BTK Inhibitors in the Frontline Management of Waldenström Macroglobulinemia

by Selleckchem | Aug 27 2023

The discovery of MYD88 (L265P) mutation led to investigating BTK inhibitors in Waldenström macroglobulinemia (WM). Ibrutinib, the first-in-class agent, was approved based on a phase II trial in relapsed/refractory patients. In the phase III iNNOVATE study, the combination of rituximab and ibrutinib was compared with rituximab and placebo in treatment-naïve and relapsed/refractory patients. Second-generation BTK inhibitor, zanubrutinib, was compared with Ibrutinib in MYD88-mutated WM patients in the phase III ASPEN trial, whereas acalabrutinib was investigated in a phase II trial. Here, we discuss the role of BTK inhibitors in treatment-naïve patients with WM based on currently available evidence.

Comments:

Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin lymphoma characterized by the presence of a MYD88 (L265P) mutation in most cases. The discovery of this mutation has led to the investigation of targeted therapies, particularly Bruton's tyrosine kinase (BTK) inhibitors, in the treatment of WM.

Ibrutinib was the first BTK inhibitor to be approved for the treatment of WM. Its approval was based on the results of a phase II trial that demonstrated significant efficacy in relapsed/refractory WM patients. In this trial, ibrutinib showed high overall response rates and durable responses, leading to its approval as a monotherapy for this patient population.

To further evaluate the role of BTK inhibitors in WM, the phase III iNNOVATE study was conducted. This study compared the combination of rituximab (an anti-CD20 monoclonal antibody) and ibrutinib with rituximab and placebo in both treatment-naïve and relapsed/refractory WM patients. The combination therapy showed superior efficacy compared to rituximab alone, with significantly higher response rates, prolonged progression-free survival, and improved quality of life. These findings support the use of ibrutinib-based combination therapy as a treatment option for both newly diagnosed and relapsed/refractory WM patients.

Another BTK inhibitor, zanubrutinib, was evaluated in the phase III ASPEN trial specifically in MYD88-mutated WM patients. This trial compared zanubrutinib with ibrutinib and demonstrated comparable efficacy between the two agents, with zanubrutinib showing non-inferiority to ibrutinib in terms of response rates and progression-free survival. These results suggest that zanubrutinib can be considered as an alternative BTK inhibitor in MYD88-mutated WM patients.

In addition to ibrutinib and zanubrutinib, acalabrutinib, another second-generation BTK inhibitor, has been investigated in a phase II trial for WM. Although the data from this trial is limited, initial results have shown promising efficacy with high response rates and durable responses in both treatment-naïve and relapsed/refractory patients.

Based on the currently available evidence, BTK inhibitors, particularly ibrutinib and zanubrutinib, have emerged as effective treatment options for both treatment-naïve and relapsed/refractory WM patients. Combination therapy with rituximab and ibrutinib has shown superior efficacy compared to rituximab alone, while zanubrutinib has demonstrated non-inferiority to ibrutinib in MYD88-mutated WM patients. Acalabrutinib also shows promise but requires further investigation. These BTK inhibitors provide targeted therapy options for WM patients, improving response rates, progression-free survival, and overall patient outcomes.