the Département d'Hématologie, H?pital Caremeau, Centre Hospitalier Universitaire (CHU), N?mes
    Département d'Hématologie, H?pital Haut-Levêque, CHU, Bordeaux
    Unité de Cytogénétique and Département d'Hématologie, H?pital Purpan, CHU, Toulouse
    Département d'Hématologie and Unité de Biostatistiques, Institut Paoli Calmettes, Marseille
    Département d'Hématologie, H?pital Michalon, CHU, Grenoble
    Département d'Hématologie, H?pital Lapeyronie, CHU, Montpellier, France.

    ABSTRACT

    PURPOSE: We analyzed the impact of allogeneic stem-cell transplantation (alloSCT) as an early consolidation for young patients with acute myeloblastic leukemia in first complete remission (CR1) through four successive protocols.

    PATIENTS AND METHODS: Of the 472 patients who achieved CR1, 182 (38%) had an HLA-identical sibling (donor group), and alloSCT was performed in 171 patients (94%). Of the 290 patients without donor (no-donor group), 62% received an autologous SCT.

    RESULTS: In an intent-to-treat analysis based on donor availability, the overall 10-year survival probability was 51% v 43% (P = .11) for the donor and no-donor groups, respectively. A Cox analysis determined that four factors had independent prognostic significance for survival (initial WBC count, French-American-British subtypes, cytogenetic risk, and number of induction courses). This permitted constitution of a simple index that reclassified 21% of the patients compared with usual cytogenetic classification and identified three subpopulations with different outcome and different impact of alloSCT.

    CONCLUSION: AlloSCT was associated with a survival advantage for an intermediate-risk group. In other groups, numbers are limited for definitive conclusion. However, early performed alloSCT does not seem to be the optimal treatment of high-risk patients or offer any advantage over intensive chemotherapy in low-risk patients.

    INTRODUCTION

    Allogeneic stem-cell transplantation (alloSCT) has been established as a potentially curative treatment for patients with acute myeloblastic leukemia (AML), but its role in the early stage of the disease remains controversial because a definitive survival advantage has not been shown in controlled studies.1-4 This is likely a result of a combination of high transplantation-related mortality and continuous improvements in non-alloSCT strategies. Over the last decade, the fear of early death as a result of the SCT procedure led to the restriction of alloSCT in first complete remission (CR1) to patients who presented with risk factors predicting that a nonallogeneic strategy would be inefficient. Retrospective and prospective studies identified such factors and notably the impact of cytogenetics risk on outcome determining standard-, intermediate-, and high-risk populations.4-7 However, this development has several deficiencies. Although a significant proportion of AML patients have no cytogenetics examination available, this approach does not deal with conflicting risk factors; is the risk the same for a patient with intermediate-risk cytogenetics who achieved CR1 in one course as in a patient who needed two courses? In addition, most of the prospective studies have used an intent-to-treat analysis in programs that often delay alloSCT after completion of several consolidation courses. As a consequence, nearly 30% of the patients scheduled to receive an alloSCT failed to receive it,5,6 limiting interpretation.

    Between 1984 and 2001, the Bordeaux Grenoble Marseille Toulouse (BGMT) intergroup followed the same proactive strategy of performing early alloSCT as a rapid consolidation after achieving CR in those patients with AML who had an HLA-identical sibling donor and were younger than 45 years old. After the same initial treatment, patients with no donor received further chemotherapy, which changed over the years according to experience from different studies. We report here the results of this long-standing prospective strategy applied to 472 consecutive patients.

    PATIENTS AND METHODS

    Patients

    In 1984, the BGMT intergroup was created in the south of France to collaboratively investigate the treatment of AML. Over a 17-year period, four prospective randomized trials (BGMT 84, BGMT 87, BGMT 91, and BGMT 95) have been completed and reported.8-11 A total of 1,007 patients were entered (85, 204, 281, and 437 patients in BGMT 84, 87, 91, and 95, respectively), of whom 592 patients (59%) were 45 years old or younger.

    Inclusion criteria in these protocols have been consistent over the years and have been previously reported.8-11 Of note, patients with AML secondary to documented myeloproliferative or myelodysplastic syndrome were excluded. All trials were approved by the ethics committee of Bordeaux, France, in accordance with the Helsinki protocol and by the review board of each participating institution. An informed consent was obtained from each patient and donor before participation in the corresponding study. Over the years, some changes were made in successive protocols based on evolution in knowledge; for instance, since 1995, patients with acute promyelocytic leukemia have been treated on separate protocols.

    For the purpose of this study, data were extensively reviewed, and notably, data for patients lost to follow-up were checked against the French national registry of death (IFR69: INSERM U472 and INSERM CépiDC, Paris). Ultimately, only two patients were lost to follow-up initially after their first induction chemotherapy course. Of the remaining 590 assessable patients, 80% reached CR, and all of them underwent a formal search for an HLA-identical sibling. If the search was unsuccessful, an alloSCT from an unrelated donor was never considered in CR1 in this program.

    HLA typing was determined serologically for class I loci. Serologic determination and mixed lymphocyte culture were initially performed to determine class II matching. This was changed to molecular typing methodology when it became available in 1993. To serve as a donor, HLA-A–, HLA-B–, and HLA-DR–loci had to be perfectly matched with the patient.

    Treatment

    All treatment details have been previously reported,8-11 and only the noteworthy features are described here.

    Induction and Consolidation Chemotherapy

    In all four protocols, induction chemotherapy consisted of intravenous administration of daunorubicin (DNR; 60 mg/m2/d for 3 days) and cytarabine (ARA-C; 100 mg/m2/d as continuous infusion for 10 days). Patients were excluded from the protocols if they did not reach CR after two cycles of induction chemotherapy. Once CR was achieved, all patients proceeded to a first consolidation chemotherapy course (2 + 7 consolidation: ARA-C 50 mg/m2/12 hours subcutaneously for 7 days and DNR 60 mg/m2/d for 2 days).

    AlloSCT

    AlloSCT was scheduled rapidly after recovery from the first consolidation. The preparative regimen for most patients was cyclophosphamide plus total-body irradiation (TBI), which consisted of cyclophosphamide (60 mg/kg/d for 2 days) intravenously followed by fractionated TBI (12 Gy). However, 15 patients were treated with busulfan (4 mg/kg/d for 4 days) and cyclophosphamide in a randomized study comparing these two regimens.12,13 Graft-versus-host disease (GVHD) prophylaxis consisted of short methotrexate (days 1, 3, and 6) and cyclosporine. Six patients received prophylactic anti–interleukin-2 receptor monoclonal antibody,14 and 15 patients received an in vitro T-cell–depleted marrow graft.15,16 After 1995, 15 patients received peripheral-blood alloSCTs investigated in two studies.17,18

    Non-Allogeneic Transplantation Treatment

    The patients who had no HLA-identical sibling donor received further consolidation chemotherapy.8-11 In summary, starting with the BGMT 87 trial, all patients received at least an intensive course of consolidation chemotherapy (ARA-C 3 g/m2/12 hours for eight doses and DNR 45 mg/m2/d for 3 days). The BGMT 84 and 87 trials randomly assigned patients between an unpurged autologous SCT (autoSCT) and chemotherapy. In the BGMT 91 and 95 trials, unpurged autoSCT was scheduled for all patients. Preparative regimen consisted of a single high dose of melphalan (140 mg/m2; BGMT 87), busulfan (4 mg/kg/d for 4 days) plus melphalan (140 mg/m2; BGMT 87 and 95), or cyclophosphamide plus TBI (BGMT 91). Overall, 256 (88%) of the 290 patients with no family donor were scheduled for an autoSCT.

    Cytogenetics

    Overall, 357 patients (76%) had cytogenetics done; the proportion increased over the study period (BGMT 84, 23%; BGMT 87, 73%; BGMT 91, 76%; and BGMT 95, 93%). For each protocol, karyotypes were described according to the evolution of the International System for Human Cytogenetic Nomenclature.19 Each patient was assigned to only one chromosomal group according to the highest-risk abnormality observed. The following prognostic groups were used: (1) favorable risk: t(15;17)(q22;q12), t(8;21)(q22;q22), or inv(16)(p13;q22) was present; (2) unfavorable risk: karyotype was complex, or del(5q)/–5, –7, 3q rearrangements or t(9;22), t(6;9), 11q23 rearrangements, except t(9;11), were present; and (3) intermediate risk: any other patients, including those with a normal karyotype. A fourth group included the patients with no assessable cytogenetics.

    Our present classification for cytogenetic risk groups was based on an update of our previous data.20 The complex karyotypes were defined as those with three or more abnormalities. We also included in this group the 11q23 rearrangements, except t(9;11), because, in our (data not shown) and other experience,21-23 they were of poor prognostic value. In the intermediate-risk group, we included all other abnormalities, especially del(7q) because it has been demonstrated by two studies22,24 that this deletion was of intermediate prognostic value.

    Statistical Analysis

    The purpose of this study was to evaluate the survival impact of early alloSCT strategy by an intent-to-treat analysis based on donor availability. Data was included through June 1, 2003, with a median follow-up time for surviving patients of 114 months (range, 29 to 222 months). Descriptive statistics are reported as frequencies or medians and ranges. Distributions of patient characteristics were compared using standard 2 tests. All outcome end points were analyzed by taking CR1 achievement as a starting point and were calculated at 10 years. Curves were drawn using Kaplan-Meier estimates25 and compared using the log-rank test.26 Graph representation was truncated at the time when less than 10 individuals were still alive. Overall survival (OS) and leukemia-free survival (LFS) were calculated by scoring death and relapse and nonrelapse death (NRD), respectively, as events, with censoring of other patients at the date of last follow-up. The estimates of relapse and NRD incidences were obtained using the cumulative incidence method, with risk of relapse and NRD being considered as competing risks.27 Assuming that the standard 10-year OS in patients treated with chemotherapy is 40%, the size of the two populations allowed for determining a statistically significant difference of 14%, with a .05 two-sided level of significance and a 0.80 power.

    In the subpopulation of patients without HLA-identical siblings, we analyzed patient and disease characteristics for their potential value on patient outcome. We chose factors for their clinical relevance and according to the fact that they were available for most of the patients. Thus, we examined patient age ( 30 v > 30 years), initial WBC count ( 30 v > 30 x 109/L), period of treatment represented by the protocol in which patients were treated (BGMT 84 v BGMT 87 v BGMT 91 v BGMT 95), French-American-British (FAB) cytologic subtypes (M0, M6, and M7 v others), cytogenetic risk group (low, intermediate, high, or not assessable), and number of course to achieve CR (one v two courses). We then introduced the factors that showed a significant impact in the univariate analysis into a multivariate analysis using the Cox proportional hazards model.28 Patients were then classified according to an index assembling independent variables influencing their outcome. Survival rates and relative risks are presented with their 95% CIs. All statistical tests were two sided at the 5% level of significance, and analyses were performed using SAS Version 8.2 (SAS Institute, Cary, NC).

    RESULTS

    Patient Characteristics and Treatment According to Donor Availability

    As indicated in Table 1, there was no statistical difference between the donor group and the no-donor group in regards to all studied variables. Of the 182 patients in the donor group, 171 (94%) underwent transplantation; 165 (91%) underwent alloSCT as an early consolidation of CR1, and six (3%) underwent alloSCT in relapse. Eleven patients did not undergo their transplantation for the following reasons: relapse (n = 3), severe chemotherapy-related toxicity (n = 5), and patient refusal (n = 3). The median times between diagnosis and alloSCT and between CR1 and alloSCT were 97 days (range, 53 to 314 days) and 60 days (range, 11 to 284 days), respectively.

    Of the 290 patients in the no-donor group treated according to the different protocols, 230 (79%) received at least one course of high-dose ARA-C, and 159 (62%) underwent autoSCT while in CR1 at a median of 114 days (range, 31 to 247 days) after achieving CR1. Ninety-three patients scheduled to receive transplantation did not receive it for the following reasons: relapse, n = 51 (54%); general toxicity, n = 22 (24%); insufficient stem-cell collection, n = 8 (9%); and patient refusal, n = 12 (13%).

    Outcome According to Donor Availability

    Overall outcome showed a trend toward survival improvement over time (7-year OS: BGMT 84, 37% ± 13%; BGMT 87, 47% ± 9%; BGMT 91, 48% ± 8%; and BGMT 95, 52% ± 8%; P = .18). These improvements were continuous, allowing pooling of the results of the different trials in regards to the end points of this analysis.

    Forty-two patients in the donor group (23%) have died from transplantation-related causes (graft-versus-host disease, n = 14; infection, n = 12; and multiorgan failure, n = 16); 49 other patients (27%) have relapsed at a median of 10 months (range, 1 to 63 months) after achieving CR (nine before and 40 after alloSCT). The 10-year cumulative incidences of relapse and NRD were 27% (95% CI, 21% to 34%) and 24% (95% CI, 18% to 31%), respectively. Ninety-one patients (50%) are alive in continuous CR at a median of 119 months (range, 18 to 220 months) after CR. The 10-year Kaplan-Meier probabilities of LFS and OS from CR were 48% (95% CI, 41% to 56%) and 51% (95% CI, 44% to 59%), respectively.

    Of the 290 patients in the no-donor group, 17 have died from nonleukemic causes (infection, n = 12; and multiorgan failure, n = 5). The majority of failures were a result of leukemic relapse (n = 156), occurring a median of 9 months (range, 1 to 84 months) after achieving CR. The 10-year cumulative incidences of relapse and NRD were 55% (95% CI, 48% to 61%) and 6% (95% CI, 3% to 8%), respectively. The 10-year Kaplan-Meier probabilities of LFS and OS from CR were 40% (95% CI, 34% to 47%) and 43% (95% CI, 38% to 49%), respectively. One hundred fifty-nine patients received an autoSCT while in CR1, for an OS of 55% (95% CI, 47% to 63%). The comparison of the outcome in the two groups showed that LFS was significantly improved in the donor group compared with the no-donor group (P = .03). The OS difference between the two groups did not reach significance (P = .11). The cumulative incidence of relapse was significantly higher in the no-donor group (P < .001), whereas the cumulative incidence of death in CR was higher in the donor group (P < .001; Fig 1).

    Risk Factors in the Non-AlloSCT Group

    Univariate analysis showed that four of the studied factors (cytogenetics, FAB subtype, number of chemotherapy courses needed to achieve CR1, and WBC count) had a statistically significant impact on relapse incidence and LFS and OS probabilities (Fig 2). Two factors did not show a statistically significant impact on outcome; these were age and period of treatment in which patients were treated. We introduced the four significant factors in a Cox model to study their relative impact on OS and found that they were all independent risk factors (Table 2). According to this model, the hazard function of survival varied with factors combined according to the following equation: exp (0.508 x cytogenetics + 0.465 x CR + 0.849 x FAB + 0.515 x WBC). Thus, each combination of the four factors (coding given in Table 3) can be expressed by a value representing its relative risk and ranging from 1 (best survival for patients with no risk factor) to 29 (worse survival for patients with all risk factors). In fact, the simple addition of the different coding values made for the same classification of the different combinations but established a simpler scale varying from 0 to 6. For instance, a patient with intermediate cytogenetics (factor value = 1), M4 FAB (factor value = 0), WBC of 50 x109/L (factor value = 1), and CR1 in two courses (factor value = 1) had a prognostic index of 3. This allowed for a division in three populations of different survival according to their index value (0 = low risk; 1 to 2 = intermediate risk; and > 2 = high risk; Table 3). Of note, the introduction of the period of treatment in the Cox model (data not shown) confirms that this variable was not an independent risk factor and did not modify the results of the Cox model based on the four initial variables.

    Then, we compared the outcome of the patients from each of these three newly redefined subpopulations with the corresponding patients presenting the same factor combinations but who had an available donor (Table 4 and Fig 3). Among patients with donors, those in the intermediate-risk group had the highest LFS and OS probabilities. Notably, differences with the non-alloSCT patients in this group were statistically significant for both LFS and OS. This was related to limited NRD rate and lower relapse probability compared with the no-donor group. Patients who underwent autoSCT achieved a 10-year OS rate of 59% (95% CI, 49% to 69%) compared with 65% (95% CI, 55% to 75%) for patients who received an alloSCT (P = not significant). However, it should be noted that time between CR1 and transplantation was 113 days (range, 31 to 247 days) and 60 days (range, 11 to 284 days) for autoSCT and alloSCT patients, respectively. In addition 53 (35%) of the 149 patients scheduled to receive autoSCT did not receive the transplantation; 29 of these patients (55%) did not receive the autoSCT because they relapsed before receiving it. In the poor-risk group, although LFS and OS in the donor group seemed to be slightly better, results were uniformly poor, with a 10-year LFS probability of less than 20% in both groups. This was mainly a result of low relapse prophylaxis, with a cumulative incidence of relapse exceeding 50% in both alternatives. The low-risk group was the only group in which LFS and OS probabilities were lower in the donor group than in the no-donor group, although the differences are not statistically significant. This is mainly a result of a low relapse rate in the no-donor group.

    DISCUSSION

    We report an analysis of a 17-year comprehensive experience of a prospective comparison of alloSCT to other modalities, notably autoSCT, which was carried out in 62% of the patients without a donor. Our strategy was based on the hypothesis that an allogeneic graft-versus-leukemia effect was more active in AML cells less exposed to chemotherapy and, thus, able to result in a reduced recurrence rate. Also, we hypothesized that an early transplantation strategy would be associated with lower transplantation-related toxicity and morbidity.29,30 Our study is unique for several reasons. First, the strategy of using alloSCT when available has been proactive since the inception of the program. Ninety-one percent of the possible alloSCTs were carried out, which is different from what has been recently reported by other groups. Notably, the Medical Research Council (MRC)5 and the European Organisation for Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA)6 groups reported rates of alloSCT compliance of 61% and 69%, respectively. Our high proportion of compliance enables us to better appreciate the true value of alloSCT in an intent-to-treat analysis and is a result of the performance of alloSCT early in CR. In this study, the median time between diagnosis and BMT was 97 days, which is comparable to the US intergroup study in which alloSCT was performed after a single less intensive consolidation chemotherapy (median time between diagnosis and bone marrow transplantation, 99 days),4 whereas other international study groups delayed transplantation after one,6 two,7 or three3 intensive consolidation courses. Second, the cytogenetics analysis completion was available in 93% of the patients treated after 1995, which compares favorably with other reports covering the same period (60% for the EORTC/GIMEMA,6 76% for the US intergroup,4 85% for the MRC,5 and recently, 94% for the German AML Study Group, Ulm).7 Finally, we present data with a 10-year median follow-up, with a range up to 18 years. This long-term follow-up implies that we covered a period of time in which treatment of AML significantly improved. It is more likely that alloSCT and non-alloSCT strategies have benefited from these improvements, allowing a reasonable comparison over this period. However, a long-term follow-up is a definitive advantage for better assessing the true impact of treatment strategies.

    This study confirms that alloSCT offers a better leukemic control, resulting in a significantly higher LFS. However, treatment-related mortality limits the survival benefit. These data are comparable to the data previously reported in registry studies31,32 and prospective trials.2-4,6,11 We also validate the impact of different risk factors on AML outcome. Cytogenetics is usually the most discriminative and the most commonly used.5,6,21,22 We confirmed its importance and showed that the unknown cytogenetics should be analyzed separately. We also validate that patients with FAB M0, M6, and M7 subtypes,33-36 initial high WBC count, and the need for more than one induction course had a poor prognosis.7,21,37,38 Conversely, we did not find age to be a prognostic factor, as others have shown.6 Also, the impact of age did not vary whether this variable was considered as a continuous variable or according to different dichotomizations. The young age of our population (ie, < 45 years old) might offer an explanation. Interestingly, the period of time in which patients were treated did not seem to statistically impact outcome.

    The novel aspect from this analysis is that the combination of all these factors can determine a prognostic index more accurate than the usual cytogenetics classification. The Cox model allowed us to study the impact of risk-factor combinations on survival and to determine three subpopulations with clearly different outcomes. Interestingly, using this index, 61 patients (21%) shifted to a category of worse prognosis compared with the standard cytogenetics classification. This index, established on a given population, has been successfully validated in the population of patients older than 45 years from the same program (data not shown) but would obviously deserve further validations in other programs. It offers an easy way to classify patients in whom cytogenetics is not available and to refine the prognostic classification of those patients who do have available cytogenetics.

    This classification allowed us to better define the place of alloSCT in AML treatment. In patients with intermediate-risk index, alloSCT was clearly beneficial, with a statistically significant higher LFS and OS. This advantage can even be increased if recent advances in alloSCT fulfilled expectations.39-41 This difference did not remain significant when we restricted the analysis to the patients who actually received transplantation; however, because of the longer delay before transplantation and the higher dropout as a result of relapse, this comparison becomes hazardous. In the other two groups, numbers are relatively limited and forbid any definitive conclusion. However, results allow interesting considerations. Patients without any adverse risk factors (index = 0) have a 10-year survival estimate of 74% after chemotherapy, with alloSCT not necessarily improving the results. This category of patients showed a low probability of relapse. Thus, even in the hypothesis of a dramatic transplantation-related mortality reduction, it is unlikely that alloSCT would achieve better results than non-alloSCT strategies. In this case, alloSCT would be better considered after relapse. At the other extreme, patients with a high-risk index face a poor outcome whatever the treatment modality, with OS and LFS rates at 10 years of less than 30% and 20%, respectively. There is no question that the graft-versus-leukemia effect exerts a more potent action than intensive chemotherapy, but more than half of the patients will eventually relapse. In the EORTC/GIMEMA6 and US intergroup21 studies, it seems that patients with unfavorable cytogenetics get the maximal benefit from undergoing alloSCT. When we used the EORTC/GIMEMA or the US intergroup cytogenetics risk category definitions, we were unable to achieve the same results in our patients (data not shown). This indicates that other parameters, such as time to alloSCT, number of courses and intensity of pretransplantation chemotherapy, other risk factors, and proportion of patients actually receiving their assigned treatment, may affect the results. However, performing alloSCT early, as we did, is optimal. The EORTC/GIMEMA study suggested that intensive chemotherapy followed by alloSCT might offer better results for this group. Although not confirmed by the MRC study, this has to be considered, along with possibilities to amplify the graft-versus-leukemia effect.42-44 High-risk patients without a donor have the worst outcome (68 of the 87 patients ultimately relapsed). These results justify these patients being initially entered onto investigational studies of new drugs or alternative strategies (unrelated or mismatch transplantation). Again, definitive assessments should be tempered in regards to patient numbers.

    We conclude that our policy of performing alloSCT in young patients with AML early after entering CR has been effective in patients with intermediate-risk AML. Further refinements might even improve present results and should be prospectively investigated.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Acknowledgment

    We thank Finn Bo Petersen, University of Utah (Salt Lake City, UT), for critical review of this manuscript. We also acknowledge the contribution of Mohamad Mohty, MD (Institut Paoli Calmettes, Marseille, France), for helpful discussions and suggestions.

    NOTES

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

    REFERENCES

    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 332:217-223, 1995

    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 Leucemies Aigues Myeloblastiques (GOELAM). Blood 90:2978-2986, 1997

    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 351:700-708, 1998

    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 Engl J Med 339:1649-1656, 1998

    Burnett 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 118:385-400, 2002

    Suciu 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/GIMEMAAML-10 trial. Blood 102:1232-1240, 2003

    Schlenk 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 17:1521-1528, 2003

    Reiffers J, Gaspard MH, Maraninchi D, et al: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: A prospective controlled trial. Br J Haematol 72:57-63, 1989

    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 10:1874-1882, 1996

    Blaise D, Attal M, Reiffers J, et al: Randomized study of recombinant interleukin-2 after autologous bone marrow transplantation for acute leukemia in first complete remission. Eur Cytokine Netw 11:91-98, 2000

    Jourdan E, Rigal-Huguet F, Marit G, et al: One versus two high-dose cytarabine-based consolidation before autologous stem cell transplantation for young acute myeloblastic leukaemia patients in first complete remission. Br J Haematol 129:403-410, 2005

    Blaise 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 79:2578-2582, 1992

    Blaise D, Maraninchi D, Michallet M, et al: Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission. Blood 97:3669-3671, 2001

    Blaise D, Olive D, Michallet M, et al: Impairment of leukaemia-free survival by addition of interleukin-2-receptor antibody to standard graft-versus-host prophylaxis. Lancet 345:1144-1146, 1995

    Maraninchi D, Gluckman E, Blaise D, et al: Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet 2:175-178, 1987

    Laurent G, Maraninchi D, Gluckman E, et al: Donor bone marrow treatment with T101 Fab fragment-ricin A-chain immunotoxin prevents graft versus host disease. Bone Marrow Transplant 4:367-371, 1989

    Blaise D, Jourdan E, Michallet M, et al: Mobilisation of healthy donors with lenograstim and transplantation of HLA-genoidentical blood progenitors in 54 patients with hematological malignancies: A pilot study. Bone Marrow Transplant 22:1153-1158, 1998

    Blaise D, Kuentz M, Fortanier C, et al: Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: A report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 18:537-546, 2000

    Mitelman F ISCN: An International System for Human Cytogenetic Nomenclature (1995)—Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature, Memphis, Tennessee, October 1994. Basel, Switzerland, S. Karger, 1995

    Dastugue N, Payen C, Lafage-Pochitaloff M, et al: Prognostic significance of karyotype in de novo adult acute myeloid leukemia: The BGMT group. Leukemia 9:1491-1498, 1995

    Slovak 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 96:4075-4083, 2000

    Byrd JC, Mrozek K, Dodge RK, et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325-4336, 2002

    Buchner T, Hiddemann W, Wormann B, et al: Double induction strategy for acute myeloid leukemia: The effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: A randomized trial by the German AML Cooperative Group. Blood 93:4116-4124, 1999

    Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial—The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92:2322-2333, 1998

    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

    Peto R, Peto J: Asymptomatically efficient rank invariant test procedures. J R Stat Soc A 135:185-198, 1972

    Klabfleisch J, Prentice R: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980

    Cox D: Regression models and life tables. J R Stat Soc B 34:187-220, 1972

    Jourdan 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 19:875-881, 1997

    Cahn JY, Labopin M, Sierra J, et al: No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission: Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:308-314, 2000

    Gale RP, Buchner T, Zhang MJ, et al: HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission. Leukemia 10:1687-1691, 1996

    Ferrant A, Labopin M, Frassoni F, et al: Karyotype in acute myeloblastic leukemia: Prognostic significance for bone marrow transplantation in first remission: A European Group for Blood and Marrow Transplantation study—Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood 90:2931-2938, 1997

    Amadori S, Venditti A, Del Poeta G, et al: Minimally differentiated acute myeloid leukemia (AML-M0): A distinct clinico-biologic entity with poor prognosis. Ann Hematol 72:208-215, 1996

    Colita A, Belhabri A, Chelghoum Y, et al: Prognostic factors and treatment effects on survival in acute myeloid leukemia of M6 subtype: A retrospective study of 54 cases. Ann Oncol 12:451-455, 2001

    Matsuo T, Bennett JM: Acute leukemia of megakaryocyte lineage (M7). Cancer Genet Cytogenet 34:1-3, 1988

    Dastugue N, Lafage-Pochitaloff M, Pages MP, et al: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): A study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Blood 100:618-626, 2002

    Harousseau JL, Attal M: The role of autologous hematopoietic stem cell transplantation in multiple myeloma. Semin Hematol 34:61-66, 1997

    Liso V, Iacopino P, Avvisati G, et al: Outcome of patients with acute myeloid leukemia who failed to respond to a single course of first-line induction therapy: A GIMEMA study of 218 unselected consecutive patients—Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Leukemia 10:1443-1452, 1996

    Taussig DC, Davies AJ, Cavenagh JD, et al: Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol 21:3060-3065, 2003

    Kroger N, Bornhauser M, Ehninger G, et al: Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol 82:336-342, 2003

    De Lima M, Anagnostopoulos A, Munsell M, et al: Non-ablative 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 104:865-872, 2004

    Mailander V, Scheibenbogen C, Thiel E, et al: Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity. Leukemia 18:165-166, 2004

    Nadal E, Fowler A, Kanfer E, et al: Adjuvant interleukin-2 therapy for patients refractory to donor lymphocyte infusions. Exp Hematol 32:218-223, 2004

    Heslop HE, Stevenson FK, Molldrem JJ: Immunotherapy of hematologic malignancy. Hematology (Am Soc Hematol Educ Program) 331-349, 2003

    Submitted June 5, 2005; accepted July 19, 2005.

查询更多Stem-Cell相关信息在本站>>

《临床肿瘤学医学期刊》2005年10月第23卷第10期