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

Huls, Gerwin; Chitu, Dana A; Pabst, Thomas; Klein, Saskia K; Stussi, Georg; Griskevicius, Laimonas; Valk, Peter J M; Cloos, Jacqueline; van de Loosdrecht, Arjan A; Breems, Dimitri; van Lammeren-Venema, Danielle; van Zeventer, Isabelle; Boersma, Rinske; Jongen-Lavrencic, Mojca; Fehr, Martin; Hoogendoorn, Mels; Manz, Markus G; Söhne, Maaike; van Marwijk Kooy, Rien; Deeren, Dries; ... (2020). Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS. Blood advances, 4(18), pp. 4267-4277. American Society of Hematology 10.1182/bloodadvances.2020002846

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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 11.5 months, 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.

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