Pediatric chronic myeloid leukemia (pCML) is a rare childhood malignancy, representing 2%–3% of all childhood leukemia. Tyrosine kinase inhibitors (TKIs) have greatly improved survival but pose challenges due to their long‐term effects on growth and bone health in children. We prospectively studied treatment‐free remission (TFR) in 45 children with pCML in chronic phase on imatinib. Eligibility criteria were as per current NCCN guidelines, with a less stringent qPCR monitoring scheduled every 3 months. TFR was successful in 71.1% (32 out of 45) of patients after a median follow‐up of 25 (range: 6–42) months. The TFR rates at 12 and 24 months were 70% and 66%, respectively. Children under 5 years had a TFR rate of 88.9%, compared to 61.8% in those over 5 years (p = 0.18). Eleven of the 13 patients who lost MMR did so within 6 months of discontinuation. The cumulative incidence of loss in MMR at 6, 12, and 24 months was 26.4%, 27%, and 33%, respectively. Ten out of 13 (76.9%) patients with discontinuation failure (DF) regained MMR within 3 (2–20) months of restarting imatinib. A significant correlation was found between higher T‐regulatory cell levels at baseline and DF (p = 0.005). More than half patients showed improved bone mineral density after 2 years of TFR. Our findings suggest that high TFR rates can be attained in pCML, with added benefits for bone health. Less frequent molecular monitoring was not associated with adverse outcomes and there seems to be a role of the immune system in sustaining TFR. The study is registered in the Clinical Trials Registry‐India (CTRI/2020/11/029199).

Chimeric Antigen Receptor-T (CAR-T) cell therapy is effective for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) but is not universally available. We developed a novel humanized CD19-directed CAR-T (HCAR19) approved for Phase 1/1b/2 trials. Patients aged 3–25 years were enrolled with r/r B-ALL and ineligible for allogeneic stem cell transplant. Lymphodepletion utilized standard-dose fludarabine and cyclophosphamide. A 3 + 3 design testing 3 dose-ranges was used to determine Phase-2 Dose (P2D): Dose-A, 1 × 10⁶ HCAR19 cells/kg, Dose-B, 3–5 × 10⁶/kg, and Dose-C, 10–15 × 10⁶/kg. Primary endpoint was overall response rate (ORR) at day-30 on bone-marrow flow-cytometry. From May-2021 to September-2023 12 patients [median age-14 (range: 5–24) years] were enrolled with median bone marrow blasts 19.5% at screening. Cytokine release syndrome occurred in 10 (83%) patients, predominantly Grades 1–2, and Grade-2 immune-cell associated neurotoxicity (ICANS) in 1. All patients had Grade-3 cytopenia. ORR was 91.7% (11/12), complete response (CR) in 8 (66.7%) and partial response in 3 (25%). Seven of 8 CRs were at Dose-levels B and C, all of which were sustained till 12 months follow-up. Patients who received dose levels below 3 × 10⁶/kg, or did not achieve CR, had early loss of response or rapid progression. HCAR19 demonstrated safety, manageable toxicity, and durable remissions. and P2D was determined as 5–10 × 10⁶ HCAR19-cells/kg. Clinical trial registration: The study is registered in the Clinical Trials Registry- India (CTRI/2021/05/033348 and CTRI/2023/03/050689).

Background: Childhood and adolescent acute lymphoblastic leukemia (ALL) survival outcomes have improved significantly, but treatment-related toxicities (TRTs) remain a major concern affecting dose intensity and quality of life. Germline pharmacogenetic variations contribute to inter-individual differences in chemotherapy response, yet consistent replication of associations has been limited by differences in treatment protocols, ethnic backgrounds, and toxicity definitions. Methods: This systematic review and meta-analysis (PROSPERO CRD42021229748) included 68 studies in the qualitative synthesis, with 42 high-quality studies undergoing structured synthesis and, where appropriate, quantitative meta-analysis. Studies focused on the toxicities of thiopurines, methotrexate, glucocorticoids, vincristine, and asparaginase. Results: Meta-analyses showed strong evidence linking the NUDT15 rs116855232 variant to thiopurine-induced myelosuppression (OR 19.0, 95% CI 1.6–224; I² = 86.5%) and a significant association between the TYMS enhancer repeat polymorphism and osteonecrosis (OR 6.66, 95% CI 3.67–12.11; I² = 0%). In contrast, MTHFR variants and VDR polymorphisms showed no significant associations with methotrexate-induced myelosuppression or osteonecrosis, respectively. Narrative synthesis highlighted clinically actionable associations: TPMT and NUDT15 with thiopurine toxicity; CEP72 with vincristine neuropathy; and HLA haplotypes with asparaginase hypersensitivity. Population allele frequency comparisons (IndiGenomes, gnomAD, UK Biobank) showed strong concordance (r = 0.919–0.997), supporting the broad generalisability of identified variants, which remains to be evaluated prospectively. The main limitations included heterogeneous toxicity definitions, non-uniform genetic models, evolving treatment protocols, population heterogeneity, and a lack of harmonised reporting. Conclusions: The review supports routine TPMT and NUDT15 genotyping and highlights the need for harmonised definitions, multi-ethnic studies, standardised data representation, and prospective validation. A literature-based candidate gene list for future PGx association studies was generated.

Background: Understanding interindividual 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, nonrandomized 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 the occurrence of early toxicities and quality of life during active ALL treatment, specific pharmacogenetic variants, and survival outcomes along with generating data to support the future implementation of personalized treatment strategies in Indian children with ALL. Methods: In this prospective, observational cohort, 556 children (≤18 years of age) with newly diagnosed ALL treated under the Indian Childhood Collaborative Leukemia–Acute Lymphoblastic Leukemia 2014 (ICiCLe-ALL-14) protocol at two Indian centers will be enrolled, aiming for a 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 Common Terminology Criteria for Adverse Events 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 a 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 version 1.0 in 2020: IEC-1167/06.11.2020 (All India Institute of Medical Sciences, New Delhi), JIP/IEC/2020/201 (Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry), and AO_2021-00048 (UNIGE, Geneva). Funding was received from Swiss National Science Foundation, Switzerland; Department of Biotechnology, India; and CANSEARCH Foundation, Switzerland. Recruitment began in December 2022 and is likely to conclude by 2027. A comprehensive analysis of the complete study cohort is anticipated to be completed by 2027. Conclusions: The MPGx-INDALL (Molecular and Pharmacogenetic Marker Evaluation in Relation to the Toxicity and Clinical Response of Acute Lymphoblastic Leukemia Treatment in Indian Children) study will generate actionable insights for individualized ALL therapy in India via systematically evaluating germline and somatic markers in a large ethnically distinct cohort.