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Sökning: WFRF:(Schaller L A) > Targeting SAMHD1 wi...

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FältnamnIndikatorerMetadata
00010579naa a2200973 4500
001oai:gup.ub.gu.se/318835
003SwePub
008240910s2022 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:150535009
009oai:DiVA.org:uu-494487
009oai:lup.lub.lu.se:56bde798-1047-4aec-b2a9-14769f617c12
0247 a https://gup.ub.gu.se/publication/3188352 URI
0247 a https://doi.org/10.1111/joim.135532 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1505350092 URI
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4944872 URI
0247 a https://lup.lub.lu.se/record/56bde798-1047-4aec-b2a9-14769f617c122 URI
040 a (SwePub)gud (SwePub)kid (SwePub)uud (SwePub)lu
041 a eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Jadersten, M.u 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 Hospital4 aut
2451 0a Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
264 c 2022-08-18
264 1b Wiley,c 2022
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicin0 (SwePub)3022 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicine0 (SwePub)3022 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Hematologi0 (SwePub)302022 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Hematology0 (SwePub)302022 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Cancer och onkologi0 (SwePub)302032 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cancer and Oncology0 (SwePub)302032 hsv//eng
653 a acute myeloid leukaemia
653 a cytarabine
653 a hydroxyurea
653 a precision medicine
653 a SAMHD1
653 a targeted therapy
653 a 1-beta-d-arabinofuranosylcytosine 5'-triphosphate
653 a cytosine-arabinoside
653 a ara-c
653 a arabinosylcytosine therapy
653 a adult patients
653 a chemotherapy
653 a fludarabine
653 a cells
653 a blood
653 a age
653 a General & Internal Medicine
653 a acute myeloid leukaemia
7001 a Lilienthal, I.u Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.4 aut
7001 a Tsesmetzis, N.u Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.4 aut
7001 a Lourda, M.u 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 Hospital4 aut
7001 a Bengtzen, S.u Karolinska Institute,Karolinska Institutet,Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.4 aut
7001 a Bohlin, A.u Karolinska Institute4 aut
7001 a Arnroth, C.u Karolinska Institute4 aut
7001 a Erkers, T.u Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden.4 aut
7001 a Seashore-Ludlow, B.u Karolinska Institute4 aut
7001 a Giraud, Geraldineu 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 Hospital4 aut0 (Swepub:uu)gergi266
7001 a Barkhordar, G. S.u Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden.,Sahlgrenska University Hospital4 aut
7001 a Tao, S. J.u Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.,Emory University4 aut
7001 a Fogelstrand, Linda,d 1974u 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 Hospital4 aut0 (Swepub:gu)xsvlin
7001 a Saft, L.u Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pathol & Canc Diagnost, Stockholm, Sweden.,Karolinska University Hospital4 aut
7001 a Ostling, P.u Karolinska Institute,Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden.4 aut
7001 a Schinazi, R. F.u Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.,Emory University4 aut
7001 a Kim, B.u Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.,Emory University4 aut
7001 a Schaller, T.u Univ Hosp Heidelberg, Dept Infect Dis, Heidelberg, Germany.;Heidelberg ImmunoTherapeut GmbH, Max Jarecki Str 21, D-69115 Heidelberg, Germany.,University Hospital Heidelberg,Guided Development GmbH4 aut
7001 a Juliusson, Gunnaru 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 Hospital4 aut0 (Swepub:lu)stem-gju
7001 a Deneberg, S.u 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 Hospital4 aut
7001 a Lehmann, Sörenu Uppsala University,Karolinska Institute,Uppsala universitet,Hematologi,Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.4 aut0 (Swepub:uu)sorle534
7001 a Rassidakis, G. Z.u Karolinska Institute,Karolinska University Hospital4 aut
7001 a Höglund, Martinu Uppsala University,Uppsala universitet,Hematologi4 aut0 (Swepub:uu)martinhl
7001 a Henter, J. I.u 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 Hospital4 aut
7001 a Herold, N.u 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 Hospital4 aut
7102 a Karolinska Institutetb Karolinska Univ Hosp, Dept Hematol, M64, SE-11186 Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.4 org
7730 t Journal of Internal Medicined : Wileyg 292:6, s. 925-940q 292:6<925-940x 0954-6820x 1365-2796
8564 u https://doi.org/10.1111/joim.13553y Fulltext
8564 u https://uu.diva-portal.org/smash/get/diva2:1728573/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
8564 u http://dx.doi.org/10.1111/joim.13553x freey FULLTEXT
8564 8u https://gup.ub.gu.se/publication/318835
8564 8u https://doi.org/10.1111/joim.13553
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:150535009
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-494487
8564 8u https://lup.lub.lu.se/record/56bde798-1047-4aec-b2a9-14769f617c12

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