Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
Martin Jädersten, Ingrid Lilienthal, Nikolaos Tsesmetzis, Magda Lourda, Sofia Bengtzén, Anna Bohlin, Cornelia Arnroth, Tom Erkers, Brinton Seashore-Ludlow, Géraldine Giraud, Giti S Barkhordar, Sijia Tao, Linda Fogelstrand, Leonie Saft, Päivi Östling, Raymond F Schinazi, Baek Kim, Torsten Schaller, Gunnar Juliusson, Stefan Deneberg, Sören Lehmann, Georgios Z Rassidakis, Martin Höglund, Jan-Inge Henter, Nikolas Herold, Martin Jädersten, Ingrid Lilienthal, Nikolaos Tsesmetzis, Magda Lourda, Sofia Bengtzén, Anna Bohlin, Cornelia Arnroth, Tom Erkers, Brinton Seashore-Ludlow, Géraldine Giraud, Giti S Barkhordar, Sijia Tao, Linda Fogelstrand, Leonie Saft, Päivi Östling, Raymond F Schinazi, Baek Kim, Torsten Schaller, Gunnar Juliusson, Stefan Deneberg, Sören Lehmann, Georgios Z Rassidakis, Martin Höglund, Jan-Inge Henter, Nikolas Herold
Abstract
Background: Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1.
Objectives: In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients.
Methods: Nine patients were enrolled and received at least two courses of ara-C (1 g/m2 /2 h b.i.d. d1-5, i.e., a total of 10 g/m2 per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m2 d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed.
Results: The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 × 109 /L and to platelet recovery >50 × 109 /L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission.
Conclusion: Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study.
Keywords: SAMHD1; acute myeloid leukaemia; cytarabine; hydroxyurea; precision medicine; targeted therapy.
Conflict of interest statement
T. S. is employed by Heidelberg ImmunoTherapeutics, not relevant to this work. J. I. H. is a consultant for SOBI, not relevant to this work. The other authors declare no conflicts of interest.
© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
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