The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed

Katerina Bakunina*, Hein Putter, Jurjen Versluis, Eva A.S. Koster, Bronno van der Holt, Markus G. Manz, Dimitri A. Breems, Bjorn T. Gjertsen, Jacqueline Cloos, Peter J.M. Valk, Jakob Passweg, Thomas Pabst, Gert J. Ossenkoppele, Bob Löwenberg, Jan J. Cornelissen, Liesbeth C. de Wreede

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.

Original languageEnglish
Pages (from-to)630-640
Number of pages11
JournalCancer Medicine
Issue number3
Early online date24 Dec 2021
Publication statusPublished - Feb 2022

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© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.


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