Next‐Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia

A dvancement in the diagnosis and treatment of pediatric acute lymphoblastic leukemia (ALL) is one of the greatest successes of modern medicine. Over the past 50 years, there has been a rapid increase in overall survival for pediatric ALL (Figure 1). Several factors have led to these remarkable improvements. First is the development of riskadapted therapy based on both clinical and biological presenting features, as well as early response to treatment. Second, the effectiveness of molecularly targeted agents for specific genetic abnormalities has boosted outcomes for some high-risk groups. Third, international collaboration among clinical trial networks has led to standardization of definitions and reporting of results, allowing comparison of data across multiple national study groups to identify optimal treatments (Table; available at www.jpeds.com). Today, the long-term survival rate for pediatric ALL is approaching 90% in many high-income countries, the highest of any type of leukemia in either children or adults. These remarkable achievements notwithstanding, a number of challenges in ALL pathology and treatment remain to be addressed. Relapse still occurs in 10%15% of patients, and death due to relapsed ALL remains one of the leading causes of cancer mortality in children. Conventional cytotoxic chemotherapy continues to be associated with both shortand long-term toxic effects and is unlikely to be modified substantially in the near future. Thus, it will be important to take advantage of emerging molecular and immunologic insights to improve risk stratification and devise targeted therapies to avoid overtreatment or undertreatment. In this review, we discuss advances in the diagnosis and treatment of pediatric ALL that are reshaping the landscape of this disease. In the future, all patients may undergo genetic sequencing of both cancer and germline genomes to increase the precision of risk stratification and hence the specificity of treatment. Patients with high-risk genetic subtypes or poor response to treatment, as measured by minimal residual disease (MRD), may benefit from molecularly targeted therapy or immunotherapy. With advances in identifying molecular lesions that are amenable to targeted therapy and in developing riskadapted therapy for ALL, we believe that precision medicine will drive ALL treatment in the future.