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Page 18 of 25 Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193

patients with baseline organ dysfunction have inferior EFS as well as higher lymphoma-related mortality
[173]
and often are not able to enroll into classically designed clinical trials . Ultimately, the future may be a
mixture of these elements: a new platform that combines novel immunological agents in conjunction with
specific small molecule agents tailored to a certain subtype of DLBCL. Regardless of the route, given the
complexity of these new DLBCL subtypes, it is likely that the future of clinical trial investigation will require
combinational therapy in order to target multiple oncogenic pathways to optimize therapeutic benefit and
avoid the development of drug resistance.

CONCLUSIONS
The therapeutic platform for the treatment of DLBCL has been inundated with novel agents spanning from
small molecule inhibitors to bispecific antibodies to cellular therapy. Although numerous agents have been
introduced, the majority have not impacted frontline therapy favorably. The use of drugs that are agnostic
to COO or DLBCL subtype may circumvent the permissive use of these complex genetic analyses in order
to prevent delays in treatment initiation. Future investigations should focus upon synergistic drug
combinations that are tailored for specific DLBCL molecular subtypes, all the while optimizing genetics
assays in order to do so. The development of rapid, reliable, and affordable companion genetic assays that
can allow us to classify patients into these newer DLBCL subclassifications is a necessity and will allow us to
translate clinical trial findings into real-world use. At the same time, we must leverage the potential of
ctDNA and other translational tools for diagnostic, prognostic and therapeutic applications. Nevertheless,
in parallel with our greater understanding of the genetic heterogeneity of DLBCL comes a plethora of
opportunities to develop novel agents that target underlying driver pathological pathways, and ultimately,
the future of DLBCL treatment paradigms will continue to evolve, including chemotherapy-free approaches.

DECLARATIONS
Author’s contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Jennifer K. Lue, Grzegorz S. Nowakowski

Availability of data and materials
Not Applicable.

Financial support and sponsorship
None.

Conflicts of interest
JKL received research support and advisory board service from Kymera Therapeutics; advisory board
service from Astex Pharmaceuticals, consultancy for Daiichi Sankyo and Kura Oncology; and Speakers’
Bureau from AstraZeneca. GSN: Grant research Support: Celgene/BMS, MorphoSys, Roche, Nonostrings;
Consultant: Celgene/BMS, Denovo Biopharma, Kite Pharma, Kymera Therapeutics, MorphoSys, Roche;
Other: Ryvu Therapeutics (scientific advisory board)

Ethical approval and consent to participate
Not Applicable.

Consent for publication
Not Applicable.