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

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 11.5 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.

Graphical abstract

Figure 1.

Study scheme. BM, bone marrow; D, day.

Figure 2.

CONSORT study diagram. Arm A = 10-day decitabine; arm B = 10-day decitabine plus ibrutinib. PD, progressive disease; Tx, treatment.

Figure 3.

Kaplan-Meier estimates for OS. Arm A = 10-day decitabine arm; arm B = 10-day decitabine plus ibrutinib. Median OS was almost 12 months in both arms.

Figure 4.

Associations between molecular and cytogenetic abnormalities (with prevalence ≥10) and response. (A) The association between individual frequently mutated genes (≥10 times) and frequently observed cytogenetic abnormalities (≥10 times) and response (CR/CRi) after 3 cycles. Odds ratios are displayed on a log₁₀ scale, with lines extending to the 95% CI. Horizontal bars indicate the proportion with a mutation in the respective gene for patients with (blue) and without (red) response, with absolute numbers given for each gene. Data on molecular abnormalities were available for 140 individuals, whereas cytogenetic abnormalities were assessed in a subset of 114 individuals with identified cytogenetic abnormalities. P values are derived from Fisher’s exact test. The association between response (CR/CRi) within 3 cycles and highest variant allele frequency (VAF) per individual (B), number of mutations per individual (C), and number of mutated genes per individual (D). P values are from Wilcoxon signed-rank test.

Figure 5.

Kaplan-Meier estimates of EFS and OS. Graphs depict data from all 57 patients with available MRD data after 3 cycles.