Acute Lymphoblastic Leukemia
Conditions
Brief summary
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.
Interventions
DRUGpegaspargase 1250 IU/m2 x 2
only for ALL of standard risk and medium risk
DRUGpegaspargase 2500 IU/m2 x 1
only for ALL of standard risk and medium risk
Sponsors
Shire
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Children and adolescents Age \> 12 months but \< 18 yearsB-lineage or T- lineage ALL * Written informed consent obtained before day 8 of treatment Non inclusion criteria: * L3 (Burkitt's leukemia) (LMB type protocols) * Mixed Phenotype Acute Leukemia (WHO criteria). * Infant ALL (age ≤ 365 days (Interfant 06 protocol) * Secondary leukemia * Patients previously treated with chemotherapy (steroid exposed patients can be included and stratified according to Section 3.5) Known allergy to pegylated products * Pregnancy. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant must have a negative serum pregnancy before inclusion and a reliable contraception except oral contraceptives. The contraception should be maintained throughout the study and for 3 months after treatment discontinuation. * Known HIV positivity * CNS thrombosis during Prophase
Exclusion criteria
* Ph+/BCR-ABL ALL (ESPhALL protocol) * CNS thrombosis before D12
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 33 of induction therapy | Day 33 | asparaginase activity \> 100 IU/L |
| Incidence of directly asparaginase-related severe toxicities (Grade ≥ 3 as assessed by CTCAE v4.0) observed during induction therapy | Between Day 12 of induction and Day 8 of consolidation | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L | Day 33 of induction | — |
| Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 40 of induction therapy | Day 40 of induction | — |
| Incidence of antibodies against asparaginase, measured in serum | Day 4 of delayed intensification | — |
| Incidence of silent inactivation | First 6-9 months | 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 |
| Percentage of patients without switch to Erwinia asparaginase | First 6-9 months | — |
| Percentage of patients receiving more than 95% of the intended dose of asparaginase | First 6-9 months | — |
| Morphological Complete Remission (CR) rates | Day 35-Day 42 | Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). |
| Minimal Residual Disease (MRD) | Day 35-Day 42, Day 65-Day 105 | 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). |
| Cumulative Incidence of relapses | 5 years | Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). |
| Cumulative Incidence of relapse according to site of relapse | 5 years | 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). |
| All other adverse events related to asparaginase | within the first 7 weeks (Day 49) of treatment and anyway before Day 8 of consolidation | Drug-induced hyperglycemia or diabetes, coagulopathy, allergy Non CNS thrombosis Grade 1-2 Adverse Events (AE): pancreatitis, hyperbilirubinemia |
| Late adverse events related to asparaginase | after Day 49 of induction or anyway at Day 8 of consolidation or after | — |
Countries
France
Outcome results
None listed