Molecular and Pharmacogenetic marker evaluation in relation to the toxicity and clinical response of acute lymphoblastic leukemia treatment in Indian children (MPGx-INDALL): A Prospective observational cohort study protocol (Preprint)

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BACKGROUND Understanding inter-individual variability in treatment response and toxicity is essential for optimizing outcomes in pediatric acute lymphoblastic leukemia (ALL). Molecular and pharmacogenetic markers hold promise in predicting treatment efficacy and adverse effects, particularly in genetically diverse populations. This protocol outlines the methodology for a prospective, non-randomized observational cohort designed to evaluate molecular and pharmacogenetic factors associated with treatment response and toxicity in Indian children diagnosed with ALL. OBJECTIVE The primary objective is to identify genetic markers associated with treatment-related toxicity and therapeutic response. Secondary objectives include evaluating associations between occurrence of early toxicities and quality of life during active ALL treatment, specific pharmacogenetic variants and survival outcomes along with generating data to support future implementation of personalized treatment strategies in Indian children with ALL METHODS In this prospective, observational cohort 556 children (≤18 years) with newly diagnosed ALL treated under the ICiCLe-ALL-14 protocol at two Indian centers will be enrolled to have minimum of 500 evaluable children. Eligible participants will be enrolled prior to the initiation of chemotherapy and followed longitudinally throughout treatment. Clinical and laboratory data (demographics, nutritional assessment, quality of life, comorbidities, treatment regimen, toxicity graded by CTCAE v5.0, remission status, and survival) will be collected at predefined intervals up to day 100 of the maintenance phase. Germline and somatic DNA will be sampled at diagnosis and remission. The first phase will use whole-exome sequencing to discover candidate variants by implementing candidate gene prioritization strategy. The second phase will genotype the top candidates in the full cohort using array technology. Associations with early treatment related toxicities, steroid response, and survival will be tested by multivariable regression and Cox models. A machine-learning approach with pharmacogenetic predictors as classifiers will be implemented further with cross-validation and sensitivity analyses. RESULTS Ethical committees approved the protocol in 2020 (IEC-1167/06.11.2020 (AIIMS, New Delhi), JIP/IEC/2020/201 (JIPMER-Puducherry) and AO_2021-00048 (UNIGE, Geneva). Funding was received from SNSF-Switzerland, DBT-India, CANSEARCH Foundation-Switzerland. Recruitment began in December 2022 and is likely to conclude before May 2026. Data analysis is expected with manuscript submission in 2027. CONCLUSIONS MPGx-INDALL will generate actionable insights for individualized ALL therapy in India via systematically evaluating germline and somatic markers in a large, ethnically distinct cohort. CLINICALTRIAL ClinicalTrials.gov NCT05512169; https://clinicaltrials.gov/study/NCT05512169

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