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Originally published as JCO Early Release 10.1200/JCO.2005.02.5940 on September 26 2005 © 2005 American Society of Clinical Oncology. Early Allogeneic Stem-Cell Transplantation for Young Adults With Acute Myeloblastic Leukemia in First Complete Remission: An Intent-to-Treat Long-Term Analysis of the BGMT ExperienceFrom the Département d'Hématologie, Hôpital Caremeau, Centre Hospitalier Universitaire (CHU), Nîmes; Département d'Hématologie, Hôpital Haut-Levêque, CHU, Bordeaux; Unité de Cytogénétique and Département d'Hématologie, Hôpital Purpan, CHU, Toulouse; Département d'Hématologie and Unité de Biostatistiques, Institut Paoli Calmettes, Marseille; Département d'Hématologie, Hôpital Michalon, CHU, Grenoble; and Département d'Hématologie, Hôpital Lapeyronie, CHU, Montpellier, France. Address reprint requests to Didier Blaise, Unité de Transplantation et de Thérapie Cellulaire, Institut Paoli Calmettes, 232 Blvd Sainte Marguerite, 13273 Marseille Cedex 9, France; e-mail: uttc{at}marseille.fnclcc.fr
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.
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 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
Induction and Consolidation Chemotherapy
AlloSCT
Non-Allogeneic Transplantation Treatment
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
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 (
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 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.
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.
The authors indicated no potential conflicts of interest.
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.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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41. 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 42. 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[CrossRef][Medline] 43. 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[CrossRef][Medline] 44. 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.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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 estimates
30 v > 30 years), initial WBC count (
