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Bakunina, K.; Putter, H.; Versluis, J.; Koster, E.A.S.; Holt, B. van der; Manz, M.G.; ... ; Wreede, L.C. de (2021)

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

Article / Letter to editor
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...Show moreClofarabine 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.Show less
AML
clofarabine
current leukemia-free survival
HSCT
multi-state model
RCT
All authors
Bakunina, K.; Putter, H.; Versluis, J.; Koster, E.A.S.; Holt, B. van der; Manz, M.G.; Breems, D.A.; Gjertsen, B.T.; Cloos, J.; Valk, P.J.M.; Passweg, J.; Pabst, T.; Ossenkoppele, G.J.; Lowenberg, B.; Cornelissen, J.J.; Wreede, L.C. de
Date
2021-12-24
Journal
Cancer Medicine
Volume
11
Issue
3
Pages
630 - 640
DOI
doi:10.1002/cam4.4392
Link
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.4392