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12-08-2016 | Acute lymphoblastic leukemia | Article

A review of new agents evaluated against pediatric acute lymphoblastic leukemia by the Pediatric Preclinical Testing Program

L Jones, H Carol, K Evans, J Richmond, P J Houghton, M A Smith, R B Lock


Acute lymphoblastic leukemia (ALL) in children exemplifies how multi-agent chemotherapy has improved the outcome for patients. Refinements in treatment protocols and improvements in supportive care for this most common pediatric malignancy have led to a cure rate that now approaches 90%. However, certain pediatric ALL subgroups remain relatively intractable to treatment and many patients who relapse face a similarly dismal outcome. Moreover, survivors of pediatric ALL suffer the long-term sequelae of their intensive treatment throughout their lives. Therefore, the development of drugs to treat relapsed/refractory pediatric ALL, as well as those that more specifically target leukemia cells, remains a high priority. As pediatric malignancies represent a minority of the overall cancer burden, it is not surprising that they are generally underrepresented in drug development efforts. The identification of novel therapies relies largely on the reappropriation of drugs developed for adult malignancies. However, despite the large number of experimental agents available, clinical evaluation of novel drugs for pediatric ALL is hindered by limited patient numbers and the availability of effective established drugs. The Pediatric Preclinical Testing Program (PPTP) was established in 2005 to provide a mechanism by which novel therapeutics could be evaluated against xenograft and cell line models of the most common childhood malignancies, including ALL, to prioritize those with the greatest activity for clinical evaluation. In this article, we review the results of >50 novel agents and combinations tested against the PPTP ALL xenografts, highlighting comparisons between PPTP results and clinical data where possible.

Leukemia 2016; 30: 2133–2141. doi:10.1038/leu.2016.192

Cancer remains the leading cause of death from disease in children, although pediatric cancers are relatively rare when compared with adult malignancies. Childhood malignancies contributed <2% of worldwide cancer incidence in 2011 and cancer deaths in children under the age of 15 comprise only 1.3% of total cancer deaths per year.1, 2, 3 Moreover, improvements in treatment modalities and supportive care over the past 50 years have resulted in an overall survival rate of ~70% across all childhood cancers,1, 4 with mortality continuing to decline.5 These survival rates are even more impressive for the most common pediatric malignancy, acute lymphoblastic leukemia (ALL), with overall 5-year survival now approaching 90%.6

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