TY - JOUR
T1 - Inferior outcome of addition of the aminopeptidase inhibitor tosedostat to standard intensive treatment for elderly patients with aml and high risk mds
AU - Janssen, Jeroen
AU - Löwenberg, Bob
AU - Manz, Markus
AU - Bargetzi, Mario
AU - Biemond, Bart
AU - von dem Borne, Peter
AU - Breems, Dimitri
AU - Brouwer, Rolf
AU - Chalandon, Yves
AU - Deeren, Dries
AU - Efthymiou, Anna
AU - Gjertsen, Bjørn Tore
AU - Graux, Carlos
AU - Gregor, Michael
AU - Heim, Dominik
AU - Hess, Urs
AU - Hoogendoorn, Mels
AU - Jaspers, Aurelie
AU - Jie, Asiong
AU - Jongen-Lavrencic, Mojca
AU - Klein, Saskia
AU - van der Klift, Marjolein
AU - Kuball, Jürgen
AU - van Lammeren-Venema, Danielle
AU - Legdeur, Marie Cecile
AU - van de Loosdrecht, Arjan
AU - Maertens, Johan
AU - Kooy, Marinus van Marwijk
AU - Moors, Ine
AU - Nijziel, Marten
AU - van Obbergh, Florence
AU - Oosterveld, Margriet
AU - Pabst, Thomas
AU - van der Poel, Marjolein
AU - Sinnige, Harm
AU - Spertini, Olivier
AU - Terpstra, Wim
AU - Tick, Lidwine
AU - van der Velden, Walter
AU - Vekemans, Marie Christiane
AU - Vellenga, Edo
AU - de Weerdt, Okke
AU - Westerweel, Peter
AU - Stüssi, Georg
AU - van Norden, Yvette
AU - Ossenkoppele, Gert
N1 - Funding Information: 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 Information: Funding: Dutch Cancer Foundation for financial support; Chroma Therapeutics for financial support and delivery of drug for free. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - 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.
AB - 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.
KW - AML
KW - Aminopeptidase inhibitor
KW - Clinical trial
KW - Elderly
KW - High-risk MDS
KW - Tosedostat
UR - http://www.scopus.com/inward/record.url?scp=85100452831&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers13040672
DO - https://doi.org/10.3390/cancers13040672
M3 - Article
C2 - 33562393
SN - 2072-6694
VL - 13
SP - 1
EP - 11
JO - Cancers
JF - Cancers
IS - 4
M1 - 672
ER -