Abstract:
Acute lymphoblastic leukemia (ALL) in infants diagnosed at less than 12 months of age is an aggressive malignancy with a poor prognosis. Rearrangements of the KMT2A gene (KMT2A-r) are present in up to 80% of cases, with 5-year event-free survival (EFS) less than 40%.1 Dose intensive chemotherapy has been incorporated into contemporary treatment regimens; however, this has increased the burden of toxicity during therapy and late effects in survivors. There is a desperate need to identify novel therapies to improve outcome. Histone deacetylase inhibition appears to be a promising therapeutic strategy for KMT2A-r infant ALL, with our recent chemo-genomic profiling identifying the potential for romidepsin. Romidepsin was shown to enhance the in vitro activity of cytarabine, a key component of infant ALL therapy, with an in vivo signal identified when combined with high-dose cytarabine. In this study, we investigate the in vivo synergy between romidepsin and cytarabine, determine the in vivo toxicity of this combination, and further explore the effect of romidepsin on the DNA damage-response to cytarabine.
Romidepsin enhances the efficacy of cytarabine in vivo, revealing HDAC inhibition as a therapeutic strategy for KMT2A-rearranged acute lymphoblastic leukemia
In this study, we investigate the in vivo synergy between romidepsin and cytarabine