Evolution of Therapy in Pediatric ALL From Aminopterin to Chimeric Antigen Receptor T-Cell Therapy: Global Advances, Indian Adaptations, and Lessons for Low- and Middle-Income Countries.

Abstract

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. 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. 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. 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.