A still major question in the field of acute lymphoblastic leukemia (ALL) in children - an extremely heterogeneous disease though curable in 80-90% of children and 70-80% of the adolescents - is the optimal use of L-asparaginase (ASNase). It is known that administering ASNase results in the depletion of asparagine circulating in the blood, which starves the leukemic cells and results in their death. But indeed the use of ASNase varies between protocols considering the different brands, the dose and the administration modalities. Oncaspar (PEGylated E. coli asparaginase, pegaspargase) was thus developed with the goal of reducing the immunogenicity of the native ASNase. This is a French prospective multicentric cohort study of children and adolescents with ALL, stratified on (i) the type of ALL ( B vs T) and (ii) the anticipated risk (stratified in 3 groups for childhood B-cell precursor (BCP)-ALL and 2 groups for T-cell ALL). It aims to answer to two different issues: 1. Randomized question: what is the best way to administer pegaspargase? A cohort of children and adolescents with standard or medium risk ALL will be randomized to receive during induction either one infusion of ONCASPAR® 2500 IU/m2 at D12 or two infusions of ONCASPAR® at 1250 IU/m2 each at D12 and D26. Patients will then receive 2500 IU/m2 or 1250 IU/m2 per dose during consolidation and delayed intensification according to the initial arm of randomization. 2. Non randomized question: In the High/Very High Risk groups, a non randomized intensification of the scheme of asparaginase administration is proposed during induction therapy: 2 infusions of 2500 IU/m2/day (D12 and D26) will be administered. All patients will receive 2500 IU/m2 per dose during consolidation and delayed intensifications.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
2,044
only for ALL of standard risk and medium risk
only for ALL of standard risk and medium risk
CHU
Amiens, France
CHU
Angers, France
CHRU
Besançon, France
CHU
Bordeaux, France
CHU
Brest, France
CHU
Caen, France
CHU
Clermont-Ferrand, France
CHU
Dijon, France
CHU
Grenoble, France
CHU
Lille, France
...and 18 more locations
Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 33 of induction therapy
asparaginase activity \> 100 IU/L
Time frame: Day 33
Incidence of directly asparaginase-related severe toxicities (Grade ≥ 3 as assessed by CTCAE v4.0) observed during induction therapy
Incidence of severe toxicities (Grade ≥ 3) directly asparaginase-related (CNS thrombosis, pancreatitis, anaphylaxis, and hyperbilirubinemia) between Day 12 and Day 49 of treatment and anyway before Day 8 of consolidation
Time frame: Between Day 12 of induction and Day 8 of consolidation
Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L
Time frame: Day 33 of induction
Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 40 of induction therapy
Time frame: Day 40 of induction
Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L
Time frame: Day 40 of induction
Incidence of antibodies against asparaginase, measured in serum
Time frame: Day 4 of delayed intensification
Incidence of silent inactivation
Silent inactivation or subclinical hypersensitivity is defined as a plasma PEGasparaginase activity level \<100 IU/L at day 7+/- 1 or \<20 IU/L at day 14 +/- 11 after administration in a patient without clinical symptoms of allergy
Time frame: First 6-9 months
Percentage of patients without switch to Erwinia asparaginase
Time frame: First 6-9 months
Percentage of patients receiving more than 95% of the intended dose of asparaginase
Time frame: First 6-9 months
Morphological Complete Remission (CR) rates
Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).
Time frame: Day 35-Day 42
Minimal Residual Disease (MRD)
MRD will be assessed by Ig/T cell receptor (TCR)-based real-time quantitative (RQ)-polymerase chain reaction (PCR), assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).
Time frame: Day 35-Day 42, Day 65-Day 105
Cumulative Incidence of relapses
Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).
Time frame: 5 years
Cumulative Incidence of relapse according to site of relapse
Bone-Marrow (BM) relapses, central nervous system (CNS) relapses, gonadal relapses, combined relapses. Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).
Time frame: 5 years
All other adverse events related to asparaginase
Drug-induced hyperglycemia or diabetes, coagulopathy, allergy Non CNS thrombosis Grade 1-2 Adverse Events (AE): pancreatitis, hyperbilirubinemia
Time frame: within the first 7 weeks (Day 49) of treatment and anyway before Day 8 of consolidation
Late adverse events related to asparaginase
Time frame: after Day 49 of induction or anyway at Day 8 of consolidation or after
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