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

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With the double aim of reducing the toxicity of the autograft procedure by using peripheral blood stem cells and granulocyte colony-stimulating factor, and decreasing the relapse rate of acute myeloid leukemia (AML) patients after autologous hematopoietic stem cell transplantation (auto-HSCT) by delivering a higher dose of chemotherapy, the GOELAMS undertook in 2001 a phase III prospective randomized trial to assess the potential benefit of adding a second auto-HSCT in younger adult AML patients in first complete remission (CR) lacking an HLA-identical sibling donor. The trial was registered at http://clinicaltrials.gov/ct no.NCT01015196. This study included 28 medical centers that enrolled, between November 2001 and April 2005, 832 patients, with previously untreated non-M3-AML and a median age of 48 years (range 17–60). The trial received approval from the institutional review board of Nantes University Hospital, France. All patients provided informed consent in accordance with the principles of the Declaration of Helsinki. Patients who had previously received chemotherapy and/or radiotherapy for a solid tumor were eligible. The design of the study is given in Figure 1. Patients were first randomized to receive, throughout the treatment course, either daunorubicin or idarubicin as anthracyclin. Search for an HLA-identical sibling donor for each patient was performed at diagnosis and was pursued up to the documentation of CR1 after induction. At that stage, patients lacking a donor were secondly randomized to receive either one auto-HSCT conditioned by busulfan+high-dose melphalan 140 mg/m2 (arm A) or an auto-HSCT conditioned by high-dose melphalan 200 mg/m2 followed by a second auto-HSCT conditioned as for arm A (arm B). The primary objective of the autograft program of the trial reported in this study was to compare leukemia-free survival between arms A and B. The final analysis, using the MedCalc software (Mariakerke, Belgium), was performed after closing the trial in September 2008.

Figure 1
figure1

Design of the trial. a Unrelated HLA-matched donors were not considered in this study. Patients with an HLA-identical sibling donor but with leukocytosis <30 × 109/l at diagnosis, t(8;21) or inv(16) and CR achievement after only one course of induction were programmed to receive only chemotherapy as consolidation and an allograft only in CR2. bThe stem cell product re-infused was preferentially that harvested after the early intensification (PBSC2), but could have been PBSC1 or PBSC 1+2. *<2 × 106 CD34+ stem cells/kg collected after PBSC 1+2. **> and <4 × 106 CD34+ stem cells/kg collected after PBSC 1+2. ***>4 × 106 CD34+ stem cells/kg collected after PBSC 1+2. Abbreviations: amsacrine/VP16, amsacrine 150 mg/m2 per day and etoposide 150 mg/m2 per day both over five consecutive days; BU/HDM 140, busulfan 4 mg/kg per day per os over 4 days from day −6 to day −3 and high-dose melphalan (HDM) 140 mg/m2 on day –2, graft on day 0; CR, complete remission; d, day(s); HDM 200, high-dose melphalan 200 mg/m2 on day–2, graft on day 0; HiDAC, high-dose Ara-C 6 g/m2 per day over 4 days; IV, intravenously; PBSC, peripheral blood stem cells; SC, subcutaneously.

The feasibility of the trial is given in Figure 2. There was no significant difference between the two groups of first randomization (idarubicin, n=412 or daunorubicin, n=411) regarding the initial characteristics (data not shown) or CR rate (idarubicin 83% versus daunorubicin 81%). No significant difference was observed either in the clinical characteristics of the patients included in the second randomization (arm A, n=206 versus arm B, n=204), except for the incidence of previous solid tumor, which was significantly higher in arm A (Table 1). The median follow-up for patients assigned to receive 1 or 2 autografts (n=410) was 53 months (range: 9–83). The proportions of patients who received the complete auto-HSCT schedule were significantly higher in arm A compared with arm B (75%, n=155/206 versus 44%, n=89/204, P<0.0001). The reasons for these differences were the higher numbers of protocol violations (n=11 versus n=26) and relapses (n=9 versus n=26) before completing the full schedule. The outcome of the whole cohort assigned to auto-HSCT (n=410) according to the intent-to-treat principle is given in Table 2, which also reports on significant prognostic factors for leukemia-free survival and overall survival. Table 3 compares the outcomes of arms A and B in intent-to-treat as well as for patients who actually received a full schedule (n=244). No significant advantage was observed for patients in arm B, both overall as well as for any of the subgroups. Comparison of outcomes between patients with the full autograft schedule, the full chemo/autograft schedule or the full chemotherapy schedule is also depicted in Table 3, confirming the absence of significantly improved outcome for all of the procedures.

Figure 2
figure2

Trial feasibility. aEight patients with inadequate diagnosis (AML >60 years, n=2; AML FAB M3, n=1; Ph+CML, n=5). One patient was excluded because he died before having received the first day of treatment. bThe 147 patients included 24 early deaths (2.9%), 12 deaths (1.4%) during aplasia, 7 deaths (0.8%) after recovery from aplasia and 104 patients (12.6%) with persistent leukemia. cCR after one induction n=579; CR after two inductionsn=97. dThe 36 patients were not considered for intensive post-remission therapy for the following reasons: extrahematologic toxicity (n=5), protocol violation (n=17), refusal (n=4) and early relapse (n=10). Abbreviations: BU, busulfan; HiDAC, high-dose Ara-C 6 g/m2 per day over 4 days; HDM 140 or 200, high-dose melphalan 140 mg/m2 or 200 mg/m2.

Table 1 Patients’ characteristics
Table 2 Outcomes of the whole cohort assigned to auto-HSCT (n=410) according to the intent-to-treat principle and significant prognostic factors for LFS and OS
Table 3 Comparison of outcomes according to different subgroups

The capacity to harvest a graft after the miniconsolidation or the early intensification was similar between both groups (arm A: 59% versus arm B: 54%, and arm A: 63% versus arm B: 57%). Thus, the ability to obtain at least one (>2 × 106 CD34+ cells/kg) or two (4 × 106 CD34+ cells/kg) graft(s) was similar in both arms (arm A: n=168 (81%) versus arm B: n=162 (79.5%), and arm A: n=132 (64%) versus arm B: n=134 (66%)). Interestingly, the first randomization had a significant impact on the amount of stem cells collected (median 9.8 (0.9–100) × 106/kg for daunorubicin versus 6.7 (0.3–307) × 106/kg for idarubicin, P<0.0001). Patients who received daunorubicin were also more liable to achieve the planned auto-HSCT program (P=0.04 in both arms). As required by the protocol, the majority of patients in arm A (75%) and in arm B (77%) received a graft collected only after the early intensification. The median number of CD34+ stem cells collected after this early intensification was significantly higher in arm B compared with arm A (5.9 (range 0–90.5) × 106/kg versus 5.2 (range 0–308) × 106/kg, P=0.04). As shown in Table 3, none of the significantly different outcomes was related to the time of graft collection.

The main objective of this phase III randomized study was to compare one (arm A) versus two (arm B) auto-HSCT(s) as post-remission therapy in adult AML patients lesser than 60 years old in first CR. The outcomes reported here compare favorably with those of previously randomized studies1, 2 and confirm the safety of a double auto-HSCT procedure with only 5% of treatment-related mortality.3 However, similar results were obtained in both arms, either in an intent-to-treat analysis or when considering only patients who effectively received the full planned schedule. Moreover, no benefit from receiving two rather than one auto-HSCT as post-remission therapy was identified in any of the prognostic subgroups of patients. These results could be explained, first, by the planned rescue strategies that were applied when auto-HSCT could not be performed as expected. Second, the feasibility of the full auto-HSCT procedure was unquestionably worse in arm B (44 versus 75% in arm A), mainly because of an unexpected threefold higher incidence of relapse in arm B between CR and auto-HSCT. There is no clear evidence to explain this phenomenon, as the incidence of high-risk patients was equally distributed between both arms. Keating et al.4 have reported that the capacity to harvest high numbers of CD34+ cells can be considered as an independent poor prognosis factor, reflecting a low sensitivity for chemotherapy with less efficient in vivo purging of leukemic stem cells. In this study, most of the patients (75%) in each arm received a graft collected after early intensification, and the capacity of mobilization was indeed significantly higher in arm B. Finally, the timing of the second auto-HSCT in arm B could also explain the lack of superiority of the double auto-HSCT schedule. Several patients in arm A did receive another auto-HSCT at relapse because of the availability of a graft collected in first-line therapy. The poor outcome of AML patients who relapse after auto-HSCT has previously been shown to be improved by a second auto-HSCT.5 Consistent with the results reported in this study, this raises the question of delaying the second auto-HSCT until relapse rather than proposing two successive auto-HSCTs straightaway. Although a recent relatively large study showed the feasibility of good CD34+ mobilization at relapse in AML patients,6 the availability of a previously collected graft could alleviate mobilization in retreated patients, and limit the risk of harvesting more resistant cells. Auto-HSCT results were particularly poor in patients with high-risk cytogenetics or in those who achieved CR after two courses of induction. The dismal prognosis of such patients suggests that they would rather benefit from allogeneic transplantation.7 Conversely, the study reported here confirms the good results of auto-HSCT in AML patients with favorable cytogenetics and no sibling donor.8

In conclusion, in spite of an acceptable toxicity, this study shows the absence of any potential benefit of adding high-dose melphalan supported by a second auto-HSCT compared with a conventional auto-HSCT conditioned by busulfan/HDM, in adult de novo AML patients under 60 years in first CR and in candidates for an auto-HSCT. Collection of stem cells for a second auto-HSCT in case of relapse and/or conditioning regimen using alternative antileukemic drugs should therefore be preferentially considered.

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Correspondence to P Chevallier.

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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 24, 1380–1385 (2010) doi:10.1038/leu.2010.111

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