Learning from the failures of drug discovery in B-cell non-Hodgkin lymphomas and perspectives for the future: chronic lymphocytic leukemia and diffuse large B-cell lymphoma as two ends of a spectrum in drug development

ABSTRACT

Introduction: Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL.

Areas covered: This article focuses on chronic lymphocytic leukemia (CLL) as a representative for indolent lymphomas and paradigmatic for the tremendous progress in treating B-NHL on the one hand and diffuse large B-cell lymphoma (DLBCL) as a representative for aggressive lymphomas and paradigmatic for many unsolved problems in lymphoma treatment or the other hand. We highlight salient points in current therapies targeting genetic, epigenetic, immunological and microenvironmental alterations. Possible reasons for drug failure in clinical trials like tumor heterogeneity, clonal evolution and drug resistance mechanisms are discussed. Based thereon, some perspectives for further drug discovery are given.

Expert opinion: In view of the pathogenetic complexity of lymphomas, therapies targeting exclusively a single alteration may fail because resistance mechanisms are present either initially or evolve during treatment. Therefore, future therapies in B-NHL may have to target the greatest possible number of genetic, immunological or epigenetic alterations still allowing tolerability and to monitor these alterations during therapy.

KEYWORDS:

• Chronic lymphocytic leukemia
• clonal evolution
• B-cell receptor targeting
• diffuse large B cell lymphoma
• drug development
• drug failure
• ibrutinib
• immunotherapy
• information technology
• molecular heterogeneity
• molecular therapy
• non-Hodgkin-lymphoma
• prognostic marker
• resistance
• rituximab
• safety
• venetoclax

Article highlights

• High throughput genome analyses have provided new insights into genetic alterations inducing lymphomagenesis and/or drug resistance, which can be considered as source for the development of new therapies in B cell Non-Hodgkin lymphomas (B-NHL).

• Targeted drugs inhibiting the B-cell receptor (BCR) and NF-kappaB signaling as well as the BCL2 inhibitors may currently be the most promising new therapeutics in B-NHL.

• In view of the pathogenetic complexity of most lymphomas, it has become clear that therapies targeting exclusively a single alteration may fail because one or more resistance mechanisms are present either initially or evolve during treatment.

• There seems to be considerable potential in the use of novel, molecular pathway-targeted drugs in combination with each other and agents targeting immunological, microenvironmental and epigenetic alterations in B-NHL.

• To dissect the right targets from a large amount of options, careful mechanistic analysis is needed in preclinical and clinical trials with a more biologically and immunologically orientated clinical drug development than previously.

This box summarizes key points contained in the article.

Declaration of interest

No potential conflict of interest was reported by the authors.