Perspectives on chemotherapy for the management of double-hit lymphoma

ABSTRACT

Introduction

Double-hit (DHL) and triple-hit lymphomas (THL) have long been among the most clinically aggressive molecular subtypes of diffuse large B-cell lymphomas. In the 2016 revised WHO classification, they represent a new entity called high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. Unlike most B-cell lymphomas, they have poor response to standard R-CHOP therapy, tend to quickly develop resistance to cytotoxic chemotherapies, and are associated with higher central nervous system (CNS) infiltration. This can lead to increased risk of relapse and worse prognosis. DHL/THL represent a subset of lymphomas with unmet medical need.

Area covered

The authors present the available data for the current treatment regimens including intensive chemotherapy regimens, hematopoietic stem-cell transplantation (HSCT), and CNS prophylaxis. They also discuss treatment for relapsed disease including targeted therapies.

Expert opinion

There is currently no accepted standard of care for DHL/THL. For frontline therapy, we recommend enrollment in a well-designed clinical trial if possible, otherwise DA-EPOCH-R with CNS prophylaxis is a commonly used first-line therapy. The authors recommend close surveillance for patients achieving complete response, but for those who fail to achieve a complete response, then clinical trials, more aggressive salvage chemotherapy regimens, or cellular therapies are usually considered.

KEYWORDS:

• Double-hit lymphoma
• intensive chemotherapy
• hematopoietic stem-cell transplantation
• chimeric antigen receptor T-cell therapy
• targeted therapy

Article highlights

• Enrollment in clinical trials is the recommended first line of therapy given the lack of well accepted standard of care.

• DA-EPOCH-R is a commonly used intensive chemoimmunotherapy regimen for untreated DHL/THL.

• Central nervous system prophylaxis is highly recommended.

• Cellular therapies such as CD-19 chimeric antigen receptor T-cell therapy and allogeneic stem-cell transplantation could be considered for fit patients with refractory/relapsed disease.

• Targeting abnormal signaling pathways using selective inhibitors of MYC, BCL2, and/or BCL6 has shown promising preclinical activity, and some are being currently evaluated in clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

V Yazbeck is on the advisory board of Seattle Genetics and Celgene and has received grants from Gilead Sciences. 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 has not been funded.