Efficacy of SAR302503, a JAK2 Inhibitor, in the Treatment of a Primary Xenograft Model of Human Acute Myeloid Leukemia,

Abstract 3624 Small molecule inhibitors targeting somatic mutations of Janus kinase 2 (JAK2) have demonstrated effectiveness in clinical trials for treatment of myeloproliferative disorders. Activated JAK2 signaling has been reported in some acute myeloid leukemia (AML) samples even though the frequency of JAK2 mutations is relatively rare in AML. Whether JAK2 inhibitors are effective in AML is not clear. Since many myeloid malignancies including AML are organized as cellular hierarchies driven by leukemia stem cells (LSC) at the apex, it is also unknown whether LSCs are sensitive to JAK2 inhibition. We report that SAR302503 (SAR503, Sanofi, Cambridge, MA), an orally administered small molecule inhibitor of JAK2, shows therapeutic efficacy in a xenograft model of human AML established by intrafemoral injection of primary human AML cells into anti-NK treated irradiated NOD. SCID mice. Drug pharmacokinetic studies confirm that SAR503 exhibits good bioavailability in NOD. SCID mice. Starting 2 weeks post transplantation to permit establishment of an AML graft, mice were orally gavaged twice a day with 60 mg/kg SAR503 or vehicle alone (0.5% methylcellulose) for 14 consecutive days. In 5 of 7 AML samples, treated mice exhibited significantly lower engraftment (3 to 18 fold; p p in vivo had high basal and marked reduction in the STAT signaling pathway after in vitro treatment, whereas non-responding samples did not. Serial transplantation studies are ongoing to evaluate the effect of JAK2 inhibition on LSCs in treated primary mice. To evaluate whether AML samples that did not respond to JAK2 inhibition alone would respond to combination therapy, we treated engrafted mice with SAR503 plus cytarabine, a standard chemotherapeutic drug used in AML. Combination therapy of one non-responding sample resulted in a significantly reduced leukemic burden (2.3%) compared to mice treated with SAR503 alone (85.8%) or cytarabine alone (16.8%; p Disclosures: Off Label Use: We describe using SAR302503 to treat AML in a mouse model.