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Targeting SAMHD1 wi...
Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
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- Jadersten, M. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Univ Hosp, Dept Hematol, M64, SE-11186 Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.,Karolinska University Hospital
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- Lilienthal, I. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.
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- Tsesmetzis, N. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.
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- Lourda, M. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Infect Med, Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.,Karolinska University Hospital
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- Bengtzen, S. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.
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- Bohlin, A. (författare)
- Karolinska Institute
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- Arnroth, C. (författare)
- Karolinska Institute
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- Erkers, T. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden.
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- Seashore-Ludlow, B. (författare)
- Karolinska Institute
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- Giraud, Geraldine (författare)
- Uppsala University,Uppsala universitet,Karolinska Institutet,Institutionen för immunologi, genetik och patologi,Uppsala Univ Hosp, Akad Childrens Hosp, Dept Pediat Oncol, Uppsala, Sweden.,Uppsala University Hospital
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- Barkhordar, G. S. (författare)
- Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden.,Sahlgrenska University Hospital
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- Tao, S. J. (författare)
- Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.,Emory University
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- Fogelstrand, Linda, 1974 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine,Sahlgrens Univ Hosp, Dept Clin Chem, Gothenburg, Sweden.;Univ Gothenburg, Inst Biomed, Dept Lab Med, Sahlgrenska Acad, Gothenburg, Sweden.,Sahlgrenska Academy,Sahlgrenska University Hospital
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- Saft, L. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pathol & Canc Diagnost, Stockholm, Sweden.,Karolinska University Hospital
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- Ostling, P. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden.
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- Schinazi, R. F. (författare)
- Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.,Emory University
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- Kim, B. (författare)
- Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.,Emory University
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- Schaller, T. (författare)
- Univ Hosp Heidelberg, Dept Infect Dis, Heidelberg, Germany.;Heidelberg ImmunoTherapeut GmbH, Max Jarecki Str 21, D-69115 Heidelberg, Germany.,University Hospital Heidelberg,Guided Development GmbH
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- Juliusson, Gunnar (författare)
- Lund University,Lunds universitet,Skane Univ Hosp, Dept Hematol, Lund, Sweden.;Lund Univ, Stem Cell Ctr, Dept Hematol, Dept Lab Med, Lund, Sweden.,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Leukemi, genetik, epidemiologi,Forskargrupper vid Lunds universitet,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Leukemia, Genetics, Epidemiology,Lund University Research Groups,Skåne University Hospital
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- Deneberg, S. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Univ Hosp, Dept Hematol, M64, SE-11186 Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.,Karolinska University Hospital
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- Lehmann, Sören (författare)
- Uppsala University,Karolinska Institute,Uppsala universitet,Hematologi,Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.
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- Rassidakis, G. Z. (författare)
- Karolinska Institute,Karolinska University Hospital
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- Höglund, Martin (författare)
- Uppsala University,Uppsala universitet,Hematologi
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- Henter, J. I. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Paediat Oncol, Stockholm, Sweden.,Karolinska University Hospital
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- Herold, N. (författare)
- Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Paediat Oncol, Stockholm, Sweden.,Karolinska University Hospital
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Karolinska Institutet Karolinska Univ Hosp, Dept Hematol, M64, SE-11186 Stockholm, Sweden;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden. (creator_code:org_t)
- 2022-08-18
- 2022
- Engelska.
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 292:6, s. 925-940
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Abstract
Ämnesord
Stäng
- 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(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) 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 x 10(9)/L and to platelet recovery >50 x 10(9)/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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- acute myeloid leukaemia
- cytarabine
- hydroxyurea
- precision medicine
- SAMHD1
- targeted therapy
- 1-beta-d-arabinofuranosylcytosine 5'-triphosphate
- cytosine-arabinoside
- ara-c
- arabinosylcytosine therapy
- adult patients
- chemotherapy
- fludarabine
- cells
- blood
- age
- General & Internal Medicine
- acute myeloid leukaemia
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Jadersten, M.
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Lilienthal, I.
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Tsesmetzis, N.
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Lourda, M.
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Bengtzen, S.
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Bohlin, A.
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visa fler...
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Arnroth, C.
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Erkers, T.
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Seashore-Ludlow, ...
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Giraud, Geraldin ...
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Barkhordar, G. S ...
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Tao, S. J.
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Fogelstrand, Lin ...
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Saft, L.
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Ostling, P.
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Schinazi, R. F.
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Kim, B.
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Schaller, T.
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Juliusson, Gunna ...
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Deneberg, S.
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Lehmann, Sören
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Rassidakis, G. Z ...
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Höglund, Martin
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Henter, J. I.
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Herold, N.
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