Dr Pearse on the Use of BTK Inhibitors in Relapsed/Refractory MCL

William B. Pearse, MD, assistant professor, medicine, University of California, San Diego School of Medicine, discusses the current role of BTK inhibitors in patients with relapsed/refractory mantle cell lymphoma (MCL) and future directions with these agents in this population.

Currently, acalabrutinib (Calquence) and zanubrutinib (Brukinsa) are the 2 covalent BTK inhibitors approved for the treatment of patients with relapsed/refractory MCL, Pearse says. Historically, the covalent BTK inhibitor ibrutinib (Imbruvica) was also FDA approved for patients with relapsed/refractory MCL. However, in 2023, the manufacturers of ibrutinib withdrew the accelerated approval in the relapsed/refractory MCL population.

In recent years, noteworthy data have emerged regarding the inclusion of BTK inhibitors in the frontline MCL setting, Pearse adds. For instance, findings from the phase 3 TRIANGLE trial (NCT02858258) examining ibrutinib plus a conventional cytarabine-containing induction chemotherapy regimen with or without stem cell transplantation were presented at the 2022 ASH Annual Meeting. Although some of the trial data remain immature, they support the potential use of first-line BTK inhibitors, Pearse emphasizes.

Moreover, BTK inhibitor–based combination therapies, which incorporate agents such as venetoclax (Venclexta), have been shown to improve overall response rates, complete response rates, and progression-free survival rates, Pearse notes. Although these combination regimens are associated with more toxicity than BTK inhibitor monotherapy in patients with relapsed/refractory MCL, studies have indicated favorable response rates in difficult-to-treat subsets, according to Pearse. One such population is patients with TP53-mutated MCL, a subgroup known for its poor prognoses with conventional induction chemoimmunotherapy and up-front stem cell transplantation, Pearse says. Combinations of BTK inhibitors and other targeted agents are not commonly used in clinical practice for all-comers but can be considered for individual patients with relapsed or refractory disease, Pearse explains.

Furthermore, patients with prior exposure to BTK inhibitors, particularly those with BTK C481 mutations, commonly develop resistance, Pearse notes. However, the noncovalent BTK inhibitor pirtobrutinib (Jaypirca), which received FDA approval in 2023 for patients with relapsed/refractory MCL, can restore BTK sensitivity in this patient population and yield long-term disease control in these patients, Pearse concludes.