Gemcitabine, Jevtana and Jakavi identified to treat pediatric AML

INDICATION: Acute myelogenous leukemia (AML)

Cell culture and mouse studies identified gemcitabine, Jevtana cabazitaxel and Jakavi ruxolitinib as drugs that could help treat pediatric AML. High throughput screening of a library of 7,389 small molecules in eight human AML cell lines derived from pediatric and young adult patients identified the generic chemotherapy gemcitabine and the tubulin inhibitor Jevtana as potent inhibitors of growth across all disease subtypes (IC₅₀ values of 2-60 nM and 0.3-1 nM, respectively), including non-Down syndrome acute megakaryoblastic leukemia (AMKL) and MLL-rearranged AML. A secondary screen of a subset of 457 small molecules in seven human pediatric AMKL cell lines identified the JAK-1/JAK-2 inhibitor Jakavi as the most potent growth inhibitor (IC₅0 values of 6.3-143 nM). In a patient-derived xenograft (PDX) and a syngeneic mouse model of pediatric AMKL and a syngeneic mouse model of MLL-rearranged pediatric AML, gemcitabine increased survival and decreased tumor burden in the peripheral blood compared with cytarabine, the standard of care. In xenograft mouse models of the two subtypes, gemcitabine or Jevtana increased survival. In the PDX, syngeneic and xenograft mouse models of AMKL, Jakavi increased survival and decreased tumor burden in peripheral blood compared with vehicle. Next steps could include testing the three drugs in combination with other chemotherapies in the models...