Nearly three decades have passed since the introduction of imatinib, the first rationally targeted leukaemia therapy, transformed the treatment of CML. While this single-target strategy delivered unprecedented survival gains for most CML patients, it has not proven to be a successful universal approach for all leukaemias/cancers.
Acute lymphoblastic leukemia (ALL) is fundamentally more complex. Comprehensive genomic and transcriptomic profiling has revealed a heterogeneous disease comprising multiple high- and standard-risk subtypes. While intensive, risk-adapted chemotherapy has dramatically improved survival for many children, relapse remains a leading cause of morbidity/death, and outcomes remain poor for infants, adolescents, and adults. Even within well-defined genomic subtypes, treatment responses vary—underscoring a critical but poorly understood interplay between leukemia genomics, therapy, and host biology.
Importantly, survivors of childhood ALL often endure lifelong treatment-related morbidities, therefore advancing ALL therapy requires a deeper understanding of the factors that shape leukemia biology, therapeutic response, and toxicity. This challenge is compounded by the fact that current regimens are approaching the limit of tolerability, leaving little scope for further intensification. Although immune-based therapies hold considerable promise, responses are inconsistent, and their long-term consequences remain uncertain.
Emerging evidence points to the gut microbiota as a key, yet underexplored, modifier of treatment response. Dysbiosis is common in ALL and has been associated with heightened pro-inflammatory states. Importantly, recent clinical studies link high body mass index and metabolic dysfunction/inflammation with poor treatment response and high-risk disease.
In an era of unprecedented biological insight, advancing ALL care will likely require a deeper understanding of host–leukemia interactions to shape the next generation of truly personalised therapeutc approaches