Novel agents for mantle cell lymphoma: molecular rational and clinical data

ABSTRACT

Introduction

Mantle cell lymphoma (MCL) is an aggressive B cell non-Hodgkin lymphoma (NHL) that is characterized by the translocation t(11;14)(q13;q32) and a poor response to rituximab-anthracycline-based chemotherapy. Intensive regimens offer durable response, but a subgroup of MCL patients will not be eligible for those regimens and hence are candidates for less toxic, novel therapies based on a more tailored personalized approach.

Areas covered

This article examines the molecular landscape of MCL, drug resistance mechanisms, and the data on emerging targeted therapies.

Expert opinion

DNA damage pathway, ATM mutation, TP53, and epigenetic abnormalities are key drivers of MCL. sBCL2, PARP, ATR, CDK inhibitors or epigenetic modifiers are among the most promising drugs under investigation in clinical trials.

The genomic landscape of MCL suggests two types of disease based on the presence of ATM or TP53 alterations which should be the framework of future molecular driven strategies. Among novel drugs, those interacting with the DNA damage response pathway offer the most effective rational for their use in MCL.

KEYWORDS:

• Mantle cell lymphoma
• MCL clinical trials
• BTK inhibitors
• BCL2 inhibitors
• PARP inhibitors
• ATR inhibitors
• epigenetic modifiers
• TP53 alterations
• ATM mutations

Article Highlights

• The prognosis of patients with MCL has been greatly improved in recent years, but the probability of a cure remains low. Many new drugs including BTK inhibitors, Imids, proteasome inhibitors and mTORC1inhibitors are active only in a subset of patients.

• Genomic studies have highlighted a molecular instability in MCL at diagnosis and during the course of the disease. This instability is not observed in other lymphomas and could be related to DNA damage repair pathway abnormalities frequently present in MCL.

• Potentially targetable DNA damage repair pathway abnormalities, mainly driven by ATM mutations, are found in 50% of the cases.

• TP53 mutations, reported in 20% of MCL at diagnosis, tend to be mutually exclusive from the ATM mutations and explain poor chemo-sensitivity of MCL. Targeting of these abnormalities is a real challenge.

• Epigenetic regulation represents another key pathway affected in MCL with resistance-associated molecular abnormalities.

• PARP or ATR inhibitors have real potential based on strong preclinical data; the first results of early phase clinical trials are eagerly awaited. New early-phase clinical trial designs that integrate molecular and biomarker analysis offer potential future therapeutic opportunities.

This box summarizes the key points contained in the article.

Declaration of interest

V Ribrag has been Principal/sub-Investigator of clinical trials for Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Astra Zeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol–Myers Squibb, Bristol–Myers Squibb International Corporation, Ca, Celgene Corporation, Cephalon, Chugai Pharmaceutical Co., Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm S.A., Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Gilead Sciences, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Philogen S.P.A., Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharmaceuticals France, Xencor, Y’s Therapeutics,

Research grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, and Sanofi. R Ribrag has also received research support from Argen and Epizyme and Consultancy fees from Servier and sits on the scientific advisory boards for

Epizyme, Servier, Nanostring, Gilead, Pharmamar, BMS, MSD, Incyte, Roche, and Infinity.

He has also received research grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, and Sanofi and non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly,

Medimmune, Merck, NH TherAGuiX, Pfizer, and Roche. The authors have no other 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

This paper was not funded.