title: Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D-MDS).
abstract: The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.|Early Clinical Trial Unit, University Cancer Centre, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wermke
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schuster
authors.affiliation: Department of Internal Medicine, St. Hedwig Hospital, Berlin, Germany.|Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Nolte
authors.affiliation: Department of Haematology and Oncology, University Hospital, Leipzig, Germany.
authors.forename: Haifa-Kathrin
authors.initials: HK
authors.lastname: Al-Ali
authors.affiliation: Department of Oncology, MVZ Oskar-Helene-Heim, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kiewe
authors.affiliation: Institute of Forensic Medicine, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schönefeldt
authors.affiliation: Institute of Pathology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Jakob
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: von Bonin
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Leopold
authors.initials: L
authors.lastname: Hentschel
authors.affiliation: Clinical Pharmacy, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Ina-Maria
authors.initials: IM
authors.lastname: Klut
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.affiliation: Institute of Pathology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baretton
authors.affiliation: Department of Haematology, Oncology and Clinical Immunology, University Hospital, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Internal Medicine I, Hospital Chemnitz, Chemnitz, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Clinics of Haematology and Medical Oncology, University Hospital, Göttingen, Germany.
authors.forename: Detelef
authors.initials: D
authors.lastname: Haase
authors.affiliation: Department of Haematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Wolf K
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.|Early Clinical Trial Unit, University Cancer Centre, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001773:Blood Cells / Q000473:pathology; D001853:Bone Marrow / Q000098:blood supply; D001854:Bone Marrow Cells / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000401:mortality; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: mTOR modulation; myelodysplastic syndromes; regulatory T-cell; temsirolimus; vascularization