Background
In 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.
Methods
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 (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.
Discussion
ICiCLe-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 registration
Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434. Registered on 11 December 2015
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.
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.
Background
To evaluate the treatment cost and cost effectiveness of a risk‐stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India.
Methods
The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B‐cell precursor ALL, and T‐ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability‐adjusted life years.
Results
One hundred and forty five patients, SR (50), IR (36), HR (39), and T‐ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T‐ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%–35% of total cost. Out‐patient costs were significantly lower for SR (
p
< 0.0001). OP costs were higher than in‐patient costs for SR and IR, while in‐patient costs were higher in T‐ALL. Costs for non‐therapy admissions were significantly higher in HR and T‐ALL (
p
< 0.0001), representing over 50% of costs of in‐patient therapy. HR and T‐ALL also had longer durations of non‐therapy admissions. Based on WHO‐CHOICE guidelines, the risk‐stratified approach was very cost effective for all categories of patients.
Conclusions
Risk‐stratified approach to treat childhood ALL is very cost‐effective for all categories in our setting. The cost for SR and IR patients is significantly reduced through decreased IP admissions for both, chemotherapy and non‐chemotherapy reasons.
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