Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia

Malachi Griffith, Obi L. Griffith, Kilannin Krysiak, Zachary L. Skidmore, Matthew J. Christopher, Jeffery M. Klco, Avinash Ramu, Tamara L. Lamprecht, Alex H. Wagner, Katie M. Campbell, Robert Lesurf, Jasreet Hundal, Jin Zhang, Nicholas C. Spies, Benjamin J. Ainscough, David E. Larson, Sharon E. Heath, Catrina Fronick, Shelly O'Laughlin, Robert S. Fulton, Vincent Magrini, Sean McGrath, Scott M. Smith, Christopher A. Miller, Christopher A. Maher, Jacqueline E. Payton, Jason R. Walker, James M. Eldred, Matthew J. Walter, Daniel C. Link, Timothy A. Graubert, Peter Westervelt, Shashikant Kulkarni, John F. DiPersio, Elaine R. Mardis, Richard K. Wilson, Timothy J. Ley

The genomic events responsible for the pathogenesis of relapsed adult B lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole genome, exome, custom capture, RNA-seq, and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. While the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched unrelated donor stem cell transplant. The patient remains in complete remission more than 4 years later. Analysis of this patient's relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate novel therapeutic interventions that could alter patient outcomes.