The Role of Targeted Therapies in Frontline Treatment of Mantle Cell Lymphoma

Tycel J. Phillips, MD

Mantle cell lymphoma (MCL) is a rare B-cell malignancy with a heterogeneous clinical course without a true standard of care. To date, several treatment regimens have been used in the treatment of patients with newly diagnosed MCL. With few randomized phase 3 trials to pull data from, most treatments are typically dictated by region and institutional preference vs clear scientific rationale. Nevertheless, there have been marked improvements in expected remission and overall survival (OS) rates even though a cure for this disease remains elusive.^1,2

Treatment for most patients is a dichotomy based on transplant eligibility: High-dose chemotherapy, which invariably includes cytarabine (Nordic regimen, R-hyper-CVAD [rituximab, cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), dexamethasone], R-DHAOx/CHOP [rituximab, dexamethasone, high-dose cytarabine, oxaliplatin/cyclophosphamide, doxorubicin, prednisone, vincristine]), is followed by an autologous stem cell transplant (ASCT) followed by maintenance R or “less intense” chemoimmunotherapy (CIT) followed by maintenance R.

In a presentation titled, “The Role of Targeted Therapies in Frontline Treatment of Mantle Cell Lymphoma,” Tycel J. Phillips, MD, clinical associate professor, University of Michigan Health in Ann Arbor, Michigan, addressed strategies to manage high-risk patients.

Two points can be emphasized:

1. Maintenance R is universally accepted as beneficial in MCL as it improves progression-free survival (PFS) and OS.
2. Data from 2 studies have established bendamustine-rituximab (BR) as superior to R-CHOP2,³ as initial therapy in patients considered unfit for ASCT and the regimen is preferred for most in this patient population.

Additionally, BR has blurred the lines of our dichotomy and has been used as a preferred pretransplant regimen for some patients based on its sound combination of efficacy and tolerance.

High-Risk Patients

However, given the toxicities of CIT and the desire to improve outcomes in very high-risk patients, studies seeking to incorporate novel therapies into the frontline treatment of patients with MCL have been undertaken. These have included combination studies of CIT plus novel agents or agents devoid of traditional chemotherapy.

One of the first studies sought to improve outcomes of patients treated with R-CHOP by substituting the proteasome inhibitor bortezomib (Velcade) for vincristine. This regimen, VR-CAP (bortezomib, rituximab, epirubicin, cyclophosphamide, prednisone),⁴ was demonstrated in a randomized study to be superior to R-CHOP in participants unfit for ASCT. The addition of bortezomib to BR was also explored in a phase 2 study.⁵ Despite positive outcomes, neither combination has equivalent uptake to BR. The SHINE study (NCT01776840)⁶ further explored combination therapy with BR and findings were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

This study randomly assigned transplant-ineligible patients with MCL to BR vs BR plus the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib (Imbruvica). Although the study met its primary end point, demonstrating a marked difference in PFS in the experimental arm, its impact on the treatment landscape is less settled.

There was no OS benefit, likely due to higher than anticipated non–disease-related deaths in the experimental arm. Questions about how this would compare with sequential therapy and the lack of tangible benefit in patients with a TP53 mutation makes mainstream adoption of the regimen doubtful.

The sister study to SHINE, ECHO (NCT02972840), which is evaluating BR with acalabrutinib (Calquence), is currently maturing. We anxiously await the results before putting any nail into the coffin of combination CIT and BTKi in frontline MCL.

Alternative Regimens

Other studies have explored BTKi without chemotherapy in frontline MCL. BGB-3111-306 (NCT04002297) is an ongoing trial that randomly assigns patients who are unfit for ASCT to receive zanubrutinib (Brukinsa) plus R vs BR. Additionally, investigators have been examining R + ibrutinib (IR) in 2 studies conducted at The University of Texas MD Anderson Cancer Center, WINDOW-I and WINDOW II.

The WINDOW-I7 study (NCT02427620) evaluated a year’s induction of IR followed by R-hyper-CVAD consolidation for up to 4 cycles. The data demonstrated a high ORR after the 1-year treatment of IR and led to the development of WINDOW II (NCT03710772),which is incorporating the BCL-2 inhibitor venetoclax into induction. In an elderly population, the investigators are again exploring IR.⁸ They noted an impressive ORR but high rates of toxicity and treatment discontinuation, suggesting that ibrutinib might not be the ideal BTKi for this patient population. The first truly chemotherapy-free regimen utilized not a BTKi but the immunomodulatory agent lenalidomide, plus R. The R2study⁹ by the Cornell group (NCT01472562) was the first to demonstrate a high and durable response rate without CIT with long-term follow up.10 Given the study design, the results offer some hope that CIT could be avoided in all patients irrespective of age or fitness. How to manage the 20% to 30% of high-risk patients, including those with aberrations of TP53, NOTCH, complex cytogenetics, and other identified high-risk features,¹¹ is a mystery, with poor OS noted with the regimens previously discussed.

Data from several ongoing studies are encouraging but remain too immature to fully comment on. Some promising treatments for these patients have yet to be explored in the frontline setting. Chimeric antigen receptor (CAR) T-cell therapy has mature and impressive efficacy in these high-risk groups but follow-up data have indicated continual relapses, suggesting this treatment might not be the “holy grail” for these patients.^12,13 However, this is confounded by the nature and complexity of relapsed disease as well as the impact of bendamustine and other therapies on the function of T cells utilized in CAR T-cell therapy. Based on a similar mechanism of action, CD20/CD3 bispecific antibodies hold significant promise in MCL, but thus far, large, mature data sets are lacking. Although CAR T-cell therapy and use of bispecific antibodies are intriguing options for frontline MCL management, especially in patients with high-risk disease, both treatments are associated with several barriers. For CAR T-cell therapy, accessibility remains a crutch that we cannot seem to overcome outside select regions of the country. The adverse event profile with cytokine release syndrome (CRS)/immune effector cell–associated neurotoxicity syndrome is still not something all hematologists/oncologists can manage and it is largely hampered by patient hesitation to travel to centers that offer CAR T-cell therapy. Bispecific antibodies hold the promise of greater accessibility with less concern about insurance approval, yet still have immature data and an adverse event profile that includes CRS, which hampers their integration into the community. All in all, several attempts have been made to move targeted agents into frontline MCL treatment, with some success but not the monumental paradigm shift that has occurred in other diseases. Nevertheless, the future for these patients holds some promise as several studies are still pending readout and several newer treatments have yet to make their entrance onto the frontline stage.

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