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Prephase therapy in older patients with DLBCL
ADL/IADL, mobility impairment measured by TUG, and CARG chemotherapy toxicity risk score. This finding sug- gests a novel, chronic inflammation-based, biologic underpinning of geriatric frailty in older lymphoma patients and several potential mechanism-based interven- tion strategies. Most importantly, this proinflammatory cytokine milieu was readily reversed with prephase ther- apy which may account for its effectiveness. Some of these cytokines were also associated with baseline lactate dehydrogenase, suggesting that tumor burden may also contribute to geriatric frailty and the SASP, consistent with a previous study showing that tumor debulking could improve lymphoma patients’ KPS.35 We could not, however, ascertain the contribution of disease-related fac- tors in our study. Nevertheless, there are several addition- al implications. First, if validated, these specific cytokines such as TNF-a, IL-6, and IL-10 could potentially serve as frailty biomarkers for older lymphoma patients. This notion is supported by previous findings where IL-6 and TNF-a were found to be associated with KPS, cytopenia, OS, and PFS.36-38 These markers are biologically and mech- anistically more specific than c-reactive protein or albu- min.9,39 It is also possible that elevated proinflammatory cytokines are caused by a combination of disease, comor- bidities, KPS, and/or other host factors, in addition to cel- lular senescence. These possibilities will need to be exam- ined in a large study. Second, the use of senolytics to deplete senescence cells is a potential strategy that could potentially reverse the SASP-associated frailty phenotype in the short term. Commercially available senolytics such as desatinib/quercetin have been studied in an early phase human trial.40,41 Finally, specific inhibitors of these frailty CK are available commercially. One of them, siltuximab, has been tested in a phase I trial for patients with hemato- logic malignancies including NHL. The drug was well tol- erated with no dose-limiting toxicity and sustained sup- pression of CRP was observed.42 Although we examined most key inflammatory cytokines, not all SASP-associated proteins were analyzed in this study and thus our results may not be generalizable to other components of SASP.
In conclusion, we show that rituximab/prednisone is a feasible and safe prephase regimen, which may have enhanced the delivery of chemoimmunotherapy for older, vulnerable patients with newly diagnosed DLBCL. Our findings of acceptable short-term toxicities and excellent long-term survival are hypothesis generating and mechanistically appealing since this strategy appears to target the aging-related SASP and the proinflammato- ry CK milieu. While requiring validation from a prospec- tive randomized study which should also examine indi- vidual components of the prephase regimen, we propose that prephase therapy with rituximab/prednisone is con- sidered for older, vulnerable NHL patients starting cura- tive-intent chemoimmunotherapy. We also strongly advocate for incorporating GA into the care of older lym-
phoma patients given its wealth of prognostic informa- tion and potential value in improving treatment toler- ance.
Disclosures
RJL sits on the advisory board for Kite, a Gilead Company; PAH has received research support and consultancy fees from Portola Pharmaceuticals, Inc.; AN has received research funding from Pharmacyclics and Raphael, honoraria from Prime Oncology, Medscape and EUSA, and sits on the advisory Board for Janssen; ADZ has received consultancy fees from Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis and Adaptive Biotechnology, has received research funding from MEI Pharmaceuticals, Roche, Gilead and Beigene, sits on the advisory Board for MorphoSys, Gilead, Genentech, Abbvie and AstraZeneca, serves as DMC chair for Beigene and is DMC member for BMS/Celgene/Juno; MJM has receieved consultancy fees or sits on the advisory boards of Genentech, Roche, GlaxoSmithKline, Bayer, Merck, Pharmacyclics, Janssen, Seattle Genetics, Takeda, Teva, Juno Therapeutics, Rocket Medical, June Therapeutics, Immunovaccine Technologies, and Daiichi Sankyo, has received research funding from Genentech Roche, GlaxoSmithKline, IGM Biosciences, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, and Immunovaccine Technology; GAS acts as a consultant and sits on the advisory board for Abbvie, Allogene, Autolus, Beigene, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Janssen, Milteniy, Morphosys, Norvartis, Roche, and Velosbio. All other authors declare no conflict of interests.
Contributions
PAH, CNO, RJL, and BK designed the research, interpreted the data, and wrote the paper; RJL, CNO, AI, MO, DLS, and ED collected and analyzed the data; PAH, CNO, ADZ, AN, DJS, SMH, AJM, PCC, AMH, AK, MJM, MLP, CLB, AY, JFG, and PRD contributed the data. All authors reviewed and approved the manuscript.
Acknowledgements
We acknowledge administrative assistance provided by Shreena Patel.
Funding
This research was supported in part by the NIH/NCI Cancer Center Support grant P30 CA008748 and the Lacher Lymphoma Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data sharing statement
Deidentified individual participant data that underlie the reported results will be made available 3 months after publication for a period of 5 years after the publication date upon request. The study protocol is included as a data supplement available with the online version of this article.
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