Dr Pearse on the Current Treatment Paradigm for Relapsed/Refractory MCL

William B. Pearse, MD, assistant professor, medicine, University of California, San Diego School of Medicine, discusses the current treatment paradigm for patients with relapsed/refractory mantle cell lymphoma (MCL), highlighting the importance of early referral when treating these patients in the community setting.

Pearse begins by saying he strongly believes that integrating BTK inhibition into upfront treatment represents a significant advancement in patient treatment. The phase 3 TRIANGLE study (NCT02858258) offers valuable insights and, although its data is still evolving, the current findings are promising, advocating for the incorporation of BTK inhibition into frontline therapy, he says. BTK inhibitors may be particularly effective when combined with traditional, more aggressive induction regimens, such as rituximab (Rituxan) and cytarabine, for patients who can tolerate these regimens. Critical evaluation of the role of these drugs in frontline treatment strategies is imperative, Pearse reports.

He goes on to elucidate that MCL management poses unique challenges due to the rarity of the disease and its heterogeneous clinical presentation, which is influenced by both genetics and molecular mechanisms driving lymphomagenesis. Given this complexity, early patient referral to academic medical centers is advisable for optimal disease management, he implores. These centers offer access to a variety of clinical trials tailored to different disease stages and prior treatment exposures, Pearse notes. Establishing partnerships between academic institutions and community practices facilitates collaborative patient treatment and ensures access to clinical trials, which is particularly crucial for patients with 

MCL management is evolving rapidly, with ongoing research shedding light on novel treatment approaches, Pearse continues. Pearse says it is important for oncologists to stay informed about emerging therapies and engage in multidisciplinary collaboration to optimize patient care. By leveraging academic resources and clinical trial opportunities, the MCL field can enhance treatment outcomes and provide tailored therapies to patients with MCL, addressing the complexities of this challenging disease, he concludes.

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William B. Pearse, MD, discusses the current treatment paradigm for patients with relapsed/refractory mantle cell lymphoma.

William B. Pearse, MD, discusses the current role of the BTK inhibitor pirtobrutinib in patients with relapsed/refractory mantle cell lymphoma.

Dr Pearse on the Utility of Pirtobrutinib in Relapsed/Refractory MCL

William B. Pearse, MD, assistant professor, medicine, University of California, San Diego (UCSD), UCSD School of Medicine, discusses the current role of the BTK inhibitor pirtobrutinib (Jaypirca) in the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL). Notably, in January 2023, 

 for the treatment of patients with this disease following at least 2 lines of systemic therapy, including a BTK inhibitor.

The optimal sequencing of pirtobrutinib and other BTK inhibitors remains an area of active investigation, Pearse begins. The ongoing MCL 135 BRUIN MCL 321 study (NCT04662255) is a phase 3, open-label, randomized trial designed to explore this question, he states, saying that the study will compare pirtobrutinib against an investigator’s choice of BTK inhibitor in patients with previously treated, BTK inhibitor–naive MCL. By evaluating pirtobrutinib's safety and efficacy relative to established BTK inhibitors, such as acalabrutinib (Calquence) or zanubrutinib (Brukinsa), researchers hope to shed light on the potential for pirtobrutinib as a frontline treatment option in MCL, Pearse elucidates.

One key aspect of the MCL 135 study is its exploration of moving pirtobrutinib earlier in the treatment sequence, he expands. This shift seeks to determine whether initiating therapy with pirtobrutinib yields improved efficacy and safety outcomes compared with standard BTK inhibitors in the second-line relapsed/refractory setting, he explains. Additionally, the study provides an opportunity for head-to-head comparisons between acalabrutinib and zanubrutinib, 2 commonly used BTK inhibitors, in the second-line setting, Pearse says. This comparative analysis promises to enrich the MCL field’s understanding of these agents' respective efficacy and safety profiles, as well as their suitability for different patient populations, he notes.

Although existing data on BTK inhibitors in the second-line relapsed/refractory setting are limited, ongoing trials, such as the MCL 135 study, hold promise for addressing critical gaps in knowledge, Pearse continues. By prospectively evaluating different BTK inhibitors and their sequencing strategies, researchers aim to refine treatment approaches for patients with MCL, according to Pearse. Ultimately, insights gleaned from these trials have the potential to inform clinical decision-making and optimize patient outcomes in the management of MCL, he concludes.

Dr Pearse on the BOVen Trial of BTK Inhibitor Combinations in TP53-Mutant MCL

William B. Pearse, MD, assistant professor, medicine, University of California, San Diego School of Medicine, explains how the ongoing phase 2 BOVen trial (NCT04463025) could shift the current roles of available BTK inhibitors and potentially address unmet needs in 

Addressing unmet needs must be a priority when designing clinical trials that incentivize the referral of patients with MCL, Pearse begins. Since MCL is considered a rarer lymphoma, it can be challenging to accrue specific patient populations for clinical trials, he explains. One significant area of clinical need in this disease is for patients whose tumors express 

mutations, as they tend to have poorer outcomes with conventional induction therapies, Pearse states. Patients with 

mutated MCL often exhibit reduced responses to cytarabine-based induction regimens and experience inferior longitudinal outcomes compared with those who do not harbor this mutation, he adds.

The BOVen trial presents a crucial opportunity to explore how BTK inhibition combined with other targeted agents may serve as a chemotherapy-sparing approaches with meaningful activity, particularly for patients with 

 mutations, Pearse continues. The trial is assessing the efficacy and safety of zanubrutinib (Brukinsa) in combination with venetoclax (Venclexta) and obinutuzumab (Gazyva) in the frontline setting. It aims to provide valuable insights into potential treatment strategies for this subset of patients, he notes.

Early data presented at the 2023 ASH Annual Meeting

 have shown that the combination elicited higher response rates and 2-year progression-free survival (PFS) rates vs those historically seen with chemoimmunotherapy in a cohort of 25 patients. The best overall response rate (ORR) was 96%, and this included a complete response rate of 88%. At a median follow-up of 23.3 months, the 2-year PFS rate was 72% and the median PFS was not reached; 11 patients were progression free at 2 years. The regimen was also reported to be generally well tolerated.

Overall, the BOVen trial holds promise in advancing the understanding and management of MCL, especially in addressing the needs of patients with 

William B. Pearse, MD, discusses the significance of the ongoing phase 2 BOVen trial in TP53-mutant mantle cell lymphoma.

Dr Pearse on Efforts to Elucidate the Optimal Sequencing of BTK Inhibitors in MCL

William B. Pearse, MD, assistant professor, medicine, University of California, San Diego School of Medicine, discusses unanswered questions regarding the sequencing of pirtobrutinib and other approved BTK inhibitors in mantle cell lymphoma (MCL), as well as ongoing research seeking to elucidate the benefit of this drug class agents when used in earlier lines of therapy.

he FDA approval of pirtobrutinib (Jaypirca)

 in patients with relapsed/refractory MCL that progressed on or during at least 2 prior therapies has led to advances in the use of BTK inhibitors in this patient population. However, questions remain regarding the agents’ optimal role within the current treatment paradigm, Pearse begins. The noncovalent BTK inhibitor was approved in January, 2023 based on primary findings from a subset of patients with MCL in the phase 1/2 BRUIN trial (NCT03740529). Long-term follow-up data from the trial confirmed pirtobrutinib's efficacy, with an overall response rate (ORR) of 49.3% (95% CI, 41.1%-57.6%) and a median time to first response of 1.8 months (range, 0.8-13.8) in covalent BTK inhibitor–exposed patients with MCL (n = 152). The agent also demonstrated a manageable toxicity profile with no new safety signals observed.

The ongoing phase 3, open-label-randomized MCL 135 study (NCT04662255) is evaluating pirtobrutinib compared with investigator’s choice of BTK inhibitor in previously treated, BTK inhibitor–naive MCL, Pearse continues. This investigates whether pirtobrutinib may offer improved safety or efficacy compared with other BTK inhibitors, such as acalabrutinib (Calquence) or zanubrutinib (Brukinsa), when moved up to the second line in the relapsed/refractory setting, he explains.

The MCL 135 trial has the potential to provide valuable insights into the role of pirtobrutinib in the treatment of MCL, Pearse states, adding that it may also contribute informative phase 3 data comparing different BTK inhibitors in patients who have not previously received these agents to the MCL paradigm. Prospective data comparing various BTK inhibitors in the second-line relapsed/refractory setting are currently limited, making this trial an important opportunity to address key questions regarding the optimal BTK inhibitor sequencing approach for patients with MCL, he concludes.

William B. Pearse, MD, discusses unanswered questions regarding the sequencing of pirtobrutinib and other BTK inhibitors in mantle cell lymphoma.

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.

 (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 

 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 

-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 

 C481 mutations, commonly develop resistance, Pearse notes. However, the noncovalent BTK inhibitor pirtobrutinib (Jaypirca), 

 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.

William B. Pearse, MD, discusses the current and future roles of BTK inhibitors in patients with relapsed/refractory mantle cell lymphoma.

William B. Pearse, MD

Articles

Dr Pearse on the Current Treatment Paradigm for Relapsed/Refractory MCL

Dr Pearse on the Utility of Pirtobrutinib in Relapsed/Refractory MCL

Dr Pearse on the BOVen Trial of BTK Inhibitor Combinations in TP53-Mutant MCL

Dr Pearse on Efforts to Elucidate the Optimal Sequencing of BTK Inhibitors in MCL

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