Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine/cytarabine‐based salvage regimens against acute myeloid leukaemia
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.
Authors
- Ioanna Xagoraris
- Nikolas Herold (ORCID: https://orcid.org/0000-0001-9468-4543)
- Elory Leonard (ORCID: https://orcid.org/0009-0004-7249-2849)
- Martin Jädersten (ORCID: https://orcid.org/0000-0001-5217-3235)
- Baek Kim (ORCID: https://orcid.org/0000-0001-7986-4335)
- Sofia Bengtzén
- R Zhang
- Nikolaos Tsesmetzis
- Huan Cai (ORCID: https://orcid.org/0000-0003-2752-5598)
- Georgios Z. Rassidakis (ORCID: https://orcid.org/0000-0002-9082-4091)
- Ingrid Lilienthal (ORCID: https://orcid.org/0000-0001-5270-7268)
- Agnes L. Sorteberg
- Shahrzad Shirazi Fard (ORCID: https://orcid.org/0000-0002-4725-5209)
- Anna Bohlin
- Vasilios Zachariadis (ORCID: https://orcid.org/0000-0001-9360-9859)
- Katja Pokrovskaja Tamm (ORCID: https://orcid.org/0000-0001-6359-1256)
- Christer Nilsson (ORCID: https://orcid.org/0000-0003-0695-0050)
- Sören Lehmann (ORCID: https://orcid.org/0000-0001-8374-8978)
- Lakshmi Sandhow (ORCID: https://orcid.org/0009-0004-2924-5412)
- Anette Langebäck
- Raymond F. Schinazi (ORCID: https://orcid.org/0000-0002-6688-3614)
- Sijia Tao
- Hong Qian (ORCID: https://orcid.org/0000-0002-2512-9199)
- Louisa Fredrikson
Institutions
- Uppsala University (SE)
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Department of Medical Sciences (RU)
- Children's Healthcare of Atlanta (US)
Publication Details
- Journal
- British Journal of Haematology
- Published
- 2025-09-27
- DOI
- https://doi.org/10.1111/bjh.70180
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.77
Funders
- Cancerfonden
- Vetenskapsrådet
- Barncancerfonden
- Radiumhemmets Forskningsfonder
- National Institutes of Health