Relevance of a One-Year Maintenance Therapy with Interleukin-2 in the Treatment of Childhood Acute Myeloid Leukemia: Results from the French Multicenter, Phase III, Randomized Controlled Sfce Trial, ELAM02
Authors: Petit Arnaud , Ducassou Stéphane , Leblanc Thierry , Pasquet Marlène , Rousseau Alexandra , Ragu Christine , Cachanado Marine , Nelken Brigitte , Bertrand Yves , Michel Gérard , Gandemer Virginie , Cuccuini Wendy , Dastugue Nicole , Fenneteau Odile , Lapillonne Hélène , Auvrignon Anne , Baruchel André , Leverger Guy 
Published: October 2019

Abstract

Background: Childhood acute myeloid leukemia (AML) remains a challenging disease as the outcome is still poor despite major improvement over the past decades; current survival rates are around 70% but event free survival (EFS) is only about 50%. No benefit of standard maintenance chemotherapy has been proven after intensive induction/consolidation chemotherapy.
Objective: To determine whether the addition of a one-year maintenance therapy using interleukin-2 (IL-2), known to stimulate antitumor immunity, decreases the risk of relapse and improves EFS in pediatric AML.
Methods: ELAM02 trial was designed to recruit patients aged from 0 to 18 years, diagnosed with primary AML. Children with acute promyelocytic leukemia and Down Syndrome were not included. The treatment consisted of one induction course (cytarabine and mitoxantrone) and three consolidation courses (course 1 and 3 with high dose cytarabine); all children without t(8;21) were candidates for hematopoietic stem cell transplant (HSCT) in complete remission (CR) after 1 to 2 courses of consolidation if a geno-identical donor was available; children with poor-prognosis karyotype were also candidates for HSCT with pheno-identical donor.
The patients not receiving HSCT and in continuous CR after the third course of consolidation were eligible for randomization for a one-year maintenance therapy consisting in monthly courses of IL-2. IL-2 (Proleukin®, Chiron, Novartis) was given subcutaneously at 2.5 MUI/m² on day 1 and at 5 MUI/m² from day 2 to 5. Cycles were planned to be given monthly for up to 12 cycles. In case of side effects such as severe (grade ≥ 3) clinical toxicities (fever >40°C, hypotension requiring IV fluids) and/or severe biological toxicities (thrombocytopenia (grade ≥ 3), renal dysfunction (grade ≥ 2), liver dysfunction (grade ≥ 3)) doses of IL-2 was lowered of 50%. In case of persistent side effects, treatment was discontinued. The control group received no maintenance treatment.
Results: The 28 French SFCE centers participated to the study, leading to the enrollment of 441 patients from March 2005 to December 2011. Among the 441 enrolled patients, 3 patients were excluded due to non-conformity of inclusion criteria; 392/438 (89%) were in CR after the first consolidation course and 116 (30%) were allografted in CR1. Out of the 241 eligible patients for randomization, i.e. still in CR after the third course of consolidation, 154 (64%) were actually randomized for maintenance therapy; causes for non-randomization were either parents refusal (n=50, 21%) or medical decision (n=37, 15%). Median follow-up is 5 years. The characteristics of the randomized patients at diagnosis were as follows:
Figure 1 Figure 1.
Median number of IL-2 cycles administered was 12 [5-12], the mean being 8.6 ± 4.2. Among the 77 patients receiving maintenance therapy, IL-2 was stopped before cycle 6 in 20 patients (26%) and after cycle 6 in 18 (23%); 39 patients (51%) received 12 cycles. Treatment was stopped because of relapse occurrence (n=15), severe persistent toxicities (n=6) or parents or medical decision (n=17). The most frequent toxicities related to IL-2 treatment were fever, chills, and cytolytic hepatitis; no toxic death related to IL-2 therapy was observed. Incidence of relapses in IL2+ group and IL2- group were 36% (n=28) and 38% (n=29) respectively. The 5-year disease free survival (DFS) was 62 % (95% CI 51-73) for the IL2- group vs. 64% (95% CI 53-75) for the IL2+ group (p=0.74). Among the CBF population, a trend in favor of the IL-2 treatment was observed as the 5-year DFS was 57% (95% CI 43-71) for the IL2- group vs. 78% (95% CI 63-94) for the IL-2+ group (p=0.08).
Conclusion: A prolonged administration of IL-2 as maintenance therapy after intensive chemotherapy is feasible in pediatric AML patients in first CR but did not improve DFS in this study.

Disclosures
No relevant conflicts of interest to declare.