Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma

Abstract

• Single-agent ibrutinib induced durable remissions (ORR 48%) with a favorable benefit-risk profile in patients with previously treated MZL.• Inhibition of BCR signaling with ibrutinib provides a treatment option without chemotherapy for an MZL population with high unmet need.Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ‡1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ‡1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ‡3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628. (Blood. 2017;129(16):2224-2232

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

“…We evaluated the anti‐proliferative activity of the BTK inhibitor, acalabrutinib, and the PI3Kδ inhibitor, ACP‐319, in 11 lymphoma cell lines, derived from ABC‐DLBCL ( n = 4), MCL ( n = 4), and MZL ( n = 3), three subtypes in which BTK inhibition is associated with clinical activity (de Claro et al , ; Wilson et al , ; Noy et al , ). After 72 h of drug exposure, acalabrutinib showed a potent anti‐proliferative activity in ABC DLBCL TMD8 and OCI‐LY‐10 (50% inhibitory concentration [IC50] 7 nmol/l and 1·5 nmol/l respectively), whereas the activity was modest in VL51 (IC50 3·2 µmol/l) and in all other cell lines (IC50s >10 µmol/l).…”

Recent Advances in Therapeutics for B-Cell Lymphoma

“…MZL is also associated with chronic inflammation, leading to continuous B cell stimulation by BCR signaling. A phase 2 trial for single-agent ibrutinib in patients with relapsed/refractory MZL showed high efficacy by disrupting the BCR signaling with ibrutinib [36]. Patients with at least one prior anti-CD20-based therapy showed ORR of 51% with median duration of response of 19 months.…”

Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies

“…Treatment with ibrutinib (PCI-32765) has been shown to induce considerable efficacy to patients with untreated and relapsed/refractory CLL, ABC-DLBCL, FL, MCL, marginal zone lymphoma, and lymphoplasmacytic lymphoma. 90–93 However, ibrutinib may have certain limitations. First, some lymphomas do not just depend on the BCR and NF-κB pathways but may depend on other BTK-independent pathways or genetic mutations; therefore, these lymphomas may show constitutive resistance to ibrutinib.…”