Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit – multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group

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Abstract

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60±4 and 48±4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52±4% for non-allografted patients and 57±7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT−) than in patients randomized for MT (77.6±8 vs 59±8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

Main

From 1989, the French group LAME has coordinated a series of clinical trials in AML.

Background and treatment strategy of the LAME (Leucémie Aiguë Myéloblastique Enfant) trials

Before 1989, children with AML had been treated according to adult AML regimens. The 01.AM.81 protocol used a drug combination including AML-specific drugs (cytarabine and anthracyclines). Out of 83 children, 76 achieved complete remission (CR); 91 vs 75% in adults. A plateau was reached early at 24 months; event-free-survival (EFS) at 84 months was 30%, higher than in adult patients (20%).1

Study LAME 89: This regimen included an induction phase (high dose of mitoxantrone plus cytarabine) and two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine. The role of myeloablative therapy followed by allo-BMT from an HLA-identical sibling for improving disease-free survival (DFS) in children with AML in CR1 was examined in this study.2 The results are now available on a long term.

Randomized study LAME 91: The major issue was how best to maintain CR for patients without an HLA sibling donor. Our group undertook a prospective randomized trial, the main aim of which was to assess the efficacy of maintenance therapy (MT) in addition to an intensive induction and consolidation chemotherapy. The results of this randomized study have been published previously.3 Results are now updated and described in a higher number of patients.

LAME SP: From 1997 to 1998, the use of timed-sequencing of the highly intensive LAME induction chemotherapy (LAME SP) was investigated in a LAME sequential pilot study and the results are reported herein.

Patients and methods

Patients

The treatment schedules of the LAME protocols including drug dosage are summarized in Table 1a, Table 2 and Figure 1. Inclusion criteria are indicated in Table 1b.

Table 1 (a) Patient accrual and follow-up and (b) Eligibility criteria
Table 2 Treatment elements in the three LAME studies 1989–1999
Figure 1
figure1

Flow diagram of studies LAME 89–91 and LAME SP.

According to the selection criteria, 309 children from 18 institutions were registered in the LAME 89/91 protocol between December 1988 and December 1998. From 1997 to 1998, 32 patients were included in the LAME SP phase, according to the same criteria (Table 1a).

Induction treatment

The previously described LAME 89/91 induction therapy3 has been detailed in Figure 1 and Table 2; patients who had more than 20% marrow blasts received reinforcement chemotherapy consisting of cytarabine at 200 mg/m2/day by continuous i.v. infusion for 3 days and mitoxantrone at 12 mg/m2/day for 2 days. Infants received two-thirds of these doses.

Timed-sequential induction treatment (LAME SP study)

From 1997 to 1998, timed-sequencing of cycles of induction chemotherapy was proposed in the LAME SP study; the second cycle was delivered despite low or dropping blood tests, 8–14 days after the first cycle (Table 2).

Allo-BMT in CR1

Allo-BMT was offered to all patients where an HLA-identical family donor was available. Allo-BMT was given after one or two courses of consolidation therapy. A total of 46 children were conditioned with 16 mg/kg busulfan and 200 mg/kg cyclophosphamide, eight received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide, and 17 patients were prepared with total-body irradiation (TBI) most often associated with 120 mg/kg of cyclophosphamide.

Autologous bone marrow transplantation for infants in CR1

While no autologous bone marrow transplantation (ABMT) in CR1 was scheduled in the LAME 89/91, 14 infants actually underwent this procedure.

Postremission therapy

The two consolidation courses were previously described3 and are summarized in Figure 1 and Table 2; infants received only the cytarabine–asparaginase combination.

Maintenance therapy

After consolidation chemotherapy, patients were treated with an 18-month maintenance program (Figure 1, Table 2). In March 1991, a decision was made by the participating centers to randomize children in first CR to receive MT or no further therapy after consolidation 2. This randomization was centrally performed at the time of hematological recovery following consolidation 2. In July 1996, owing to the preliminary results, a decision was made to delete this therapeutic phase (Table 2).

Total cumulative doses (induction, consolidations and maintenance): see Supplementary Figure 1

Total cumulative dose of intercalating agents was 460 mg/m2 (given as daunorubicin dose with the conversion factors, daunorubicin/doxorubicin: mitoxantrone, 1 : 5). Additionally, a 450 mg/m2 amsacrine cumulative dose was delivered. Total cumulative dose of cytarabine was 13 400 mg/m2 for patients with MT and 9800 mg/m2 for patients without MT.

CNS prophylaxis

CNS prophylaxis was administered to patients with the M4 or the M5 FAB subtypes and to patients with an initial white blood cells (WBC) count higher than 50 × 109/l. These patients were given intrathecal chemotherapy (IT) with five doses of cytarabine, methotrexate and steroid: two IT during induction therapy and three during consolidation 1. Patients with initial CNS involvement were given three additional IT doses (two during induction and one during consolidation 1) and 24 Gy cranial radiation after hematological recovery from consolidation 2.

Statistical methods

The analysis was performed in April 2004 with a follow-up which was at least 3 years for all the patients in CCR. Distributions of qualitative variables were compared with the χ2-test or with the two-tailed Fisher's exact test. Comparisons of continuous variables were made using the Student's t-test. Median values of these quantitative variables were given with their 95% interval. EFS, DFS, and overall survival (OS) were estimated with the Kaplan–Meier method. Survival was calculated from the date of diagnosis to death of any cause or last follow-up. EFS was based on the total group of patients who entered the study, whether or not they had achieved complete remission. EFS was calculated from the date of diagnosis to last follow-up or first event (failure to achieve remission, resistant leukemia, relapse, second malignancy or death of any cause). For DFS, the relevant event was either relapse of leukemia, second malignancy, or death regardless of cause, with a starting point from the time of remission. To study the impact of MT, DFS and OS were also calculated from the day of randomization. For nonrandomized patients, the end point was calculated as from the time of hematological recovery following consolidation 2. All the patients in CR1 with an HLA-identical family donor actually received the scheduled allo-BMT; the comparisons between chemotherapy and allo-BMT were adjusted for time-to-transplant.

Results

Patients characteristics

A total of 341 patients entered the LAME protocols: LAME 89 (n=47), LAME 91 (n=262), LAME SP (n=32). The distribution according to gender, age, WBC count, CNS involvement, FAB classification and cytogenetics have been described in Table 3. Of the 309 patients who entered the LAME 89/91 protocol, 146 were boys and 163 were girls, with a median age of 6.9 years, 42 children (13%) were under 1-year old and the median of the WBC count at diagnosis was 25.6 × 109/l.

Table 3 Initial patient data of studies LAME 89, LAME 91 and LAME SP

Induction outcome of LAME 89 and LAME 91

Detailed results of induction outcome in LAME 89 and LAME 91 protocols are reported in Table 4a. Taken together, 277 of the 309 children achieved a CR (90%). The median duration of neutropenia (neutrophils <0.5 × 109/l) was 31 days (range: 6–85) and the median duration of thrombopenia (platelets <25 × 109/l) was 27 days (range: 5–118). The induction death rate was 5%; there were six deaths before day 8, nine toxic deaths and 17 leukemic failures. No clinical prognostic factor was associated with achievement of CR among the following variables: age (<1-year old vs 1-year old), WBC count (<50 × 109/l vs 50 × 109/l), FAB subtypes (M4–M5 vs others), meningeal involvement and need for an additional course at day 21.

Table 4 Results in studies LAME 89, LAME 91 and LAME SP: (a) total groups and patients 0–14 years of age at diagnosis and (b) death before or during induction and intensification (total groups)

Induction outcome: LAME SP phase

Of the 32 children included in the LAME SP 27 achieved complete remission (84%). Data are reported on Table 4a. The induction death rate was 3%; there was no death before day 8 and one toxic death. The median duration of neutropenia (neutrophils <0.5 × 109/l) and of thrombopenia (platelets <25 × 109/l) was, respectively, 51 and 47 days. The median duration between day 1 of induction therapy and day 1 of consolidation 2 was significantly higher in the LAME SP study than in the LAME 89/91 (98 vs 76 days; P=0.01).

Treatment allocation in LAME 89/91 protocol: see Supplementary Figure 2

All the 74 patients in CR1 with an HLA-identical family donor actually received the scheduled allo-BMT (median of duration of the CR-BMT period: 82 days).

The treatment-related mortality of the two courses of postremission therapy was 6%. Two toxic deaths were recorded during consolidation 1 (septicemia and toxic shock) and 10 during consolidation 2, all of them related to infection (interstitial pneumonia; n=1, pneumonia; n=3, aspergillosis; n=3, septicemia and toxic shock; n=3). Following consolidation 2, the median duration of neutropenia (ANC <0.5 × 109/l) was 37 days (range: 3–100) and the median duration of thrombopenia (platelets <25 × 109/l) was 36 days (range: 3–190).

Potential biases or confounding variables (randomized study)

Details regarding randomized and nonrandomized patients were reported previously as well as the reasons why patients were not randomized.3 Overall compliance of patients for randomization was 68.6%; 70 were randomized and evaluable (36 with and 34 without MT). The pretreatment characteristics of patients in the two randomized arms were similar.

Global results

The results of the LAME 89, LAME 91 and LAME SP studies are given in Table 4a. The global LAME 89/91 EFS, DFS and OS at 5 years were, respectively, 48±4 (Figure 2), 53±4 and 60±4% (see Supplementary Figures 3 and 4). The results in 0–14-year-old patients are presented separately in order to facilitate the comparisons with other studies (Table 4a).

Figure 2
figure2

Event-free survival in patients of the LAME 89/91 study (n=309); at 5-year EFS was 48±4%.

For the 32 patients included in the LAME SP study, the EFS, DFS and OS were, respectively, 54.8±10, 61.6±10 and 71.9±8% (Table 4a).

Results of allo-BMT (LAME 89/91)

The DFS was 52±4% for non-allografted patients and 57±7% for allografted patients (P=0.18). The OS was 55.4±4% for non-allografted patients and 70.5±7% for allografted patients (P=0.006).

Results according to prognostic factors in LAME 89/91

Table 5 details the results according to different risk parameters in study LAME 89/91. A 5-year pEFS was significantly higher in patients with low WBC count (P=0.02). Differences did not reach statistical significance for age, FAB classification, cytogenetic subtypes and percentage of marrow blasts on day 20. Moreover, OS was significantly higher in patients with favorable cytogenetic findings (t(8;21), t(9;11), t(15;17), inv(16) vs others; P=0.005), in patients with low WBC count (P=0.01), in patients achieving a CR1 with less than 20% marrow blasts on day 20 (P=0.03) and in patients receiving an allo-BMT in CR1 (P=0.006) (Table 5). Gender, age, CNS involvement and FAB subtype were of no prognostic significance.

Table 5 Results according to different risk parameters in study LAME 89–91 (5-year pEFS (%))

Results in infants (LAME 89/91)

Out of 42 infants 36 (85%) achieved a CR. In all, 17 relapses and two deaths in CR occurred. The EFS was 37.3±8%. DFS was 64±25% with autograft (n=14) and 15±17% with chemotherapy alone (n=18) (P=0.12), and OS was, respectively, 82±21 vs 15±17% (P=0.01).

Results according to maintenance treatment (LAME 89/91)

For randomized patients, DFS was 51±8% with MT and 62.4±8 without MT (P=0.25) (see Supplementary Figure 5), and OS was, respectively, 59±8 vs 77.6±8% (Figure 3; P=0.05). One toxic death occurred during MT and was related to Fulminans hepatitis. Out of 70 patients 31 relapsed; MT−randomized patients had a higher likelihood of achieving a second CR than did MT+ patients (11/13 vs 8/18; P=0.03).

Figure 3
figure3

Overall survival comparison of randomized patients with maintenance therapy vs those without maintenance therapy, with time from the day of randomization. LAME 91 5-year pOS with MT (- - - - - -): 59±8% (n=36); 5-year pOS without MT (——): 77.6±8% (n=34). P=0.05.

For the whole population, including randomized and nonrandomized patients, the DFS was 51.9±6% for MT+ patients and 62.2±6% for MT− patients (P=0.2). The OS was 60.2±6% for MT+ patients and 73.4±6% for MT− patients (P=0.1). The probability to achieve a second CR was significantly higher for MT− patients than for MT+ patients (19/28 vs 14/34; P=0.04).

Discussion

With the LAME 89/91 SP intensive chemotherapy regimen, more than half of the children have been cured. Either drug intensity or each of the therapeutic phases may have contributed to the improvement in outcome.

Induction therapy

The 90% CR rate is within the range of the best results recently reported from large trial groups.4, 5, 6, 7, 8, 9, 10, 11 The only previously reported remission rate above 90% was obtained with the MRC AML 10 protocol after four courses of chemotherapy, while the CR rate was 63% after one course and 82% after two courses of induction therapy.8 Intensifying induction therapy has been demonstrated to improve long-term prognosis in AML, irrespective of the postremission regimen, chemotherapy or autograft or allograft.6

On the other hand, timed-sequencing of cycles of the very intensive LAME induction chemotherapy led to extremely prolonged durations of neutropenia and thrombopenia in the LAME SP regimen and failed to translate into further increase of drug intensity. Ultimately, this LAME SP approach did not further improve either CR rate or EFS.

Allo-BMT in CR1

Overall, superiority of allo-BMT in reducing the relapse risk and increasing DFS was suggested in our preliminary LAME 89/91 report.2 Busulfan–cyclophosphamide at 200 mg/kg appeared as the best conditioning regimen.12 However, this difference was no longer significant on a long term and the better OS for allografted patients, which was shown in our study, could be related either to allo-BMT early in CR1 or to the availability of an HLA-identical family donor for a second allo-BMT in CR2.13

In the large CCG-2891 trial, allo-BMT in first remission is the treatment of choice for AML in children and adolescents with a matched related donor, irrespective of the induction therapy.14 However, in the French adult and children AML Intergroup experience (including LAME 89/91 cohort), allo-BMT in CR1 did not significantly improve the outcome of patients with t(8;21) or inv(16) AML.15, 16

Postremission therapy

In the LAME 89/91 protocol, consolidation 2 consisted of an intensive sequentially timed association of high-dose cytarabine, asparaginase and amsacrine. Dose escalation of cytarabine was used in most of the recent pediatric studies and the CCG 213P trial demonstrated the importance of the timing of high-dose cytarabine consolidation.17 The optimal number of postremission cycles has still not been determined. The best results were documented with a very short, four-course, induction and cyclic intensification therapy in the MRC AML 10 protocol.8, 10 Of note is that the MRC AML and LAME protocols are the only ones to include, according to various modalities, three different DNA intercalators, daunorubicin, mitoxantrone and amsacrine (Figure 1).

Toxicity of drug-intensive regimens

The induction and consolidation lethal toxicity (5 and 6%, respectively) with the LAME 89/91 SP regimen were substantial (Table 4b), within the range of rates reported elsewhere in large multicenter studies of AML.6, 18

Postremission therapy in infants

In our study, despite a satisfactory CR rate in infants, the high relapse rate resulted in an extremely low OS for those treated with chemotherapy alone (15%); of note is that infants were treated without amsacrine. Comparison of the results of ABMT with outcome of chemotherapy was not randomized; the apparent improvement of OS in autografted patients might be due as well to time censoring of the transplant cohort as to more intensive therapy.

Maintenance therapy

MT can improve DFS in adult AML.19 The BFM protocol has successfully explored this approach in childhood.11 In our randomized study, MT not only failed to improve the 5-year DFS and to prevent relapse, but MT+ patients did significantly worse than MT− patients in terms of OS.3 Similarly, in the randomized CCG trial 213, MT was demonstrated to be inferior, in terms of survival, to stopping therapy.20 The LAME 89/91 trial results suggested that the survival benefit in MT− patients was related to a higher salvage after relapse.3, 13 It may be that long-term exposure to low-dose cytarabine in the maintenance group will increase MDR1 gene upregulation in AML blasts.21 Alternatively, mechanisms other than MDR1 might be responsible for the development of clinical drug resistance.22, 23, 24

Cure rate in AML has improved with intensive induction and postremission therapy with optimized timing. The best results were obtained with the most drug-intensive regimens. In our experience, low-dose MT is of no benefit in childhood AML after intensive chemotherapy.

Our LAME SP preliminary results have suggested that further intensified induction therapy leads to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity, the indication of which could be limited to poor-risk leukemia and relapse, according to a risk-directed strategy in AML. Alternatively, while allo-BMT from a matched family donor remains the treatment of choice for most patients in CR1, this procedure might be postponed until CR2 in subgroups (t(8;21) and/or inv(16)).

Alternative approaches or new better agents are necessary. The clinical impact of differentiating, immune or targeted therapies25, 26, 27, 28, 29 could be assessed at the best once minimal residual disease has been achieved, after consolidation therapy.

The following options will be prospectively addressed in the forthcoming LAME protocol:

  • to carry on with an intensive regimen including the LAME 89/91 unmodified induction therapy and three consolidations delivered over a short period;

  • to match treatment with prognostic factors (cytogenetics, marrow response on day 15);

  • to offer an allo-BMT to non-low risk patients where an HLA-identical family donor is available;

  • to determine whether the use of low-dose IL2, delivered after intensive induction and consolidation therapy appears manageable and confers any advantage in childhood AML.

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Correspondence to Y Perel.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu).

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Perel, Y., Auvrignon, A., Leblanc, T. et al. Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit – multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group. Leukemia 19, 2082–2089 (2005) doi:10.1038/sj.leu.2403867

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Keywords

  • childhood
  • acute myeloid leukemia
  • dose intensification
  • bone marrow transplantation
  • maintenance therapy

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