Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS

Jeroen Janssen; Bob Löwenberg; Markus Manz; Mario Bargetzi; Bart Biemond; Peter von dem Borne; Dimitri Breems; Rolf Brouwer; Yves Chalandon; Dries Deeren; Anna Efthymiou; Bjørn-Tore Gjertsen; Carlos Graux; Michael Gregor; Dominik Heim; Urs Hess; Mels Hoogendoorn; Aurelie Jaspers; Asiong Jie; Mojca Jongen-Lavrencic; Saskia Klein; Marjolein van der Klift; Jürgen Kuball; Danielle van Lammeren-Venema; Marie-Cecile Legdeur; Arjan van de Loosdrecht; Johan Maertens; Marinus van Marwijk Kooy; Ine Moors; Marten Nijziel; Florence van Obbergh; Margriet Oosterveld; Thomas Pabst; Marjolein van der Poel; Harm Sinnige; Olivier Spertini; Wim Terpstra; Lidwine Tick; Walter van der Velden; Marie-Christiane Vekemans; Edo Vellenga; Okke de Weerdt; Peter Westerweel; Georg Stüssi; Yvette van Norden; Gert Ossenkoppele

doi:10.3390/cancers13040672

Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS

Jeroen Janssen
, Bob Löwenberg
, Markus Manz
, Mario Bargetzi
, Bart Biemond
, Peter von dem Borne
, Dimitri Breems
, Rolf Brouwer
, Yves Chalandon
, Dries Deeren
, Anna Efthymiou
, Bjørn-Tore Gjertsen
, Carlos Graux
, Michael Gregor
, Dominik Heim
, Urs Hess
, Mels Hoogendoorn
, Aurelie Jaspers
, Asiong Jie
, Mojca Jongen-Lavrencic

Saskia Klein, Marjolein van der Klift, Jürgen Kuball, Danielle van Lammeren-Venema, Marie-Cecile Legdeur, Arjan van de Loosdrecht, Johan Maertens, Marinus van Marwijk Kooy, Ine Moors, Marten Nijziel, Florence van Obbergh, Margriet Oosterveld, Thomas Pabst, Marjolein van der Poel, Harm Sinnige, Olivier Spertini, Wim Terpstra, Lidwine Tick, Walter van der Velden, Marie-Christiane Vekemans, Edo Vellenga, Okke de Weerdt, Peter Westerweel, Georg Stüssi, Yvette van Norden, Gert Ossenkoppele

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Abstract

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.

Original language	English
Article number	672
Number of pages	11
Journal	Cancers
Volume	13
Issue number	4
DOIs	https://doi.org/10.3390/cancers13040672
Publication status	Published - 2 Feb 2021

Keywords

Aminopeptidase inhibitor
AML
Clinical trial
Elderly
High-risk MDS
Tosedostat

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Janssen, J., Löwenberg, B., Manz, M., Bargetzi, M., Biemond, B., Borne, P. V. D., Breems, D., Brouwer, R., Chalandon, Y., Deeren, D., Efthymiou, A., Gjertsen, B.-T., Graux, C., Gregor, M., Heim, D., Hess, U., Hoogendoorn, M., Jaspers, A., Jie, A., ... Ossenkoppele, G. (2021). Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS. Cancers, 13(4), Article 672. https://doi.org/10.3390/cancers13040672

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title = "Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS",

abstract = "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.",

keywords = "Aminopeptidase inhibitor, AML, Clinical trial, Elderly, High-risk MDS, Tosedostat",

author = "Jeroen Janssen and Bob L{\"o}wenberg and Markus Manz and Mario Bargetzi and Bart Biemond and Borne, \{Peter von dem\} and Dimitri Breems and Rolf Brouwer and Yves Chalandon and Dries Deeren and Anna Efthymiou and Bj{\o}rn-Tore Gjertsen and Carlos Graux and Michael Gregor and Dominik Heim and Urs Hess and Mels Hoogendoorn and Aurelie Jaspers and Asiong Jie and Mojca Jongen-Lavrencic and Saskia Klein and Klift, \{Marjolein van der\} and J{\"u}rgen Kuball and Lammeren-Venema, \{Danielle van\} and Marie-Cecile Legdeur and Loosdrecht, \{Arjan van de\} and Johan Maertens and Kooy, \{Marinus van Marwijk\} and Ine Moors and Marten Nijziel and Obbergh, \{Florence van\} and Margriet Oosterveld and Thomas Pabst and Poel, \{Marjolein van der\} and Harm Sinnige and Olivier Spertini and Wim Terpstra and Lidwine Tick and Velden, \{Walter van der\} and Marie-Christiane Vekemans and Edo Vellenga and Weerdt, \{Okke de\} and Peter Westerweel and Georg St{\"u}ssi and Norden, \{Yvette van\} and Gert Ossenkoppele",

note = "Funding Information: Funding: Dutch Cancer Foundation for financial support; Chroma Therapeutics for financial support and delivery of drug for free. Funding Information: Dutch Cancer Foundation for financial support; Chroma Therapeutics for financial support and delivery of drug for free. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = feb,

day = "2",

doi = "10.3390/cancers13040672",

language = "English",

volume = "13",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "4",

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Janssen, J, Löwenberg, B, Manz, M, Bargetzi, M, Biemond, B, Borne, PVD, Breems, D, Brouwer, R, Chalandon, Y, Deeren, D, Efthymiou, A, Gjertsen, B-T, Graux, C, Gregor, M, Heim, D, Hess, U, Hoogendoorn, M, Jaspers, A, Jie, A, Jongen-Lavrencic, M, Klein, S, Klift, MVD, Kuball, J, Lammeren-Venema, DV, Legdeur, M-C, Loosdrecht, AVD, Maertens, J, Kooy, MVM, Moors, I, Nijziel, M, Obbergh, FV, Oosterveld, M, Pabst, T, Poel, MVD, Sinnige, H, Spertini, O, Terpstra, W, Tick, L, Velden, WVD, Vekemans, M-C, Vellenga, E, Weerdt, OD, Westerweel, P, Stüssi, G, Norden, YV & Ossenkoppele, G 2021, 'Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS', Cancers, vol. 13, no. 4, 672. https://doi.org/10.3390/cancers13040672

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 - Borne, Peter von dem

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 - Klift, Marjolein van der

AU - Kuball, Jürgen

AU - Lammeren-Venema, Danielle van

AU - Legdeur, Marie-Cecile

AU - Loosdrecht, Arjan van de

AU - Maertens, Johan

AU - Kooy, Marinus van Marwijk

AU - Moors, Ine

AU - Nijziel, Marten

AU - Obbergh, Florence van

AU - Oosterveld, Margriet

AU - Pabst, Thomas

AU - Poel, Marjolein van der

AU - Sinnige, Harm

AU - Spertini, Olivier

AU - Terpstra, Wim

AU - Tick, Lidwine

AU - Velden, Walter van der

AU - Vekemans, Marie-Christiane

AU - Vellenga, Edo

AU - Weerdt, Okke de

AU - Westerweel, Peter

AU - Stüssi, Georg

AU - Norden, Yvette van

AU - Ossenkoppele, Gert

N1 - Funding Information: Funding: Dutch Cancer Foundation for financial support; Chroma Therapeutics for financial support and delivery of drug for free. Funding Information: 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 - Aminopeptidase inhibitor

KW - AML

KW - Clinical trial

KW - Elderly

KW - High-risk MDS

KW - Tosedostat

UR - https://www.scopus.com/pages/publications/85100452831

U2 - 10.3390/cancers13040672

DO - 10.3390/cancers13040672

M3 - Article

C2 - 33562393

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 4

M1 - 672

ER -

Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS

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