Novel synthetic drugs for the treatment of non-Hodgkin lymphoma

ABSTRACT

Introduction: Over the past two decades, deeper understanding of B-cell signaling pathways and other mechanisms of lymphomagenesis have yielded promising targets for novel drugs in the treatment of non-Hodgkin lymphoma.

Areas covered: This article provides a comprehensive review of approved synthetic drugs targeting the BTK, PI3K, immunomodulation, proteasome, HDAC, EZH2, and nuclear export pathways in non-Hodgkin lymphoma. The review includes coverage of the pharmacology, efficacy, toxicity, and active areas of research for each drug. The authors also provide their expert perspectives on the field and their opinions for the future.

Expert opinion: Although novel synthetic drugs have generally not impacted clinical practice to the same extent as immune and cellular therapies, there remains an important role for targeted drugs in the treatment of non-Hodgkin lymphoma, particularly in the relapsed setting and for patients ineligible for more intensive therapies. Clinical outcomes and tolerability may improve further with the development of newer generations of synthetic drugs and emerging combination regimens with other targeted and immune therapies.

KEYWORDS:

• Non-Hodgkin lymphoma
• btk inhibitors
• pi3k inhibitors
• immunomodulatory drugs (imids)
• proteasome inhibitors
• HDAC inhibitors
• ezh2 inhibitors
• sine

Article highlights

• Novel synthetic drugs are typically administered until disease progression or intolerance, and clinicians should be aware of their unique toxicity profiles

• The immunomodulator lenalidomide is active in relapsed follicular lymphoma (FL) and mantle cell lymphoma (MCL) but did not improve outcomes for the initial treatment of FL or diffuse large B cell lymphoma (DLBCL)

• Ibrutinib has an established role in MCL and Waldenstrom’s macroglobulinemia (WM), and second-generation BTK inhibitors with less off-target toxicity are showing promise

• PI3K inhibitors are approved for the treatment of relapsed FL but use is limited by infectious and immune-related adverse events

• HDAC inhibitors have demonstrated activity in the poor prognosis setting of relapsed/refractory peripheral T cell lymphoma (PTCL) which has otherwise limited treatment options

• Tazemetostat and selinexor were recently approved for relapsed FL and DLBCL, respectively

This box summarizes key points contained in the article.

Declaration of interest

D Stewart has received honoraria for ad hoc advisory boards from Roche, Janssen Pharmaceuticals, AbbVie, Gilead Sciences, Celgene, Novartis, AstraZeneca, Amgen Sandoz, and Teva Pharmaceuticals. 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This manuscript was not funded.