Mantle cell lymphoma: insights into therapeutic targets at the preclinical level

ABSTRACT

Introduction

Mantle cell lymphoma (MCL) is a chronically relapsing B-cell non-Hodgkin lymphoma characterized by recurrent molecular-cytogenetic aberrations that lead to deregulation of DNA damage response, cell cycle progression, epigenetics, apoptosis, proliferation, and motility. In the last 10 years, clinical approval of several innovative drugs dramatically changed the landscape of treatment options in the relapsed/refractory (R/R) MCL, which translated into significantly improved survival parameters.

Areas covered

Here, up-to-date knowledge on the biology of MCL together with currently approved and clinically tested frontline and salvage therapies are reviewed. In addition, novel therapeutic targets in MCL based on the scientific reports published in Pubmed are discussed.

Expert opinion

Bruton tyrosine-kinase inhibitors, NFkappaB inhibitors, BCL2 inhibitors, and immunomodulary agents in combination with monoclonal antibodies and genotoxic drugs have the potential to induce long-term remissions in majority of newly diagnosed MCL patients. Several other classes of anti-tumor drugs including phosphoinositole-3-kinase, cyclin-dependent kinase or DNA damage response kinase inhibitors have demonstrated promising anti-lymphoma efficacy in R/R MCL. Most importantly, adoptive immunotherapy with genetically modified T-cells carrying chimeric antigen receptor represents a potentially curative treatment approach even in the patients with chemotherapy and ibrutinib-refractory disease.

KEYWORDS:

• Mantle cell lymphoma
• targeted therapy
• drug resistance
• preclinical
• therapeutic targets
• oncogenic signaling pathways

Article highlights

• with bendamustine, bortezomib, high-dose cytarabine, ibrutinib, venetoclax, and lenalidomide the treatment options and outcome of MCL patients have dramatically changed

• with relevant patient stratification based on disease biology outcome of MCL patients can significantly improve already with the currently approved drugs and their combinations

• adoptive immunotherapy with CAR19 T cells will play a dominant role in the treatment of ibrutinib failures by the end of next decade

• new classes of innovative agents including bispecific antibodies, antibody-drug conjugates, or PI3 kinase inhibitors will further broaden treatment options in the relapsed MCL

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work of the author is funded by Czech Health Research Council grant AZV 17-28980A, Grant Agency of the Czech Republic GA20-25308S, Charles University Center of Excellence UNCE/MED/016 and Ministry of Education, Youth and Sports grants PROGRES Q26/LF1 and PROGRES Q28/LF1.