Clinical Experience With Ibrutinib Alone or in Combination With Either Cytarabine or Azacitidine in Patients With Acute Myeloid Leukemia

Abstract

Preclinical studies have suggested that ibrutinib may have a clinical benefit in acute myeloid leukemia (AML). Treatment with ibrutinib alone or in combination with cytarabine or azacitidine was evaluated in 36 patients with AML. The study was terminated because of limited efficacy. Safety was consistent with established safety profiles of the individual drugs. The potential utility of ibrutinib in AML remains uncertain. Background: Preclinical studies have suggested a role for Bruton tyrosine kinase (BTK) as a potential therapeutic target in acute myeloid leukemia (AML), and anti-AML activity in vivo has been demonstrated with BTK inhibitors. Patients and Methods: In this open-label phase 2a study, patients with AML were treated with ibrutinib 560 mg per day alone (cohort 1; n ¼ 7), or ibrutinib in combination with either cytarabine 20 mg administered subcutaneously twice daily for 10 days of a 28-day cycle (cohort 2; n ¼ 21) or azacitidine 75 mg/m 2 administered intravenously once daily on days 1 to 7 of a 28-day cycle (cohort 3; n ¼ 8). Best overall response (primary end point), overall survival, and safety were summarized. Results: A total of 36 patients were enrolled and received treatment; median duration of ibrutinib treatment was 5.4 weeks, and median time on study was 16 months. Of 24 patients evaluable for response, 1 partial remission (cohort 3) and 1 complete remission (cohort 2) were observed; the remaining responses were treatment failures. Median overall survival was 4.0 months in cohort 1, 2.2 months in cohort 2, 2.8 months in cohort 3, and 2.4 months for the overall population. No unexpected safety signals were identified. Grade 3 or higher adverse events that occurred in ! 10% of patients included AML progression, febrile neutropenia, pneumonia, anemia, thrombocytopenia, fatigue, asthenia, and respiratory failure. Conclusion: Ibrutinib alone or in combination with cytarabine or azacitidine demonstrated an acceptable safety profile. However, limited efficacy with ibrutinib was observed in patients with AML.

Electrostatic anti-CD33-antibody–protamine nanocarriers as platform for a targeted treatment of acute myeloid leukemia

“…Ibrutinib is a covalent binder of BTK, which also has been proposed to be a relevant drug target in AML [23]. To illustrate the platform-characteristic of our anti-CD33-mAB-based nanocarrier, we show that ibrutinib-Cy3.5 can act as an efficient inhibitor of BTK in AML cells, as postulated before [24][25][26].…”

“…This supports that our nanocarrier can not only be adapted to the desired target cell by choice of the internalizing antibody and by the definition of an siRNA against a respective oncogene, but also by the complexation of other molecules rendered anionic. The application of ibrutinib in AML, predominantly in combination with cytotoxic agents such as decitabine or azacytidine, as well as BCL2 inhibitors such as venetoclax is currently under consideration [24,25]. Here, we tested the effectivity of the strongly anionic derivative of ibrutinib, ibrutinib-Cy 3.5 to form an αCD33-mAB-P/P nanoparticle that can be safely applied to target the CD33 expressing AML cell line OCI-AML2.…”

BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia

“…The open-label phase 2a multicenter clinical study, which evaluates the efficacy and safety of ibrutinib alone or in combination with either cytarabine or azacitidine in adult patients with AML (for whom the standard treatment had failed or who had not received prior therapy and who refused standard treatment options) was terminated due to limited efficacy. Apparently, the use of ibrutinib alone or in combination with chemotherapy in AML does not improve the treatment outcomes [40]. Clinical studies on the efficacy and safety of abivertinib in patients with AML are planned.…”

Therapeutic targeting of the inflammasome in myeloid malignancies

“…It was shown to suppress IL-1β maturation and caspase 1 activation in PBMCs of Ibrutinib treated cancer patients and is currently under phase 1 trials in combination with lenalidomide and 5′-Azacytidine for MDS (NCT03359460 and NCT02553941). Unfortunately, a phase II trial of ibrutinib alone or in combination with cytarabine or AZA in AML patients unfit for standard therapy or with relapsed/refractory disease, did not show any clinically relevant anti-leukemia activity [ 84 ]. Orally active Caspase 1 inhibitor such as VX-765 [ 85 ] and other caspase 1 inhibitors such as soluble analogs of Parthenolide (anti-inflammatory sesquiterpene lactone compound) can also be potential drug targets in hematological lineage bias disorders such as MDS and AML, which have only been studied in epilepsy and dermatologic conditions so far.…”