Increased Molecular Understanding Informs Mantle Cell Treatment Choices

Andre H. Goy, MD

The treatment paradigm for mantle cell lymphoma (MCL) is shifting as novel agents are incorporated into prior standard regimens and as next-generation sequencing becomes more readily used, allowing us to identify—well beyond clinical prognostic models—distinct molecular features predictive of poor outcome with conventional approaches, according to Andre H. Goy, MD. Goy is physician in chief at Hackensack Meridian Health Oncology Care Transformation Service, chairman and chief physician officer at John Theurer Cancer Center, the Lydia Pfund Chair for Lymphoma, academic chairman of oncology at Hackensack Meridian School of Medicine, and professor of medicine at Georgetown University in Hackensack, New Jersey.

“Traditionally, MCL was dichotomized based on the age of the patient and their ability to tolerate intensive therapy, [but] now we have to take into consideration biological differences across patients that go well beyond age,” Goy said. The increased understanding of the molecular diversity of MCL and the development of targeted nonchemotherapy options, especially Bruton tyrosine kinase (BTK) inhibitors, have revolutionized the field.

“[Although] a finite molecular subclassification of MCL is not yet available, there are distinct features that predict a very poor outcome, even in the frontline setting and regardless of therapy intensity,” Goy said. In particular, TP53 mutations are a significant independent molecular marker of poorer outcomes, leading to median overall survival of 1 to 2 years. Mutations in NOTCH1/2, MYC, and others as well as complex karyotype are associated with aggressive disease.¹ In his presentation on September 30, 2022, during the Mantle Cell Lymphoma sessionof the 10th Annual Meeting of the Society of Hematologic Oncology, Goy will discuss how our understanding of the molecular mechanisms in MCL has guided the evolving therapeutic approaches.

MCL Heterogeneity

According to Goy, patients with MCL can be divided into 3 groups. “About 10% to 15% of cases are indolent and remain stable for years. These patients are genetically stable, do not have a complex karyotype, have an IGHV-mutated status, and rarely carry TP53 mutations and/or deletions, although these can be acquired over time,” Goy said. “Clinically, these patients have a high white blood cell count, splenomegaly with no or minimal lymphadenopathy. Although they overexpress cyclin D1, they have a very low proliferation rate and are typically SOX11 negative. GEP [gene expression profiling] studies would show a different profile comparing to other MCL, consistent with a distinct pathogenesis.

“On the other end of the spectrum, [10% to 15% of patients with MCL] have the aggressive blastoid MCLs that have TP53 mutations/deletions, other mutations associated with high-risk disease, frequent complex karyotypes, and high proliferation rate,” Goy continued. “These patients do very poorly with standard therapy, particularly if they are TP5 positive. And even with intensive therapy, the median survival is 1 to 2 years.

“In between, fall the majority of MCL cases [70% to 80%], with a spectrum of clinical presentations,” Goy said. “This includes the ‘smoldering MCL’—asymptomatic patients with very low tumor burden who can be monitored and show a median time to start therapy of around 1 to 2 years, [whereas] all other MCL cases are managed following the age/intense therapy–fit dichotomy paradigm.”

Therapeutic Approaches

The initial approach for frontline treatment of MCL was largely based on patient-specific factors, such as age and overall performance status, along with underlying comorbidities.² Validated prognostic tools, such as MIPI-c (a combination of the Mantle Cell Lymphoma International Prognostic Index and the Ki-67 proliferation index), and early predictors of treatment response, such as positron emission tomography imaging and minimal/measurable residual disease (MRD) analysis, as well as genomic alterations, are taken into consideration when deciding on treatment approaches for each patient.¹

Traditionally for young, transplant-eligible patients, treatment consists of chemoimmunotherapy with rituximab (Rituxan), an anti-CD20 monoclonal antibody, and cytarabine-containing regimens, followed by stem cell transplant consolidation and maintenance with rituximab.2 Other chemotherapy agents are used for patients who are not candidates for this approach.^2,3

Although this chemotherapy-based frontline treatment yields high complete response (CR) rates (61%-89%) and a median progression-free survival beyond 7 to 8 years, a significant number of patients eventually relapse.⁴ Furthermore, these regimens are associated with short- and longer-term toxicities, including secondary malignancies.⁵

Novel Therapies for MCL

“Though the field is still evolving, we can distinguish 3 strategies aiming at integrating novel agents to chemoimmunotherapy and illustrating a definite shift happening in MCL,” Goy said. The first is adding biologicals to chemotherapy (addition of ibrutinib [Imbruvica] in the Triangle trial [NCT02858258])⁶; the second is using biologicals before chemotherapy (induction with rituximab and ibrutinib)7,8; and the third is aiming at fully replacing chemotherapy (monotherapy with lenalidomide [Revlimid], bortezomib [Velcade], or venetoclax [Venclexta]) with very promising preliminary results.^2,3

“I think we have entered a new era in MCL, where novel therapies, particularly BTK inhibitors and their combinations, have changed the field,” Goy said.

Finally, brexucabtagene autoleucel (Tecartus), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, had an overall response rate greater than 90% and a CR rate greater than 60% in heavily pretreated MCL.9 More than 70% of patients who were MRD negative at 3 to 6 months post–CAR T-cell therapy are still progression free at 3 years and potentially cured.9 “This, in itself, would justify bringing CAR T-cell therapy earlier in patients with high-risk disease and/or early progression,” Goy said.

Further Investigations

Goy highlighted several areas for further investigation in the MCL field. It remains unclear how patients with MCL treated with nonchemotherapy options in the frontline setting would respond to salvage therapy. Ongoing trials are looking at chemotherapy-free options and other combinations to answer these questions. This shifting paradigm represents an attractive area in MCL, which has the potential to help not only the patients with low-bulk/smoldering MCL and patients older than 75 years—and not expose them to chemotherapy—but more importantly, the growing proportion of patients with molecular features indicative of poor responses to chemotherapy-based approaches. These patients are now more readily identifiable thanks to increasing access to routine molecular diagnostics and next-generation sequencing.

“These encouraging times obligate us to double down our efforts for trials that will help settle the new standards our patients deserve,” Goy said.

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_{7. Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (<65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. Lancet Oncol. 2022;23(3):406-415. doi:10.1016/S1470-2045(21)00638-0}

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_{9. CAR T-cell therapy approved by FDA for mantle cell lymphoma. Cancer Currents blog. August 24, 2020. Accessed Auguest 25, 2022. https://www.cancer.gov/news-events/cancer-currents-blog/2020/fda-brexucabtagene-mantle-cell-lymphoma}