Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS

Dutch-Belgian Hemato-Oncology Coop, Swiss Grp Clinical Canc Res SAKK, Gerwin Huls*, Dana A. Chitu, Thomas Pabst, Saskia K. Klein, Georg Stussi, Laimonas Griskevicius, Peter J. M. Valk, Jacqueline Cloos, Arjan A. van de Loosdrecht, Dimitri Breems, Danielle van Lammeren-Venema, Isabelle van Zeventer, Rinske Boersma, Mojca Jongen-Lavrencic, Martin Fehr, Mels Hoogendoorn, Markus G. Manz, Maaike SohneRien van Marwijk Kooy, Dries Deeren, Marjolein W. M. van der Poel, Marie Cecile Legdeur, Lidwine Tick, Yves Chalandon, Emanuele Ammatuna, Sabine Blum, Bob Lowenberg, Gert J. Ossenkoppele

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
8 Downloads (Pure)

Abstract

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index >= 3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.

Original languageEnglish
Pages (from-to)4267-4277
Number of pages11
JournalBlood
Volume4
Issue number18
DOIs
Publication statusPublished - 22-Sep-2020

Keywords

  • ACUTE MYELOID-LEUKEMIA
  • MINIMAL RESIDUAL DISEASE
  • HYPOMETHYLATING AGENT THERAPY
  • CONVENTIONAL CARE REGIMENS
  • MYELODYSPLASTIC SYNDROME
  • AZACITIDINE THERAPY
  • TREATMENT RESPONSE
  • CLINICAL-RESPONSE
  • SURVIVAL
  • TRIAL

Cite this