https://orcid.org/0000-0002-2045-6238
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ABSTRACT
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Recent advances in immunotherapy such as chimeric antigen receptor T-cell therapy have significantly improved the outcomes in patients. Despite those advances, disease still recurs in many patients after multiple lines of therapy, and they eventually die. Many novel agents are under investigation. In this review, we focus on the synthetic drugs, usually small-molecule oral agents, that target a specific tumor-cell survival pathway.
Areas covered
We discuss immunomodulatory drugs, cereblon E3 ligase modulators, Bruton tyrosine kinase degraders, B-cell lymphoma-2 inhibitors, Enhancer of Zeste 2 inhibitors, IRAK4 inhibitors/IRAK4 protein degraders, bromodomain and extraterminal inhibitors, cyclin-dependent kinase 9 inhibitors, and menin inhibitors. We focus on their mechanisms of action, activities in DLBCL, and, in some cases, toxicity. We also discuss the challenges in developing synthetic drugs in DLBCL.
Expert opinion
Synthetic drugs hold great potential for treating DLBCL. Many phase 1/2 trials are ongoing. To maximize their clinical benefit, a better understanding of the biology of this heterogeneous group of diseases is needed, synergic combinations need to be identified, and the sequencing of therapies needs to be considered.
Article highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Improved understanding of the biology and pathogenesis in the past decades has provided a platform to develop synthetic drugs, usually small-molecule oral agents, to target a specific tumor survival pathway.
In this review, we discussed the data on immunomodulatory drugs, cereblon E3 ligase modulators, bruton tyrosine kinase (BTK) degraders, B-cell lymphoma-2 (BCL2) inhibitors, Enhancer of Zeste 2 (EZH2) inhibitors, IRAK4 inhibitors/IRAK4 protein degraders, bromodomain and extraterminal (BET) inhibitors, cyclin-dependent kinase 9 (CDK9) inhibitors, and menin inhibitors in the treatment of DLBCL.
Many preclinical and clinical trials are ongoing testing the synthetic drugs in DLBCL. Some drugs may achieve regulatory approval in the near future and benefit the patients.
List of abbreviations
| ABC | = | activated B-cell subtype |
| ADCs | = | antibody-drug conjugates |
| AML | = | acute myeloid leukemia |
| ASCT | = | autologous stem cell transplantation |
| BCR | = | B-cell antigen receptor |
| BET | = | bromodomain and extraterminal |
| BETi | = | BET inhibitor |
| BITEs | = | bispecific T-cell engagers |
| BR | = | Bendamustine – Rituximab |
| BTK | = | Bruton tyrosine kinase |
| BTKis | = | BTK inhibitors |
| CAR-T | = | CD19 chimeric antigen receptor T-cell therapies |
| CDK9is | = | CDK9 inhibitors |
| CDKs | = | Cyclin-dependent kinases |
| CELMoD | = | cereblon E3 ligase modulators |
| CHOP-R | = | cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab |
| CHP-R | = | cyclophosphamide, doxorubicin, prednisone, rituximab |
| CLL | = | chronic lymphocytic leukemia |
| COO | = | cell of origin |
| CR | = | complete response |
| CTCL | = | cutaneous T-cell lymphoma |
| CTMs | = | chimeric targeting molecules |
| DA-EPOCH-R | = | dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab |
| DH | = | double-hit |
| DLBCL | = | Diffuse large B-cell lymphoma |
| FL | = | follicular lymphoma |
| GCB | = | germinal-center B-cell-like |
| GEP | = | Gene-expression profiling GEP |
| HGBCL | = | High-Grade B-Cell Lymphoma |
| IHC | = | immunohistochemistry |
| IMiDs | = | Immunomodulatory agents |
| IRAK | = | interleukin-1 receptor-associated kinase |
| mAb | = | monoclonal antibody |
| MCL | = | mantle cell lymphoma |
| MDS | = | myelodysplastic syndrome |
| MM | = | multiple myeloma |
| NF-κB | = | nuclear factor κB |
| NHL | = | non Hodgkin lymphoma |
| NOS | = | not otherwise specified |
| ORR | = | Overall Response Rate |
| OS | = | overall survival |
| P-TEFb | = | positive transcription elongation factor b |
| PFS | = | progression-free survival |
| Pi3K | = | Phosphoinositide 3-kinase |
| R-DHAP | = | rituximab, dexamethasone, cytarabine, cisplatin |
| R-GDP | = | rituximab, gemcitabine, dexamethasone, cisplatin |
| R-GemOx | = | rituximab, gemcitabine, oxaliplatin |
| R-ICE | = | rituximab, ifosfamide, carboplatin, etoposide |
| R/R | = | relapsed/refractory |
| ViPOR | = | venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide |
Declaration of interest
N Dong receives research support provided by EUSA Pharma, a Recordati Group company and is a recipient of the Robert A. Winn Diversity in Clinical Trials Career Development Award, funded by Gilead Sciences. J C Chavez declares doing Consulting and Advisory work for Genmab, ADC Therapeutics, Kite/Gilead, AdiCet, Novartis, TG Therapeutics; being on the Speaker Bureau for Epizyme, BeiGene; and receiving a Research/Grant Support from Adaptive, ADC Therapeutics, AstraZeneca, Merck, Janssen. 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.