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

Jädersten, Martin ; Lilienthal, Ingrid ; Tsesmetzis, Nikolaos ; Lourda, Magda ; Bengtzén, Sofia ; Bohlin, Anna ; Arnroth, Cornelia ; Erkers, Tom ; Seashore-Ludlow, Brinton and Giraud, Géraldine , et al. (2022) In Journal of Internal Medicine 292(6). p.925-940
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.... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
acute myeloid leukaemia, cytarabine, hydroxyurea, precision medicine, SAMHD1, targeted therapy
in
Journal of Internal Medicine
volume
292
issue
6
pages
925 - 940
publisher
Wiley-Blackwell
external identifiers
  • pmid:35934913
  • scopus:85137004073
ISSN
0954-6820
DOI
10.1111/joim.13553
language
English
LU publication?
yes
id
56bde798-1047-4aec-b2a9-14769f617c12
date added to LUP
2022-11-08 13:34:30
date last changed
2024-04-18 07:20:38
@article{56bde798-1047-4aec-b2a9-14769f617c12,
  abstract     = {{<p>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/m<sup>2</sup>/2 h b.i.d. d1-5, i.e., a total of 10 g/m<sup>2</sup> per course), hydroxyurea (1–2 g d1-5) and daunorubicin (60 mg/m<sup>2</sup> 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 &lt;0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery &gt;1.0 × 10<sup>9</sup>/L and to platelet recovery &gt;50 × 10<sup>9</sup>/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.</p>}},
  author       = {{Jädersten, Martin and Lilienthal, Ingrid and Tsesmetzis, Nikolaos and Lourda, Magda and Bengtzén, Sofia and Bohlin, Anna and Arnroth, Cornelia and Erkers, Tom and Seashore-Ludlow, Brinton and Giraud, Géraldine and Barkhordar, Giti S. and Tao, Sijia and Fogelstrand, Linda and Saft, Leonie and Östling, Päivi and Schinazi, Raymond F. and Kim, Baek and Schaller, Torsten and Juliusson, Gunnar and Deneberg, Stefan and Lehmann, Sören and Rassidakis, Georgios Z. and Höglund, Martin and Henter, Jan Inge and Herold, Nikolas}},
  issn         = {{0954-6820}},
  keywords     = {{acute myeloid leukaemia; cytarabine; hydroxyurea; precision medicine; SAMHD1; targeted therapy}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{925--940}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Internal Medicine}},
  title        = {{Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia : Results from the HEAT-AML trial}},
  url          = {{http://dx.doi.org/10.1111/joim.13553}},
  doi          = {{10.1111/joim.13553}},
  volume       = {{292}},
  year         = {{2022}},
}