Dr Kahl on Persisting Unmet Needs in the Treatment of Mantle Cell Lymphoma

“For years, we've been looking for ways to dial down the intensity of the treatments for our younger patients [with MCL], and we seem to have achieved that now with the addition of novel agents.”

Brad Kahl, MD, professor of medicine, co-chair of the SCC Protocol Review and Monitoring Committee, and director of the Lymphoma Program at Washington University School of Medicine in St. Louis, discussed the ongoing treatment challenges in mantle cell lymphoma (MCL), emphasizing the need for continued therapeutic innovation across diverse patient subgroups.

Although significant progress has been made in MCL management, curative outcomes remain elusive for most patients, Kahl explained. Historically, treatment approaches for younger, fit patients have relied on intensive chemotherapy and consolidation with autologous stem cell transplant (ASCT). However, findings from recent studies suggested that novel agents could enable de-escalation strategies without compromising efficacy, according to Kahl. For example, findings from the phase 3 TRIANGLE trial (NCT02858258) demonstrated that incorporating a BTK inhibitor into frontline therapy could allow for omission of ASCT in certain patients without compromising outcomes.

Similarly, the phase 2 ECOG-ACRIN EA4181 trial (NCT01415752) showed that the addition of a covalent BTK inhibitor like acalabrutinib (Calquence) to standard induction regimens may eliminate the need for high-dose cytarabine, a component often associated with increased toxicity, Kahl continued. These data have helped support the emerging paradigm of integrating targeted therapies into frontline regimens to improve tolerability, particularly in younger patients, Kahl noted.

Beyond de-intensification, there is growing interest in chemotherapy-free strategies for MCL, Kahl continued. Several trials are now exploring combinations of targeted agents as primary therapy, reflecting a broader effort to minimize reliance on cytotoxic agents. Although these approaches are still under investigation, they represent a promising direction for reducing treatment-related morbidity.

However, one of the most pressing unmet needs in MCL involves patients with high-risk disease, particularly those harboring TP53 mutations. Kahl emphasized that standard chemoimmunotherapy regimens have limited efficacy in this population, and optimal treatment strategies remain undefined. Whether these patients should receive only novel regimens or early cellular therapies such as CAR T-cell therapy is an area of active investigation.

He pointed to the phase 2 BOVen study (NCT03824483), which is evaluating a combination of venetoclax (Venclexta), obinutuzumab (Gazyva), and zanubrutinib (Brukinsa) in the frontline setting. Early findings suggest promising activity, including in high-risk subgroups, but additional data are needed to guide clinical decision-making.

Kahl concluded by underscoring the need for continued research to refine treatment strategies across MCL subtypes, particularly for patients with biologically aggressive disease who derive limited benefit from existing standards of care.