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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
Author(s): ,
Martin Jädersten
Affiliations:
Department of Hematology,Karolinska University Hospital,Stockholm,Suède;Department of Hematology,Karolinska University Hospital,Stockholm,Schweden;Department of Hematology,Karolinska University Hospital,Stockholm,Svezia;Department of Hematology,Karolinska University Hospital,Stockholm,Sweden;Department of Hematology,Karolinska University Hospital,Stockholm,Suecia;Department of Hematology,Karolinsk
,
Ingrid Lilienthal
Affiliations:
Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suède;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Schweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Svezia;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Sweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suecia;Childhood Cancer Research Unit,Karolinska Institu
,
Nikolaos Tsesmetzis
Affiliations:
Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suède;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Schweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Svezia;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Sweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suecia;Childhood Cancer Research Unit,Karolinska Institu
,
Magda Lourda
Affiliations:
Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suède;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Schweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Svezia;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Sweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suecia;Childhood Cancer Research Unit,Karolinska Institu
,
Sofia Bengtzén
Affiliations:
Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Suède;Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Schweden;Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Svezia;Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Sweden;Centre for hematology and regenerative medicine,Kar
,
Anna Bohlin
Affiliations:
Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Suède;Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Schweden;Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Svezia;Centre for hematology and regenerative medicine,Karolinska Institutet,Stockholm,Sweden;Centre for hematology and regenerative medicine,Kar
,
Cornelia Arnroth
Affiliations:
Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suède;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Schweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Svezia;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Sweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suecia;Department of Oncology-Pathology,Karoli
,
Tom Erkers
Affiliations:
Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suède;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Schweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Svezia;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Sweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suecia;Department of Oncology-Pathology,Karoli
,
Brinton Seashore-Ludlow
Affiliations:
Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suède;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Schweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Svezia;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Sweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suecia;Department of Oncology-Pathology,Karoli
,
Géraldine Giraud
Affiliations:
Department of Immunology,Uppsala University,Uppsala,Suède;Department of Immunology,Uppsala University,Uppsala,Schweden;Department of Immunology,Uppsala University,Uppsala,Svezia;Department of Immunology,Uppsala University,Uppsala,Sweden;Department of Immunology,Uppsala University,Uppsala,Suecia;Department of Immunology,Uppsala University,Uppsala,Zweden;Department of Immunology,Uppsala University,U
,
Giti Shah Barkhordar
Affiliations:
Department of Clinical Genetics and Genomics,Sahlgrenska University Hospital,Gothenburg,Suède;Department of Clinical Genetics and Genomics,Sahlgrenska University Hospital,Gothenburg,Schweden;Department of Clinical Genetics and Genomics,Sahlgrenska University Hospital,Gothenburg,Svezia;Department of Clinical Genetics and Genomics,Sahlgrenska University Hospital,Gothenburg,Sweden;Department of Clini
,
Sijia Tao
Affiliations:
Department of Pediatrics,Emory University,Atlanta,États-unis;Department of Pediatrics,Emory University,Atlanta,Vereinigte Staaten;Department of Pediatrics,Emory University,Atlanta,Stati Uniti;Department of Pediatrics,Emory University,Atlanta,United States;Department of Pediatrics,Emory University,Atlanta,Estados Unidos;Department of Pediatrics,Emory University,Atlanta,Verenigde Staten;Department o
,
Linda Fogelstrand
Affiliations:
Department of Laboratory Medicine,Sahlgrenska Academy at University of Gothenburg,Gothenburg,Suède;Department of Laboratory Medicine,Sahlgrenska Academy at University of Gothenburg,Gothenburg,Schweden;Department of Laboratory Medicine,Sahlgrenska Academy at University of Gothenburg,Gothenburg,Svezia;Department of Laboratory Medicine,Sahlgrenska Academy at University of Gothenburg,Gothenburg,Sweden
,
Leonie Saft
Affiliations:
Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suède;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Schweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Svezia;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Sweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suecia;Department of Oncology-Pathology,Karoli
,
Päivi Östling
Affiliations:
Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suède;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Schweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Svezia;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Sweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suecia;Department of Oncology-Pathology,Karoli
,
Raymond Schinazi
Affiliations:
Department of Pediatrics,Emory University,Atlanta,États-unis;Department of Pediatrics,Emory University,Atlanta,Vereinigte Staaten;Department of Pediatrics,Emory University,Atlanta,Stati Uniti;Department of Pediatrics,Emory University,Atlanta,United States;Department of Pediatrics,Emory University,Atlanta,Estados Unidos;Department of Pediatrics,Emory University,Atlanta,Verenigde Staten;Department o
,
Baek Kim
Affiliations:
Department of Pediatrics,Emory University,Atlanta,États-unis;Department of Pediatrics,Emory University,Atlanta,Vereinigte Staaten;Department of Pediatrics,Emory University,Atlanta,Stati Uniti;Department of Pediatrics,Emory University,Atlanta,United States;Department of Pediatrics,Emory University,Atlanta,Estados Unidos;Department of Pediatrics,Emory University,Atlanta,Verenigde Staten;Department o
,
Torsten Schaller
Affiliations:
Department of Infectious Diseases,University Hospital Heidelberg,Heidelberg,Allemagne;Department of Infectious Diseases,University Hospital Heidelberg,Heidelberg,Deutschland;Department of Infectious Diseases,University Hospital Heidelberg,Heidelberg,Germania;Department of Infectious Diseases,University Hospital Heidelberg,Heidelberg,Germany;Department of Infectious Diseases,University Hospital Hei
,
Gunnar Juliusson
Affiliations:
Department of Hematology,Skåne University Hospital,Lund,Suède;Department of Hematology,Skåne University Hospital,Lund,Schweden;Department of Hematology,Skåne University Hospital,Lund,Svezia;Department of Hematology,Skåne University Hospital,Lund,Sweden;Department of Hematology,Skåne University Hospital,Lund,Suecia;Department of Hematology,Skåne University Hospital,Lund,Zweden;Department of Hematol
,
Stefan Deneberg
Affiliations:
Department of Hematology,Karolinska University Hospital,Stockholm,Suède;Department of Hematology,Karolinska University Hospital,Stockholm,Schweden;Department of Hematology,Karolinska University Hospital,Stockholm,Svezia;Department of Hematology,Karolinska University Hospital,Stockholm,Sweden;Department of Hematology,Karolinska University Hospital,Stockholm,Suecia;Department of Hematology,Karolinsk
,
Sören Lehmann
Affiliations:
Department of Medical Sciences,Uppsala University,Uppsala,Suède;Department of Medical Sciences,Uppsala University,Uppsala,Schweden;Department of Medical Sciences,Uppsala University,Uppsala,Svezia;Department of Medical Sciences,Uppsala University,Uppsala,Sweden;Department of Medical Sciences,Uppsala University,Uppsala,Suecia;Department of Medical Sciences,Uppsala University,Uppsala,Zweden;Departmen
,
Georgios Rassidakis
Affiliations:
Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suède;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Schweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Svezia;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Sweden;Department of Oncology-Pathology,Karolinska Institutet,Stockholm,Suecia;Department of Oncology-Pathology,Karoli
,
Martin Höglund
Affiliations:
Department of Medical Sciences,Uppsala University,Uppsala,Suède;Department of Medical Sciences,Uppsala University,Uppsala,Schweden;Department of Medical Sciences,Uppsala University,Uppsala,Svezia;Department of Medical Sciences,Uppsala University,Uppsala,Sweden;Department of Medical Sciences,Uppsala University,Uppsala,Suecia;Department of Medical Sciences,Uppsala University,Uppsala,Zweden;Departmen
,
Jan-Inge Henter
Affiliations:
Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suède;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Schweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Svezia;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Sweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suecia;Childhood Cancer Research Unit,Karolinska Institu
Nikolas Herold
Affiliations:
Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suède;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Schweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Svezia;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Sweden;Childhood Cancer Research Unit,Karolinska Institutet,Stockholm,Suecia;Childhood Cancer Research Unit,Karolinska Institu
(Abstract release date: 05/12/22) EHA Library. Jädersten M. 06/10/22; 357406; P543
Martin Jädersten
Martin Jädersten
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P543

Type: Poster presentation

Session title: Acute myeloid leukemia - Clinical

Background
Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-CTP levels through targeted inhibition of SAMHD1. 

Aims
To evaluate feasibility, safety, and efficacy of adding hydroxyurea to standard AML-directed therapy according to national guidelines.

To perform translational studies including SAMHD1-staining on bone marrow sections, pharmacokinetics and drug-sensitivity analysis on leukemic cells ex vivo.

Methods
This phase-1 trial (EudraCT-number: 2018-004050-16) was run at two sites (Karolinska University Hospital and Uppsala University Hospital, Sweden). Eligibility criteria included age >18 years, newly diagnosed non-promyelocytic AML, and fitness for intensive chemotherapy. Patients with CBF-AML eligible for treatment with gemtuzumab-ozogamicin were excluded. Treatment comprised 2 to 4 cycles of ara-C 1000 mg/m2 i.v. b.i.d. on day 1-5 during all 4 cycles and daunorubicin 60 mg/m2 i.v. q.d. on day 1-3 during cycles 1 and 2, and on day 1-2 during cycle 3. Patients with FLT3-mutated AML received midostaurin 50 mg b.i.d. on day 8-21 of each cycle. Risk-adapted allo-HSCT was performed at the discretion of the treating haematologist. The dose of hydroxyurea was escalated in a 3+3 design: 500 + 500 mg (level 1), 1000 + 500 mg (level 2), and 1000 + 1000 mg (level 3), each dose being given 1 hour prior to start of the ara-C infusion b.i.d. on day 1-5.

Here we report the results of the first 9 patients in the run-in phase 1 part of the study. The phase 2 part will include an additional 60 patients. Recruitment is ongoing, utilizing the highest dose of hydroxyurea.

Expression of SAMHD1 was assessed using a double-immunostaining method (SAMHD1/CD68), an autostainer system (BenchMark Ultra, Ventana, Rotkreuz, Switzerland) and previously validated protocols20. CD68+/SAMHD1+ histiocytes (macrophages) served as internal controls in all bone marrow biopsies assessed. 

Drug sensitivity analysis was performed on AML mononuclear cells utilized a high-throughput system evaluating >500 cytotoxic agents including combinations of ara-C and hydroxyurea in different doses.

Results
All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow-cytometry or RT-qPCR) had an MRD level <0.1% after two cycles of chemotherapy. Six of nine patients underwent hematopoietic stem cell transplantation. With a median follow-up of 13.2 months, no relapse has been observed.

No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in ara-CTP levels (1.5-fold; P=0.04) in the 6 patients receiving single doses of 1000 mg hydroxyurea. Drug-sensitivity analysis indicated an additive effect of ara-C and hydroxyurea on leukemic cells ex vivo. There was no apparent correlation between expression of SAMHD1-expression and efficacy; all patients had deep responses.

Conclusion
The high rate of complete remission and MRD negativity together with the pharmacokinetic and ex vivo evidence suggest that the efficacy of cytarabine-based AML treatment can be enhanced by addition of hydroxyurea as a targeted inhibitor of SAMHD1. Importantly, orally administered hydroxyurea may provide a safe, inexpensive, and broadly accessible strategy to improve outcome in AML. These results will have to be validated in a larger patient cohort.

Keyword(s): Drug resistance, Drug sensitivity

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P543

Type: Poster presentation

Session title: Acute myeloid leukemia - Clinical

Background
Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-CTP levels through targeted inhibition of SAMHD1. 

Aims
To evaluate feasibility, safety, and efficacy of adding hydroxyurea to standard AML-directed therapy according to national guidelines.

To perform translational studies including SAMHD1-staining on bone marrow sections, pharmacokinetics and drug-sensitivity analysis on leukemic cells ex vivo.

Methods
This phase-1 trial (EudraCT-number: 2018-004050-16) was run at two sites (Karolinska University Hospital and Uppsala University Hospital, Sweden). Eligibility criteria included age >18 years, newly diagnosed non-promyelocytic AML, and fitness for intensive chemotherapy. Patients with CBF-AML eligible for treatment with gemtuzumab-ozogamicin were excluded. Treatment comprised 2 to 4 cycles of ara-C 1000 mg/m2 i.v. b.i.d. on day 1-5 during all 4 cycles and daunorubicin 60 mg/m2 i.v. q.d. on day 1-3 during cycles 1 and 2, and on day 1-2 during cycle 3. Patients with FLT3-mutated AML received midostaurin 50 mg b.i.d. on day 8-21 of each cycle. Risk-adapted allo-HSCT was performed at the discretion of the treating haematologist. The dose of hydroxyurea was escalated in a 3+3 design: 500 + 500 mg (level 1), 1000 + 500 mg (level 2), and 1000 + 1000 mg (level 3), each dose being given 1 hour prior to start of the ara-C infusion b.i.d. on day 1-5.

Here we report the results of the first 9 patients in the run-in phase 1 part of the study. The phase 2 part will include an additional 60 patients. Recruitment is ongoing, utilizing the highest dose of hydroxyurea.

Expression of SAMHD1 was assessed using a double-immunostaining method (SAMHD1/CD68), an autostainer system (BenchMark Ultra, Ventana, Rotkreuz, Switzerland) and previously validated protocols20. CD68+/SAMHD1+ histiocytes (macrophages) served as internal controls in all bone marrow biopsies assessed. 

Drug sensitivity analysis was performed on AML mononuclear cells utilized a high-throughput system evaluating >500 cytotoxic agents including combinations of ara-C and hydroxyurea in different doses.

Results
All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow-cytometry or RT-qPCR) had an MRD level <0.1% after two cycles of chemotherapy. Six of nine patients underwent hematopoietic stem cell transplantation. With a median follow-up of 13.2 months, no relapse has been observed.

No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in ara-CTP levels (1.5-fold; P=0.04) in the 6 patients receiving single doses of 1000 mg hydroxyurea. Drug-sensitivity analysis indicated an additive effect of ara-C and hydroxyurea on leukemic cells ex vivo. There was no apparent correlation between expression of SAMHD1-expression and efficacy; all patients had deep responses.

Conclusion
The high rate of complete remission and MRD negativity together with the pharmacokinetic and ex vivo evidence suggest that the efficacy of cytarabine-based AML treatment can be enhanced by addition of hydroxyurea as a targeted inhibitor of SAMHD1. Importantly, orally administered hydroxyurea may provide a safe, inexpensive, and broadly accessible strategy to improve outcome in AML. These results will have to be validated in a larger patient cohort.

Keyword(s): Drug resistance, Drug sensitivity

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