Background The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli‐derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low‐middle‐income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure Seven biogeneric EcASNases (P1–P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2/dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug‐related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high‐risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch‐to‐batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. Conclusions Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high‐quality asparaginases remains an unmet therapeutic need.

Karyotyping along with a 3-probe fluorescence in situ hybridization (FISH) strategy was used to risk stratify therapy in 303 children with B-cell precursor acute lymphoblastic leukaemia. Of the 166 patients risk stratified, karyotype identified 91 (55%). FISH identified all karyotypes accurately, with the exception of hypodiploidy, and risk stratified an additional 75 patients. The frequency of ETV6-RUNX1 is lower and high hyperdiploidy, higher than reported in the west. An adapted 3-probe FISH strategy identified two patients with ETV6-ABL1 fusion who received imatinib. In limited-resource settings, a 3-probe FISH approach provides a practical approach for risk-stratified therapy in childhood ALL.

Summary The feasibility of bortezomib (BZB) in induction and reduced cytarabine doses in intensification was evaluated in children with relapsed acute lymphoblastic leukaemia (rALL) at a single centre in India. Of 55 children with rALL, 23 received supportive care and 7 refused treatment, with a median survival of 2 (interquartile range 1–6) months. Twenty‐two (88%) of 25 children who were treated achieved second remission and 9 (69%) of 13 had end‐of‐induction minimal residual disease of <10−4. The lower cytarabine dose was associated with decreased hospitalisation. One‐year event‐free and overall survival for the treated group was 74·7% (95% confidence interval 52–88) and 79·6% (58–91) respectively.

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Whole genome copy number alterations, targeted gene-panel and RNA sequencing were used to investigate differences in high hyperdiploid (HH) B-cell acute lymphoblastic leukemia (ALL), with and without whole chromosome uniparental isodisomy (wUPD). Patients with wUPD demonstrated a higher modal number of chromosomes with gains of chromosome 5. Mutations in genes within epigenetic pathways with upregulation of genes involved in cellular response to stress and stimuli were seen in wUPD, in contrast to mutations in RAS/RTK pathways and upregulation of genes in RNA Polymerase III pathway in noUPD. AP-1 transcription factors and NUDT18, potentially implicated in thiopurine drug resistance, were upregulated in wUPD. wUPD was associated with female gender, higher presenting white cell count and lower end of induction minimal residual disease levels, though survival rates were similar in the two groups. Genome-wide differences in HH ALL with and without UPD suggest plausible biological explanations for the heterogeneity in therapeutic response.

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