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

J. Janssen*, B. Lowenberg, M. Manz, M. Bargetzi, B. Biemond, P.V. Borne, D. Breems, R. Brouwer, Y. Chalandon, D. Deeren, A. Efthymiou, B.T. Gjertsen, C. Graux, M. Gregor, D. Heim, U. Hess, M. Hoogendoorn, A. Jaspers, A.S. Jie, M. Jongen-LavrencicS. Klein, M. van der Klift, J. Kuball, D. van Lammeren-Venema, M.C. Legdeur, A. van de Loosdrecht, J. Maertens, M.V. Kooy, I. Moors, M. Nijziel, F. van Obbergh, M. Oosterveld, T. Pabst, M. van der Poel, H. Sinnige, O. Spertini, W. Terpstra, L. Tick, W. van der Velden, M.C. Vekemans, E. Vellenga, O. de Weerdt, P. Westerweel, G. Stussi, Y. van Norden, G. Ossenkoppele

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

Abstract

Simple SummaryTreatment results of acute myeloid leukemia (AML) in elderly patients are unsatisfactory. We investigated in an open label randomized phase II study whether addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy would improve outcome in this population. 231 AML patients > 65 years of age were randomly assigned to receive standard chemotherapy with or without tosedostat for two cycles. We found that complete bone marrow leukemia clearance was not significantly different between both arms. After two years, survival was 33% for the standard arm versus 18% for the tosedostat arm. More patients died due to infectious complications in the tosedostat arm than after standard treatment. Also, a cardiac rhythm abnormality called atrial fibrillation was more often seen in the tosedostat arm. We conclude that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly patients with acute myeloid leukemia.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/m(2) 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 languageEnglish
Article number672
Number of pages11
JournalCancers
Volume13
Issue number4
DOIs
Publication statusPublished - 1 Feb 2021

Keywords

  • aminopeptidase inhibitor
  • aml
  • clinical trial
  • elderly
  • high-risk mds
  • tosedostat
  • AML
  • high-risk MDS

Cite this