Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS.
Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS.pdf
AML; aminopeptidase inhibitor; clinical trial; elderly; high-risk MDS; tosedostat; Oncology; Cancer Research
Abstract :
[en] Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.
Disciplines :
Hematology
Author, co-author :
Janssen, Jeroen; Amsterdam University Medical Centers, loc. VUmc, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Löwenberg, Bob; Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
Manz, Markus ; Universitätsspital Zürich, 8091 Zürich, Switzerland
Brouwer, Rolf; Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands
Chalandon, Yves ; Division of Hematology, Department of Oncology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, 1211 Geneve, Switzerland
Deeren, Dries; AZ Delta, 8800 Roeselare, Belgium
Efthymiou, Anna ; Hôpital Fribourgeois, 1708 Fribourg, Switzerland
Gjertsen, Bjørn-Tore ; Haukeland University Hospital, 5021 Bergen, Norway
Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS.
Conflicts of Interest: J.J.: Research support: Novartis, BMS. President, Apps for Care and Science, nonprofit foundation supported by Amgen, Astellas, Daiichi-Sankyo, Janssen, Olympus, Incyte, BMS, Sanofi Genzyme, Servier, Jazz, Takeda. Honoraria: Abbvie, Novartis, Pfizer, Incyte. G.O.: Research support: Novartis, J&J, Celgene, Becton Dickinson; Consultancy: J&J, Sunesis, Celgene, Roche; Advisory board: Novartis, Pfizer, BMS, J&J, Sunesis, Celgene, Agios, Amgen, Astellas, Roche, Jazz Pharmaceuticals, Merus. Others: None declared. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.Funding: Dutch Cancer Foundation for financial support; Chroma Therapeutics for financial support and delivery of drug for free.
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