Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine/cytarabine‐based salvage regimens against acute myeloid leukaemia

Summary Despite intensive treatment, patients with relapsed or refractory acute myeloid leukaemia (AML) have a dismal prognosis. A cornerstone therapy for relapsed/refractory AML is a combination of fludarabine (F‐ara‐A) and cytarabine (ara‐C), so‐called FLA. As the enzyme SAMHD1 mediates resistance to both ara‐C and F‐ara‐A, we investigated whether SAMHD1 inhibition via hydroxyurea (hydroxycarbamide; HU) could improve FLA efficacy. Here, we show that HU synergistically enhanced ara‐C‐, F‐ara‐A‐ and FLA‐induced cytotoxicity in an SAMHD1‐dependent manner in AML cell lines, primary AML cells and an immunocompetent AML mouse model. Mechanistically, HU significantly increased the active metabolite triphosphates of ara‐C and F‐ara‐A in FLA combinations. Furthermore, leukaemic SAMHD1 protein expression negatively correlated with overall survival in a cohort of FLA‐treated refractory AML patients. Our findings suggest that the addition of HU improves the efficacy of FLA‐based regimens and warrant clinical trials to test the safety and efficacy of this combination in patients with relapsed/refractory AML.