Treatment landscape for mantle cell lymphoma: An update

The virtual Lymphoma Hub Satellite Symposium on the sequencing of therapies in high-risk relapsed/refractory (R/R) lymphoma and chronic lymphocytic leukemia (CLL) is fast approaching. It will take place on Friday, June 18, 2021, at the 16th International Conference on Malignant Lymphoma (ICML), where a panel of international experts—Steven Le Gouill, Francesc Bosch, Andrew Davies, Loretta Nastoupil, and Lymphoma Hub Chair Gilles Salles—will provide their insights on difficult-to-treat patient cases.­­

We look forward to a presentation by Steven Le Gouill, who will be discussing the case of a patient with TP53-mutated mantle cell lymphoma (MCL). This article brings together the latest Lymphoma Hub content on the background and advances in the treatment of MCL in preparation for the upcoming symposium!

Introduction

MCL is a B-cell non-Hodgkin lymphoma (B-NHL) that has been associated with increased age. Due to disease heterogeneity, treatment options vary from watchful waiting to high-dose therapy and autologous stem cell transplantation (auto-SCT). Until fairly recently, the prognosis for patients with MCL was poor, with median overall survival rates of 3–5 years. Since the introduction of chemoimmunotherapy with cytarabine in combination with a CD20-directed antibody, patient survival has improved in the MCL setting; however, patients with relapsed or refractory (R/R) disease have limited effective treatment options.¹

Treatment

Currently, the standard of care for most patients with MCL is a chemotherapy-based induction regimen followed by auto-SCT consolidation. Maintenance therapy with the anti-CD20 monoclonal antibody (mAb), rituximab, has further improved survival outcomes following auto-SCT in transplant-eligible patients and after induction in patients who are ineligible for intensive therapy. For patients with R/R MCL, second-line treatment involves Bruton's tyrosine kinase inhibitors (BTKi), such as ibrutinib or acalabrutinib.

The Lymphoma Hub recently provided a comprehensive summary of the clinical and molecular characteristics of MCL, including an overview of the available and prospective treatment approaches for the management of patients with aggressive MCL—read it here. This article focuses on the progress made since, consolidating all the relevant Lymphoma Hub content!

For a summary of the key features at diagnosis and conventional treatment options for MCL, click here. Watch the interviews below with Martin Dreyling and Michael Wang for their take on the recent advances and novel therapies for the treatment of MCL.

Auto-SCT

Auto-SCT has been a key player in the treatment paradigm for MCL but with emerging targeted treatments, could it end up redundant? Marco Ladetto discusses this in the podcast ‘Can we eliminate auto-SCT for patients with MCL?’ The Lymphoma Hub also spoke to Mehdi Hamadani who outlined the role of auto-SCT, as well as newer cell-based therapies in MCL.

CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of a number of cancers and has been particularly successful in the treatment of hematologic malignancies. Watch the videos below addressing the impact of CAR T-cell therapy in the MCL setting and discussing what patients with R/R MCL may benefit from CAR T-cell therapy.

The autologous anti-CD19-transduced CD3+ CAR T-cell therapy, KTE-X19, has demonstrated encouraging response rates in patients with R/R MCL in the phase II ZUMA-2 trial, which lead to its approval for the treatment of MCL by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2020; read about these decisions here:

• Brexucabtagene autoleucel receives FDA approval for the treatment of R/R MCL
• KTE-X19 receives conditional approval in Europe for the treatment of R/R MCL
• NICE recommends KTE-X19 for the treatment of R/R MCL

The Lymphoma Hub was pleased to speak to Michael Wang about how prior treatment with BTK inhibitors can affect the efficacy of KTE-X19 in patients with MCL—take a look at the video below.

Although KTE-X19 is the frontrunner CAR T-cell therapy in the MCL setting, there are a variety of alternative CAR-based therapies in the pipeline. The following resources introduce some of these prospective treatments:

• Liso-cel updates from TRANSCEND-CLL-004 and TRANCEND-NHL-001 trials
• Tandem CD20–CD19 CAR T-cell therapy for relapsed B-cell malignancies
• FDA grants fast track designation to novel combination CAR T-cell therapy, CLBR001 + SWI019, for B cell malignancies

Antibody-based therapy

The anti-CD20 mAb, rituximab, led the way for antibody-based therapies for MCL, but responses with an alternative anti-CD20 mAb, obinutuzumab, have been promising. Catch up on the latest from the phase II LyMa-101trial (NCT02896582) evaluating obinutuzumab plus DHAP (dexamethasone + high-dose cytarabine [Ara-C] + cisplatin) for transplant-eligible, untreated patients with MCL using these resources:

• LyMa-101 trial update: Obinutuzumab for the treatment of mantle cell lymphoma
• Obinutuzumab and the LyMa-101 trial – Expert discussion

Kinase inhibitors

An increased understanding of the pathophysiological drivers of MCL has resulted in the development of a number of kinase-specific inhibitors. BTK and phosphoinositide 3-kinases (PI3K) are among the most well understood disease mediators, and there is currently a selection of clinically approved inhibitors. There have been efforts to improve the specificity, side effect profile, and efficacy of such agents, as reflected by the following resources:

• FDA grants fast track and orphan drug designations to VLS-101 for the treatment of patients with MCL
• Orelabrutinib receives approval in China for the treatment of R/R CLL, SLL, and R/R MCL
• Expansion of the phase Ib study of zandelisib (ME-401) in combination with zanubrutinib to include disease-specific B-cell malignancy cohorts

Novel combinations

Therapy combinations have demonstrated superiority over monotherapy in a number of circumstances—the Lymphoma Hub is pleased to provide the latest data regarding novel combinations under evaluation for the treatment of MCL:

• Results from the OAsis phase I/II trial on ibrutinib, venetoclax plus obinutuzumab in patients with newly diagnosed mantle cell lymphoma
• Phase III SYMPATICO study on ibrutinib plus venetoclax in MCL

Sequencing of therapy

Finally, take a look at the Lymphoma Hub article exploring the impact of second-line regimens on outcomes in younger patients with MCL and watch our video with Mats Jerkeman on the feasibility of a response-adapted treatment approach to MCL.

COVID-19

The Lymphoma Hub is dedicated to providing the latest guidance concerning the treatment of patients with lymphoma throughout the coronavirus pandemic. Read the latest guidelines for lymphoma-specific treatment and management, as well as COVID-19 vaccination support here:

• Lymphoma and COVID-19: Management guidelines
• NCCN COVID-19 vaccination recommendations for patients with hematologic malignancies

Conclusion

The recent advances in the treatment of patients with MCL are undoubtably a step in the right direction. However, there is not a one-size-fits-all approach to MCL care, and there are a number of factors to take into account when making treatment decisions for patients with MCL. Efforts have also focused on identifying prognostic markers driving high-risk disease. Tune into the satellite symposium for more on the decisions that shape the sequencing of therapy in high-risk MCL.