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Impact of Addition of Maintenance Therapy to Intensive Induction and Consolidation Chemotherapy for Childhood Acute Myeloblastic Leukemia: Results of a Prospective Randomized Trial, LAME 89/91

From the Centres Hospitalo-Universitaires de Bordeaux, Paris-Trousseau, Paris-St Louis, Rouen, Marseille, Lille, Rennes, Nancy, Tours, Limoges, Paris Bicetre, and Dijon, France.

Address reprint requests to Yves Perel, MD, Unité d’Onco-Hématologie, Département de Pédiatrie, Hôpital des Enfants, Groupe Hospitalier Pellegrin, Place Amélie Raba-Léon, 33076 Bordeaux Cédex, France; email: yves.perel{at}chu-bordeaux.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To determine whether the use of maintenance therapy (MT) delivered after intensive induction and consolidation therapy confers any advantage in childhood acute myeloid leukemia (AML).

PATIENTS AND METHODS: A total of 268 children with AML were registered in the Leucámie Aiquë Myéloïde Enfant (LAME) 89/91 protocol. This regimen included an intensive induction phase (mitoxantrone plus cytarabine) and, for patients without allograft, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase, and amsacrine. In the LAME 89 pilot study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to receive or not receive MT.

RESULTS: A total of 241 (90%) of 268 patients achieved a complete remission. The overall survival and event-free survival at 6 years were 60% ± 6% and 48% ± 6%, respectively. For the complete responders after consolidation therapy, the 5-year disease-free survival was not significantly different in MT-negative and in MT-positive randomized patients (respectively, 60% ± 19% v 50% ± 15%; P = .25), whereas the 5-year overall survival was significantly better in MT-negative randomized patients (81% ± 13% v 58% ± 15%; P = .04) due to a higher salvage rate after relapse.

CONCLUSION: More than 50% of patients can be cured of AML in childhood. Either drug intensity or each of the induction and postremission phases may have contributed to the outstanding improvement in outcome. Low-dose MT is not recommended. Exposure to this low-dose MT may contribute to clinical drug resistance and treatment failure in patients who experience relapse.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
OVER THE PAST 20 years, the outcome of treatment of acute myeloid leukemia (AML) in children has improved substantially. In the 1980s, in our previous experience,^1,2 complete remission (CR) was achieved in nearly 90% of patients, but event-free survival (EFS) was 30%, as in other protocols.^3,4 Myeloablative therapy followed by allogenic bone marrow transplantation (allo-BMT) from an HLA-identical sibling was demonstrated, in our experience, to be the treatment of choice for improving disease-free survival (DFS) in children with AML in first remission.⁵ The major issue was how best to maintain CR for patients without an HLA-matched sibling donor.

Several childhood AML regimen protocols introduced intensified consolidation therapy and high-dose cytarabine.^6-8 In a pilot study (Leucámie Aiquë Myéloïde Enfant [LAME] 89), we tested the feasibility of intensive consolidation with high-dose cytarabine, asparaginase, and amsacrine, followed by maintenance treatment. Maintenance therapy (MT) in acute lymphoblastic leukemia is considered to be a prerequisite for cure, but the efficacy of such a treatment for AML, after intensive postremission therapy, has been controversial; although the Children’s Cancer Group (CCG)-213 study was under way,⁹ no large, cooperative, randomized study had reported their findings regarding the efficacy of MT at the time when the LAME protocol was initiated. Although several groups continued to include low-dose MT^10-12 and others decided to omit it,^13,14 our group undertook a prospective randomized trial (LAME 91 protocol), the main aim of which was to assess the efficacy of MT in addition to an intensive induction and consolidation chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
Inclusion criteria in the LAME 89/91 protocol were as follows: de novo AML with a French-American-British (FAB) subtype ranging from M1 to M6, age less than 20 years, and written informed consent of the patient or parent. Patients with M0, M7, or biphenotypic leukemia and secondary AML and patients with Down’s syndrome were not included. According to the selection criteria, 268 children from 18 institutions were registered in the protocol between December 1988 and June 1996.

Treatment
Induction therapy was a combination of cytarabine at 200 mg/m²/d by continuous intravenous (IV) infusion from day 1 to day 7 and mitoxantrone at 12 mg/m²/d IV from day 1 to day 5. Children younger than 1 year received two thirds of these doses. Bone marrow aspiration was performed on day 20, and patients who had more than 20% blasts received additional chemotherapy consisting of cytarabine at 200 mg/m²/d by continuous IV infusion for 3 days and mitoxantrone at 12 mg/m²/d for 2 days. CR was defined as less than 5% blasts in a normocellular bone marrow with no evidence of extramedullary leukemia and normal blood counts.

All the patients in first CR (CR1) with an HLA-identical family donor were treated with an allo-BMT. Patients without an HLA-matched family donor were treated with two courses of consolidation therapy.

Consolidation 1 was a combination of etoposide (100 mg/m²/d IV, 1-hour infusion from day 1 to day 4), cytarabine (100 mg/m²/d as a continuous IV infusion from day 1 to day 4), daunorubicin (40 mg/m²/d IV, 1-hour infusion from day 1 to day 4). Consolidation 2, which was given after complete hematologic recovery, consisted of two cycles of cytarabine infusions, administered at 7-day interval (each cycle; 1 g/m², 1-hour infusion, once every 12 hours, four doses, followed by one dose of asparaginase at 6,000 U/m²). Between the two cytarabine cycles, children older than 1 year received amsacrine at 150 mg/m²/d IV by 1-hour infusion on days 4, 5, and 6.

After consolidation chemotherapy, patients were treated with an 18-month maintenance program consisting of continuous oral mercaptopurine at 50 mg/m²/d and monthly pulses of subcutaneous cytarabine at 25 mg/m² twice a day for 4 days. 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 hematologic recovery after consolidation 2.

CNS prophylaxis was administered to patients with the M4 or the M5 FAB subtypes and to patients with an initial WBC count higher than 50 x 10⁹/L. These patients were provided intrathecal chemotherapy with five doses of cytarabine, methotrexate, and corticosteroid. Two intrathecal chemotherapy sessions were performed during induction therapy (on day 1 and at the time of hematologic recovery) and three during consolidation 1 (on days 1, 5, and 20). Patients with initial CNS involvement were provided three additional intrathecal chemotherapy doses (two during induction and one during consolidation 1) and 24-Gy cranial radiation after hematologic recovery from consolidation 2. Patients who experienced relapse were treated according to various chemotherapy regimens with or without stem-cell transplantation, depending on the availability of a suitable donor.

Statistical Analysis
The analysis was performed in December 1999. Distributions of qualitative variables were compared with the ² test or with the two-tailed Fisher’s exact test. Comparisons of continuous variables were performed by Student’s t test. Median values of these quantitative variables were given with their 95% confidence interval. EFS, DFS, and overall survival (OS) were estimated with the Kaplan-Meier method. EFS was calculated from the day of diagnosis and was defined as the estimated number of patients alive and free of disease, based on the total group of patients who entered the study, whether or not they had achieved CR.

For DFS, the relevant event was either relapse of leukemia or death regardless of cause, with a starting point from the time of remission (from the date of transplantation for patients who received allografts). To study the effect 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 hematologic recovery after consolidation 2. These probabilities are reported with their 95% confidence interval. In the univariate analysis, comparisons of Kaplan-Meier curves were made by log-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
Of the 268 patients who entered the protocol, 128 were boys and 140 were girls, with a median age of 6.9 years. A total of 33 children (12%) were younger than 1 year. The median of the WBC count at diagnosis was 25.6 x 10⁹/L, and the distribution of FAB subtypes was as follows: M1 (n = 34), M2 (n = 77), M3 (n = 17), M4 (n = 40), M_4Eo (n = 16), M5 (n = 77), and M6 (n = 7). Bulky hepatosplenomegaly, defined as either spleen or liver enlargement below the umbilicus, was observed in 29 patients (11%). Twenty-eight children (10%) had initial CNS involvement.

Induction Outcome
A total of 241 (90%) of 268 children achieved CR, 225 after one course of induction chemotherapy (84%) and 16 after the day 21 reinforcement. The median duration of neutropenia (neutrophils < 0.5 x 10⁹/L) was 31 days (range, 6 to 85 days) and the median duration of thrombocytopenia (platelets < 25 x 10⁹/L) was 27 days (range, 5 to 118 days). The induction toxic death rate was 5%; there were four early deaths (< 8 days), eight toxic deaths, and 15 leukemic failures. No clinical prognostic factor was associated with achievement of CR among the following variables: age (< 1 year old v 1 year old), WBC count (< 50 x 10⁹/L v 50 x 10⁹/L), FAB subtypes (M4 and M5 v others), bulky hepatosplenomegaly, meningeal involvement, and need for an additional course at day 21.

Treatment Allocation
Patient numbers according to treatment arms are illustrated in Fig 1. Of the 241 patients in CR, 66 were given an allo-BMT; all the patients in CR1 with an HLA-identical family donor actually received the scheduled allo-BMT. The results of allo-BMT and of the comparison between allo-BMT and intensive postremission chemotherapy have been previously reported in detail.⁵ A total of 160 patients were provided consolidation 1 therapy, and 152 were provided consolidation 2 therapy. The treatment-related mortality of the two courses of postremission therapy was 6%.

View larger version (50K): [in this window] [in a new window]   Fig 1. Flow diagram showing the numbers of patients according to treatment arm.

Potential Biases or Confounding Variables
Table 1 lists the pretreatment characteristics of patients in the two randomized arms. A total of 139 patients were eligible for MT; 70 were randomized and assessable (36 with and 34 without). Sixty-nine were not randomized (MT-positive, n = 35; MT-negative, n = 34); 22 were scheduled for MT and seven for no further treatment because they had been included in the pilot phase. In eight patients, poor hematologic recovery from consolidation 2 (> 3 months of neutropenia or thrombocytopenia) or severe infectious complications (lung aspergillosis) did not allow the administration of further therapy. If patients of the pilot phase and for whom no further therapy could be administered are excluded, overall compliance of patients for randomization was 68.6%.

Table 2 lists the relapsing randomized patient characteristics and treatments. Relapsing patients were treated according to various chemotherapy regimens; the median of CR1 duration was 8 months (mean, 10 months; range, 3 to 32 months) and 10 months (mean, 14 months; range, 6 to 50 months) for MT-positive and MT-negative relapsing patients, respectively. Patients in second CR were given a genoidentical allo-BMT (from an HLA-identical sibling born after CR1 achievement; n = 2), a cord-blood transplantation from an HLA-identical sibling (n = 1), an allo-BMT from an HLA-identical unrelated donor or from a mismatched donor (n = 4), or an autologous BMT (n = 12).

View larger version (12K): [in this window] [in a new window]   Fig 2. EFS (n = 268, solid line) and OS (n = 268, dotted line) in patients of the LAME 89/91 study. At 6 years, EFS was 48% ± 6%, and OS was 60% ± 6%.

View larger version (9K): [in this window] [in a new window]   Fig 3. DFS of patients who did not receive allografts in the LAME 89/91 study with time from the date of remission. At 6 years, DFS of these patients was 50% ± 7%.

View larger version (11K): [in this window] [in a new window]   Fig 4. OS comparison of randomized patients with MT versus without MT, with time from the day of randomization. Dotted line, OS with MT (n = 36); solid line, OS without MT (n = 34) (P = .04).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
With the LAME 89/91 intensive chemotherapy regimen, more than half of the children have been cured (Figs 2 and 3). This is a tremendous improvement over our previous experience.^1,2 Our results compare favorably with the more recently published studies of AML in children (Table 4).^10-17 It should be noted that there is some heterogeneity regarding criteria of inclusion or definition of end points in these studies, and any conclusion should be interpreted with great caution. The hallmark of the LAME 89/91 protocol is drug intensity; only three intensive cycles were delivered over a short period, including induction therapy and two consolidations. Either drug intensity or each of these therapeutic phases may have contributed to the improvement in outcome.

Cytarabine infusion daily in combination with 3 days of mitoxantrone at 12 mg/m² was reported to be at least as effective as cytarabine with 3 days of daunorubicin at 45 mg/m² in adult patients.²⁰ At the time we embarked on this study, the dose of mitoxantrone at 12 mg/m² for 5 days was established as the maximum tolerated dose and was scheduled accordingly.²¹ Intensifying induction therapy has been claimed to improve long-term prognosis in AML.¹⁸ In 1996, Woods et al¹⁵ reported the results of the randomized CCG-2891 trial, which definitely supported this approach in childhood AML. Patients were randomly assigned to receive an intensive timing induction (a second identical dexamethasone, cytarabine, 6-thioguanine, etoposide, and daunorubicin cycle 10 days after the first one) or the standard timing regimen (second cycle 14 days or later from the beginning of the first cycle, depending on response). CR rates were identical, but the DFS rate of patients achieving remission was better for intensive timing induction, irrespective of the postremission regimen, chemotherapy, or autograft or allograft.¹⁵

Children who achieve CR have occult residual disease requiring intensified therapy or allo-BMT early in first remission.^3,19 Superiority of allo-BMT in reducing the relapse risk and increasing DFS was suggested in our previous LAME 89/91 report.⁵ In the large CCG-2891 trial, allo-BMT in first remission is the treatment of choice for AML children and adolescents with a matched related donor, irrespective of the induction therapy.²² In the LAME 89/91 protocol, for patients lacking a family donor, consolidation 2, consisting of a sequentially timed combination of high-dose cytarabine, asparaginase, and amsacrine, was the most intensive phase of the postremission therapy. Dose escalation of cytarabine has been the paradigm for intensification in AML in both children and adults.^8,23 It was used in most of the recent studies in children.^10-17 The CCG-213 trial demonstrated the importance of timing of high-dose cytarabine consolidation, in that two courses of cytarabine and asparaginase at 7-day interval, as designed by Capizzi et al,²⁴ gave a better 5-year survival than the same therapy delivered at a 28-day interval.^7,25

The optimal number of postremission cycles has still not been determined.^12,13,22 The best results were documented with a short, four-course, induction and cyclic intensification therapy in the MRC AML 10 protocol.¹³ Equally good long-term results were obtained with the use of only three induction and intensification courses in the LAME 89/91 protocol (Table 4), evidencing the role of drug intensity. Of note is that these two protocols are the only ones to include, according to various modalities, three different DNA intercalators, ie, daunorubicin, mitoxantrone, and amsacrine (Table 4).

The induction lethal toxicity (5%) with the LAME 89/91 regimen is within the range of rates reported elsewhere in large multicenter studies of AML, ie, 5% in the Pediatric Oncology Group (POG) 8498 AML study,⁸ 6% in the MRC AML 10 protocol,²⁶ or 8% in the CCG-2891 protocol.¹⁵ On the whole, the treatment-related mortality of the two courses of postremission therapy was still substantial, at 6%; the median time for neutrophilic recovery (37 days) after the second consolidation leads to a high infectious mortality rate. Similarly, a 6% mortality rate in CR was reported with the AML 10 protocol, the postremission therapy of which was based on three cycles of intensive chemotherapy²⁶; and at least equally high mortality rate (7.6%) was reported after the intensive consolidation approach of the CCG-213 protocol.⁹

After standard-dose induction therapy, low-dose MT can improve DFS compared with no further therapy, at least in a subset of patients,²⁷ both in adults^28,29 and in children.³ The Berlin-Frankfurt-Munster protocol has successfully explored this approach. With an 8-week intensive induction-consolidation and cranial radiation therapy, followed by 2 years of moderate-dose MT, CR was achieved in 79% of patients with a 5-year EFS at 43%^11,30; improved results were obtained with the introduction of an intensification block with a 5-year EFS at 51%.¹² In our randomized study, MT not only failed to improve the 5-year DFS and to prevent relapse, but MT-positive patients did significantly worse than MT-negative patients in terms of OS.

Several potential prognostic factors^31-33 were examined for any confounding effect (Table 1). Only 70 of 139 eligible patients were randomized; we have no evidence that, in terms of risk factors,^31-33 there was any difference between MT-positive and MT-negative patients (Table 1). Additionally, patients fared no differently whether the allocation to MT was electively or randomly assigned; the negative predictive value of MT is demonstrated in randomized patients and is also suggested in all patients as treated. Similarly, low-level MT was previously reported to confer no apparent advantage in survival after intensive induction and consolidation therapy.³⁴ In the randomized CCG-213 trial, a phase of aggressive intensification eliminates the benefit of MT, which was, in addition, even demonstrated to be inferior, in terms of survival, to stopping therapy.⁹

It is worth noting that the good long-term EFS for patients without allograft with the AML 10 MRC regimen was obtained without any low-dose MT.¹³ We therefore advise against the delivery of low-dose MT after intensive regimens for AML in children. However, we cannot rule out that use of intermittent higher-dose MT might still be beneficial, especially after standard-dose induction therapy; 12 courses of maintenance intensification produced better DFS than four courses (48% v 34%) in AML in adults.³⁵ In the POG 8498 AML study,⁸ the Leucamia Acuta Mieloide 8204 Associazone Italiena Ematologica ed Oncologica Pediatrica study,¹⁷ the postremission chemotherapy regimens consisted of cyclic maintenance intensification courses, with long-term DFS at 36% and 27%.

In the LAME 89/91 trial, only one death in CR occurred during MT, with the result that the difference in terms of OS could not be related to toxicity. On the other hand, although the prognosis for patients with marrow relapse is poor, the prospect of salvage therapy is not unattainable.³⁶ The probability of achieving a second CR was significantly better for MT-negative patients than for MT-positive patients, both in the randomized study and in all patients as treated. We suggest that the benefit in MT-negative patients—that is, a better survival without either a significantly better DFS or a lowered toxic death rate—is related to the higher rate of salvage therapy after relapse (Table 3).

The mechanism leading to treatment failure in relapsing MT-positive patients remains unclear. Acquired drug resistance in the maintenance group might help to explain the lower second CR rates. P-glycoprotein (Pgp), which is the product of the multidrug resistance gene (MDR1), has been reported to be an important predictor of treatment outcome in AML.^37,38 It has been suggested that Pgp expression in AML blasts could be strongly upregulated by cytarabine, and that it is correlated with clinical drug resistance³⁹; it may be that long-term exposure to low-dose cytarabine will increase Pgp expression and that this MDR1 gene upregulation will ultimately be associated, as in our study, with a higher rate of refractory disease after relapse in MT-positive patients. However, a study in paired samples of patients with AML demonstrated that there was no evidence of a multidrug-resistance–related clonal selection in the evolution of AML to relapse or refractory disease⁴⁰; mechanisms other than MDR1 might be responsible for the development of clinical drug resistance.^41,42 Finally, although we had no evidence that in term of risk factors, reinduction therapy or BMT in the second CR, there was any difference between relapsing MT-positive and MT-negative patients (Table 2), we cannot rule out that the poor response to salvage therapy might be due to a primary resistance to chemotherapy.

The cure rate in AML has improved with intensive induction and postremission therapy with optimized timing.^12,13,15 The best results were obtained with the most drug-intensive regimens.^12-13 We have demonstrated that low-dose MT is of no benefit in childhood AML after intensive chemotherapy. Other strategies, such as further increased intensity⁴³ or new, better agents (interleukin-2,⁴⁴fludarabin,⁴⁵ 2-chlorodeoxy-adenosine,⁴⁶ or chemotherapy resistance modifier⁴⁷), should be explored. However, the benefits of further intensification of chemotherapy should be balanced against the risks of severe or lethal toxicity.^26,48 Alternatively, the indication of further intensified chemotherapy or new drugs could be limited to poor-risk leukemia, provided that a uniform prognostic index is widely recognized and therefore applied for stratification and risk-directed therapy in AML.^31,32 These options will be prospectively addressed in the currently elaborated LAME 2001 protocol.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

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Submitted July 10, 2001; accepted March 12, 2002.

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