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A cornerstone therapy for relapsed\/refractory AML is a combination of fludarabine (F\u2010ara\u2010A) and cytarabine (ara\u2010C), so\u2010called FLA. As the enzyme SAMHD1 mediates resistance to both ara\u2010C and F\u2010ara\u2010A, we investigated whether SAMHD1 inhibition via hydroxyurea (hydroxycarbamide; HU) could improve FLA efficacy. Here, we show that HU synergistically enhanced ara\u2010C\u2010, F\u2010ara\u2010A\u2010 and FLA\u2010induced cytotoxicity in an SAMHD1\u2010dependent manner in AML cell lines, primary AML cells and an immunocompetent AML mouse model. Mechanistically, HU significantly increased the active metabolite triphosphates of ara\u2010C and F\u2010ara\u2010A in FLA combinations. Furthermore, leukaemic SAMHD1 protein expression negatively correlated with overall survival in a cohort of FLA\u2010treated refractory AML patients. Our findings suggest that the addition of HU improves the efficacy of FLA\u2010based regimens and warrant clinical trials to test the safety and efficacy of this combination in patients with relapsed\/refractory AML.<\/jats:p>","DOI":"10.1111\/bjh.70180","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T12:10:52Z","timestamp":1758975052000},"page":"2462-2474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine\/cytarabine\u2010based salvage regimens against acute myeloid leukaemia"],"prefix":"10.1111","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5270-7268","authenticated-orcid":false,"given":"Ingrid","family":"Lilienthal","sequence":"first","affiliation":[{"name":"Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health Karolinska Institutet  Stockholm 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