The goal of precision medicine cancer therapies is to use drugs that target the molecular aberrations that drive cancers to improve cure rates and decrease toxicity. The Children’s Oncology Group (COG) high risk acute lymphoblastic leukemia (HR ALL) TARGET Project is a large collaborative effort led by Stephen Hunger, MD, and involving the the National Cancer Institute Office of Cancer Genomics, and investigators from Children's Hospital of Philadelphia, Nationwide Children’s Hospital, St. Jude Children’s Research Hospital, the University of Florida, the University of New Mexico and the University of California San Francisco.
The research team has used next generation sequencing technology to study high risk ALL, leading to a large number of observations that have revolutionized understanding of the genomic landscape of ALL and identified new therapeutic targets in ALL subsets with poor treatment outcome. Based on findings from these studies, the COG AALL1131 clinical trial for children, adolescents and young adults with HR ALL was recently amended to add a treatment arm utilizing combination chemotherapy plus dasatinib for patients defined as Philadelphia chromosome-like (Ph-like) with a predicted tyrosine kinase inhibitor-sensitive mutation.
During the first month of therapy, NCI HR ALL patients from over 200 centers in the US, Canada, Australia and New Zealand will be screened by Low Density Array (LDA) technology to identify the subset with Ph-like ALL who will undergo downstream molecular testing to identify the underlying genomic lesions. Those with Ph-like ALL and a mutation that is predicted to be sensitive to the tyrosine kinase inhibitor (TKI) dasatinib will be assigned to receive combination chemotherapy plus dasatinib. In parallel, this research team has developed COG AALL1521 (A Phase 2 Study of the JAK1/JAK2 Inhibitor Ruxolitinib With Chemotherapy in Children With De Novo High-Risk CRLF2-Rearranged and/or JAK Pathway–Mutant Acute Lymphoblastic Leukemia) in collaboration with Incyte, which is chaired by Sarah Tasian, MD.
Children enrolled in AALL1131 who are found to have Ph-like ALL and a JAK/STAT pathway genomic lesion will be eligible to enroll in AALL1521 and receive the JAK 2 inhibitor ruxolitinib plus combination chemotherapy. Both of these clinical trials are direct translational extensions of genomic findings from the TARGET high risk ALL project.