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Evolution of Therapy in Pediatric ALL From Aminopterin to Chimeric Antigen Receptor T-Cell Therapy: Global Advances,
Debabrata Mohapatra1, Jagdish Prasad Meena1, Aditya Kumar Gupta1
1Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Insights
Childhood leukemia survival in India is improving due to adapted global treatments, but challenges like treatment toxicity and access to new therapies persist. Further adaptations and collaboration are key to bridging the gap with high-income countries.
Area of Science:
- Pediatric Oncology
- Hematology
- Global Health
Background:
- Childhood acute lymphoblastic leukemia (ALL) survival has significantly improved globally since the mid-20th century.
- Low- and middle-income countries (LMICs) are gradually narrowing the survival gap with high-income nations.
- Decades of research and therapeutic advancements have driven these survival gains.
Purpose of the Study:
- To review the evolution of childhood ALL treatment principles and survival trends.
- To analyze the adaptation of global therapeutic innovations in the Indian context.
- To identify factors influencing childhood ALL outcomes in India.
Main Methods:
- Conducted a narrative literature review from 1948 to 2025.
- Examined key therapeutic principles and landmark trials in childhood ALL.
- Assessed the historical adaptation of these treatments in India.
Main Results:
- Global ALL management evolved through multiagent chemotherapy, CNS-directed therapy, risk stratification, MRD-guided treatment, and immunotherapy, increasing survival from 4% to 96%.
- India adopted these principles sequentially, improving survival from ~10% to 61%-76%.
- Challenges in India include treatment-related mortality, CNS relapses, and limited access to novel therapies, resulting in outcomes ~20% lower than global benchmarks.
Conclusions:
- Evidence-based protocol adaptations and health system strengthening are crucial for improving childhood ALL outcomes in LMICs.
- Multicentric collaboration can overcome challenges like financial constraints and limited drug access.
- Despite persistent challenges, locally adapted regimens and indigenous CAR T-cell therapy show promise for reducing the survival gap.
Purpose:
Survival outcomes for childhood ALL in low- and middle-income countries (LMICs) have shown gradual improvement, closely following the remarkable outcomes achieved in high-income countries, albeit with some time lag. This has been achieved by decades of efforts since the 1940s.
Methods:
We conducted a narrative review of the previous literature, therapeutic innovations, and landmark trials in the evolution of childhood ALL from 1948 to 2025 and drew an analogy of how they have been adapted in the Indian context. The review gives a historical summary of the key therapeutic principles and survival trends over time.
Results:
Globally, the principles of multiagent chemotherapy, CNS-directed therapy, risk-stratified intensification, minimal residual disease-guided treatment, and immunotherapy have shaped the backbone of modern ALL management. Each step has contributed to the steady rise in survival from 4% in the 1960s to 96% in the current era. In India, these principles were adopted sequentially with multicentre protocol 841, International Network for Cancer Treatment and Research protocols, and finally the risk-adapted Indian Collaborative Childhood Leukaemia protocol, resulting in improved survival from nearly 10% in the 1970s to 61%-76% in recent trials. However, survival remains approximately 20% lower than global benchmarks because of treatment-related mortality (12%), CNS relapses, and limited access to newer drugs, immunotherapy, and advanced diagnostics. Lately, low-intensity locally adapted regimens and affordable indigenous (CD19) chimeric antigen receptor T-cell therapy offer promise to partly narrow the gap although treatment toxicity and limited blinatumomab access remain challenging.
Conclusion:
The care of childhood ALL in India demonstrates how evidence-based protocol adaptations, health system strengthening, and multicentric collaboration can improve outcomes in LMICs despite several challenges, including financial constraints, limited drug access, late presentation, and treatment abandonment.
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