy at a higher dose intensity while still allowing appropriate stem cell products to be collected [27, 28]. These two conditions were fulfilled within the prospective GOELAMS LAM-2001 trial, but overall comparison of chemotherapy vs. auto-HSCT as consolidation showed no significant differences in terms of outcomes [9]. Here, we demonstrate retrospectively that auto-HSCT may benefit to some subgroups of NK-AML patients, providing a significantly longer LFS and OS than chemotherapy alone.

In conclusion, molecular analysis of available samples from the prospective randomized GOELAMS LAM-2001 trial confirmed the major prognostic impact of the NPM1/FLT3-ITD molecular status in younger NK-AML patients. Auto-HSCT provided a similar outcome as allo-HSCT or chemotherapy alone as consolidation therapy for good prognosis of NPM1+/FLT3-ITD− patients. For patients with adverse molecular profiles, allo-HSCT remains strongly recommended but auto-HSCT has to be considered if no HLA-matched donor is available. Such results provide necessary preliminary data with the aim to design future prospective trials evaluating the indications of auto-HSCT for specific subsets of AML patients.

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

RG and PC analyzed data, recruited patients, provided clinical care, performed bibliographic search, and wrote the manuscript. MCB performed data collection management, validation, and statistical analyses and wrote the manuscript. PCL and OB produced and validated molecular data. BL recruited patients, provided clinical care, and performed data collection management and validation. AP, CR, BW, NF, CEB, DB, NV, MD, PT, CH, JLH, FD, and NI recruited patients and provided clinical care. All the above authors approved the manuscript for publication purposes.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References

The authors thank Cindy Grandjenette for her help in collecting and verifying the raw data and all the data managers (CRA) of the GOELAMS, especially Roselyne Delepine, who all contributed to construct an exquisitely comprehensive database of the trial.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. References
  • 1
    Thiede 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: 40114020.
  • 2
    Schnittger 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: 37333739.
  • 3
    Gale RE,Green C,Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111: 27762784.
  • 4
    Döhner 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: 37403746.
  • 5
    Schlenk RF,Döhner K,Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 19091918.
  • 6
    Ghanem H,Tank N,Tabbara IA. Prognostic implications of genetic aberrations in acute myelogenous leukemia with normal cytogenetics. Am J Hematol 2012; 87: 6977.
  • 7
    Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 2012; 87: 8999.
  • 8
    Döhner H,Estey EH,Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453474.
  • 9
    Chevallier P,Fornecker L,Lioure B, et al. Tandem versus single autologous peripheral blood stem cell transplantation as post-remission therapy in adult acute myeloid leukemia patients under 60 in first complete remission: Results of the multicenter prospective phase III GOELAMS LAM-2001 trial. Leukemia 2010; 24: 13801385.
  • 10
    Lioure B,Bene MC,Pigneux A, et al. Early matched sibling hematopoietic-cell transplantation for adult AML in first remission using an age-adapted strategy: Long-term results of a prospective GOELAMS study. Blood 2012; 119: 29432948.
  • 11
    Boissel N,Renneville A,Biggio V, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 36183620.
  • 12
    Kiyoi H,Naoe T,Yokota S, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997; 11: 14471452.
  • 13
    Ferrara F,Izzo T,Criscuolo C, et al. Favorable outcome in patients with acute myelogenous leukemia with the nucleophosmin gene mutation autografted after conditioning with high-dose continuous infusion of idarubicin and busulfan. Biol Blood Marrow Transplant 2010; 16: 10181024.
  • 14
    Gorin N-C,Labopin M,Frassoni F, 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: 31833188.
  • 15
    Kuwatsuka Y,Miyamura K,Suzuki R, et al. Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes. Blood. 2009; 113: 20962103.
  • 16
    Zittoun RA,Mandelli F,Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: 217223.
  • 17
    Reiffers 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: 18741882.
  • 18
    Ravindranath Y,Yeager AM,Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 1996; 334: 14281434.
  • 19
    Harousseau JL,Cahn JY,Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 1997; 90: 29782786.
  • 20
    Burnett AK,Goldstone AH,Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet 1998; 351: 700708.
  • 21
    Cassileth PA,Harrington DP,Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Eng J Med 1998; 339: 16491656.
  • 22
    Nathan 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: 3845.
  • 23
    Levi 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: 605612.
  • 24
    Henon PR,Liang H,Beck-Wirth G, et al. Comparison of hematopoietic and immune recovery after autologous bone marrow or blood stem cell transplants. Bone Marrow Transplant 1992; 9: 285291.
  • 25
    To LB,Roberts MM,Haylock DN, et al. Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants. Bone Marrow Transplant 1992; 9: 277284.
  • 26
    Martín C,Torres A,León A, et al. Autologous peripheral blood stem cell transplantation (PBSCT) mobilized with G-CSF in AML in first complete remission. Role of intensification therapy in outcome. Bone Marrow Transplant 1998; 21: 375382.
  • 27
    Michel G,Landman-Parker J,Auclerc MF, et al. Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: A randomized trial in very high-risk childhood acute lymphoblastic leukemia. J Clin Oncol 2000; 18: 15171524.
  • 28
    Harousseau JL,Witz B,Lioure B, et al. Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: Results of a randomized trial of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques. J Clin Oncol 2000; 18: 780787.