Abstract IA02: Precision medicine in acute lymphoblastic leukemia

Abstract

Abstract Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor. Despite overall favorable treatment outcomes in children, relapsed ALL remains a leading cause of cancer death in young people. Current treatment regiments are mostly non-targeted and accompanied by significant toxicities, and new treatments tailored to patient-specific tumor vulnerabilities are required to further improve treatment outcomes. ALL has long been known to be genetically diverse. Recent genomic sequencing efforts have provided multiple new insights into the classification and genetic basis of ALL. ALL is now known to comprise multiple subtypes that have distinct constellations of chromosomal rearrangements, DNA copy number alterations and sequence mutations that perturb a limited number of key cellular pathways including lymphoid development, Ras and kinase signaling, tumor suppression drug metabolism and epigenetic regulation. These findings have several implications for precision medicine approaches. First, different subtypes have distinct associations with relapse risk that will enable tailoring of the intensity of therapy, the requirement for intensive treatment approaches such as transplantation, and the potential for pathway-directed approaches such as BCL2 inhibitors, PI3K inhibitors and Ras inhibitors. Secondly, several subtypes have genetic alterations that are logical candidates for genomic testing and individualized targeted therapy. An important recent advance has been the identification of Ph-like ALL, a common high risk subtype of leukemia characterized by a range of genetic alterations activating cytokine receptor and kinase signaling amenable to ABL-class and JAK-STAT inhibitors. Large precision medicine trials identifying Ph-like ALL, the underlying genetic alterations, and directing patients to targeted kinase inhibitor therapy are currently in development. Thirdly, studies sequencing sequential samples obtained during therapy have identified several genes and pathways selectively mutated at relapse, including epigenetic regulators, that are logical targets for therapeutic intervention. Finally, genome sequencing is being used to develop highly sensitive approaches to detect and track response to treatment. Examples of each of these paradigms will be presented that highlight the potential of precision medicine to further improve treatment outcomes in ALL. Citation Format: Charles G. Mullighan. Precision medicine in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA02.