Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial

• Type of Material: Article
• Authors: Martin Jadersten, Karolinska University Hospital; Ingrid Lilienthal, Karolinska Institutet; Nikolaos Tsesmetzis, Karolinska Institutet; Magda Lourda, Karolinska Institutet; Sofia Bengtzen, Karolinska Institutet; Anna Bohlin, Karolinska Institutet; Corneila Arnroth, Karolinska Institutet; Tom Erkers, Karolinska Institutet; Brinton Seashore-Ludlow, Karolinska Institutet; Géraldine Giraud, Uppsala University; Giti S Barkhordar, Sahlgrenska University Hospital; Sijia Tao, Emory University; Linda Fogelstrand, Sahlgrenska University Hospital; Leonie Saft, Karolinska Institutet; Päivi Östling, Karolinska Institutet; Raymond Schinazi, Emory University; Baek Kim, Emory University; Torsten Schaller, University Hospital Heidelberg; Gunnar Juliusson, Skane University Hospital; Stefan Deneberg, Karolinska University Hospital; Sören Lehmann, Karolinska Institutet; Georgios Z Rassidakis, Karolinska Institutet; Martin Höglund, Uppsala University; Jan-Inge Henter, Karolinska Institutet; Nikolas Herold, Karolinska Institutet
• Language: English
• Date: 2022-08-18
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 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.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/joim.13553
• Title of Journal or Parent Work: JOURNAL OF INTERNAL MEDICINE
• Volume: 292
• Issue: 6
• Start Page: 925
• End Page: 940
• Keywords: General & Internal Medicine; CELLS; CYTOSINE-ARABINOSIDE; ADULT PATIENTS; SAMHD1; FLUDARABINE; SURVIVAL; Medicine, General & Internal; BLOOD; targeted therapy; acute myeloid leukaemia; cytarabine; CHEMOTHERAPY; precision medicine; hydroxyurea; ARA-C; Life Sciences & Biomedicine; Science & Technology; ARABINOSYLCYTOSINE THERAPY; 1-BETA-D-ARABINOFURANOSYLCYTOSINE 5'-TRIPHOSPHATE
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

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.