Genetics Directing Therapy in Acute Lymphocytic Leukemia: Identifying Risk, Defining Targets
Authors: Biondi Andrea , Cazzaniga Giovanni 
Published: October 2019

In contemporary clinical trials, the 5-year survival rate in pediatric ALL, has risen above 85% in developed countries. This achievement is due at least in part to better defined patient risk classification, optimization of antileukemic agents, and improved supportive care. In order to refine the approach to define the risk of patients and to cope with these challenges, the use of MRD tests has become prominent in ALL management. The main reasons for this development have been the progressive improvement of standardized methodologies applicable to virtually all patients and the conduct of clinical studies that used MRD evaluation as a marker of in vivo early response to allocate patients into different risk-based treatments to improve outcome. This hold true for BCP-ALL as well for T-ALL. This is the context where over the past decade, genome sequence and adequate analytical platforms, such as gene expression profiling, single nucleotide polymorphism arrays, and, more recently, next generation sequencing, has expanded our knowledge and definition of new molecular ALL entities. These achievements have also provided critical insights regarding potentially targetable lesions for development of new therapeutic approaches in the era of precision medicine. The current genetic landscape of childhood ALL with emphasis upon patient outcomes with contemporary treatment regimens will be reviewed. While the assessment of new genetic lesions as potential new risk factors are currently evaluated in the MRD-based clinical ALL studies, defining targets for new therapeutic intervention is still very challenging. In vitro and in vivo evaluation of new agents in ALL model systems remains a lengthy and often imperfect system. Single-agent biologic activity in murine models does not always translate into clinical activity in patients, and improper drug schedule can result in untoward clinical outcomes. Moreover, for the emerging knowledge on the clonal evolution in cancer in general and in leukemia as well it is evident that leukemia evolves by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscape of tissue ecosystem. The dynamics is complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy leukemia clones but it can provide also a potent pressure for the expansion of resistant variants. This Darwinian character of leukemia can be the primary reason for therapeutic failure but it may hold the key for a more effective control. In this increasingly smaller subsets of patients, clinical trial design for evaluation of new agents also represents a new challenge, and development of robust biomarkers of response will be necessary to define clinical activity. The trend to reduce subgroups further sustain the need for continuous collaboration among researchers, clinical oncologists, government agencies, and pharmaceutical industries. Finally, the progressive and functional definition of genetic entities that can benefit of tailored treatment will have relevant implications for clinical studies.

Disclosures
No relevant conflicts of interest to declare.