acp-196 and Lymphoma--B-Cell--Marginal-Zone

Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5). Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%). Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients. Acalabrutinib was active and well tolerated in patients with R/R MZL.

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell, Marginal Zone; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrazines; Treatment Outcome

The B-cell receptor and the phosphatidylinositol 3-kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B-cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. The two compounds showed activity in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP-319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on-going current trials with acalabrutinib and ACP-319 as single agents and provide the basis for the investigation of their combination as well.

Topics: Adenosine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Humans; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mice, SCID; Protein Kinase Inhibitors; Pyrazines; Quinolines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays