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

Abstract

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.