Acute Lymphoblastic Leukemia Therapies Informed by Genomic Analyses

Overview

Previous work performed by University of New Mexico Comprehensive Cancer Center (UNMCCC) investigators has revealed previously unknown genomic mutations in children, adolescents, and young adults with high-risk B and T cell precursor acute lymphoblastic leukemia (ALL). Using genomic and next generation DNA sequencing technologies, these investigators revealed that 14% of children with high-risk ALL have "Philadelphia chromosome-like" ("Ph-like") ALL. Patients with this form of ALL were found to have a significantly increased risk of treatment failure and death. Further work revealed that there are more than 40 distinct gene rearrangements and fusions that can result in Ph-like ALL. Cell lines and human leukemic cells expressing some of these different gene fusions were sensitive to currently available drugs. This suggests that Ph-like ALL patients with these specific distinct gene fusions should be targeted in future clinical trials to be treated with appropriate therapy. Further work is also needed to identify other potentially targetable genetic alterations in ALL patients. Therefore, the goal of this study is to perform genomic screening of all newly diagnosed ALL patients seen at UNM and to use this information to enroll patients onto available National Clinical Trial Network (NCTN) clinical trials. If an appropriate NCTN trial is not available, best clinical management will be pursued.

The work performed by UNMCCC investigators and others as described briefly above has provided major insights into the biologic and clinical features and the genomic landscape of Ph-like ALL, which is strikingly heterogeneous. Gene expression profiling and RNA/transcriptomic, exome, and whole genome sequencing have identified several distinct subclasses of kinase activating lesions in 91% of the Ph-like ALL cases studied to date, most commonly kinase and cytokine receptor gene rearrangements and fusions. UNMCCC investigators are now collaborating with Children's Oncology Group (COG) and the adult National Cancer Institute (NCI) Cooperative Groups (Southwest Oncology Group (SWOG), Eastern Cooperative Oncology Group (ECOG) - American College of Radiology Imaging Network (ACRIN), The Alliance) to develop national clinical trials for pediatric, adolescent and young adult (AYA), and adult ALL patients that incorporate their genomic diagnostic screens, molecular diagnostics, and next generation sequencing studies to identify underlying genomic lesions in ALL and target patients to appropriate therapeutic regimens. In this feasibility study, next generation sequencing (NGS) technologies will inform an acute lymphoblastic leukemia risk classification system, which may be adapted to identify patients who might benefit from targeted therapies; such patients will be targeted to NCTN National Treatment trials or UNMCCC-sponsored trials where appropriate, through detailed genomic data analysis performed under College of American Pathologists (CAP)/CLIA conditions and in individual case discussions in a Molecular Tumor Board. In addition, the association of race and ethnicity with the spectrum of ALL-associated genomic mutations in the New Mexico and regional ALL population, which includes a significant proportion of underrepresented minorities, will be studied. This may ultimately allow for the development of an ancestry-based risk classification system.