Abstract
BackgroundIn the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes.MethodsPatients 1–18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (< 50 × 109/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation.DiscussionICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation.Trial registrationClinical Trials Registry-India (CTRI) CTRI/2015/12/006434. Registered on 11 December 2015
Highlights
Background and rationale {6a} Survival rates for childhood acute lymphoblastic leukaemia (ALL) approach 90% in high-income countries [1]
While randomised comparisons suggest superior event-free survival with dexamethasone compared to prednisolone [9, 10], dexamethasone treatment is associated with increased induction mortality [11]
Philadelphia-chromosome positive ALL (Ph+ALL) In patients with Ph+ALL and other ABL-class fusions, the ABL tyrosine kinase inhibitor imatinib is recommended in combination with cytotoxic chemotherapy
Summary
Patients 1–18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCPALL) patients with low presentation leucocyte count (< 50 × 109/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young nonhigh-risk BCP-ALL. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation
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