Diffuse large B cell lymphoma (DLBCL) is among the most common subtypes of lymphoma globally, accounting for approximately a third of all nonHodgkin lymphoma. As such, it affects millions of individuals annually and represents a significant burden to healthcare systems across the world. 

The CHOP regimen (consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone) has been used to treat patients with DLBCL for over 40 years. It remains a staple treatment for patients newly diagnosed with DLBCL. Recently, rituximab has been added into the mix, resulting in the new acronym R-CHOP. 

Read more about DLBCL etiology 

Studies indicate that R-CHOP has substantial efficacy as a chemotherapy treatment, curing up to 2 in 3 patients with DLBCL. The remaining third of patients who fare poorly on this treatment regimen tend to experience refractory/relapsed disease due to resistance to the drug cocktail. 

These data back the fact that cancer remains a leading cause of death globally. Researchers are cautiously pursuing 2 approaches to find more effective means to counter cancer in the context of DLBCL: developing novel anticancer therapies, as well as optimizing the use of existing drugs. 

There is an interesting line of thought pursued by Kim and colleagues in JCI Insight, proposing that the delivery time of a particular chemotherapy regimen can influence outcomes. This is echoed in a study of patients with ovarian cancer who experienced fewer dose delays and reductions if treatment—doxorubicin and cisplatin—were administered in the morning and the evening respectively. 

“Indeed, during the past 30 years, several experimental and clinical studies have demonstrated positive associations between the circadian clock and drug responses in patients with cancer,” they wrote. 

This is a fascinating proposal because it may hold the key to improving clinical outcomes with minimal effort (changing when chemotherapy is administered). To be fair, the medical literature surrounding the effects of chronotherapy is limited; the trial that presents the best case for chronotherapy is 1 involving colorectal cancer, in which the evidence suggests that the chronomodulated delivery of fluorouracil, oxaliplatin, and leucovorin improves drug delivery and subsequent outcomes. 

“On the other hand, the effect of chronotherapy on hematologic malignancy treatment outcomes requires further exploration,” Kim and colleagues acknowledged. 

They hence sought to conduct a study to see if chronomodulated immunochemotherapy has any effects in patients with DLBCL. The reason that Kim et al chose this cancer for investigation is that R-CHOP remains the “sole treatment option for most DLBCL cases,” they wrote. In DLBCL, R-CHOP remains 1 of the most effective (and indeed the only effective) therapeutic option; attempts to diversify treatment have had little to show for.  

In addition, at the clinical center of Kim et al, chemotherapy is administered either at 8.30 am or 2.30 pm — these binary timings set the perfect stage for investigating the relevance of chronotherapy in DLBCL care. 

The research team recruited 2 cohorts: 210 patients in the survival cohort, and 129 in the adverse events cohort. These cohorts were determined based on their reaction to R-CHOP treatment. Approximately half of the participants had stage 3 or 4 of the disease. 

Kim et al reported that patients in the survival consort had an overall survival of 86 months. Most achieved complete remission upon completion of treatment. In female patients, those receiving treatment in the morning had more frequent disease progression compared to those receiving treatment in the afternoon. Statistical analysis revealed that female patients receiving treatment in the morning had a shorter progression-free survival compared to female patients receiving the treatment in the afternoon. No differences were observed between male patients. 

A multivariable analysis revealed that 3 factors contributed to a poorer prognosis: chemotherapy delivery in the morning, chemotherapy delivery at stage 3/4 of the disease, and chemotherapy delivery at older age.

As for the adverse event cohort, the researchers found that female patients in the morning group experienced more dose delays compared to those in the afternoon group; hence, a greater proportion of patients in the morning group received less than 80% of planned dose density. No statistical abnormalities were found among male patients. Researchers also reported a notable reduction in cyclophosphamide among female patients; this was mostly due to dose delays or absolute dose reduction due to rituximab-related pneumonitis. 

“The importance of our study lies in suggesting that (1) the timing of chemoimmunotherapy delivery can affect the treatment outcomes in relation to maximal tolerated dose; (2) a chronotherapeutic approach influences women and men differently; and (3) these differences are reflected by underlying diurnal variations in serum biochemical and hematological measurements,” the study authors concluded. 

Newer Therapies in the Pipeline 

The approach to adjust the timing of drug administration to improve outcomes is indeed laudable; in a world of tight budgets and increasing constraints on what 1 can or cannot do in clinical trials, it is refreshing to know that something so simple can affect clinical outcomes in a meaningful way. 

Regardless of the effect of chronotherapy on outcomes, it remains true that a third of patients fail at R-CHOP treatment. As such, scientists are wasting no time in exploring treatment alternatives for patients with DLBCL. One promising lead is the use of chimeric antigen receptor (CAR)-based cell therapies. CAR T cells, used in combination with novel molecular inhibitors or 4th-generation CAR T cells, has been shown to improve both the efficacy and safety profile of treatments used in DLBCL. 

Read more about DLBCL treatment 

Multiple streams of research occurring simultaneously in DLBCL is particularly important, because “it is impossible to cure DLBCL with monotherapy because no driver gene aberrations have been identified for DLBCL,” Wang and colleagues wrote in the Journal of Hematology & Oncology. 

However, there is every evidence that precision medicine may soon become a reality in DLBCL care. With diligence, flexibility, and perseverance, we are likely to see the landscape of DLBCL evolve signficantly again within the next decade. 


Wang L, Li LR, Young KH. New agents and regimens for diffuse large B cell lymphomaJ Hematol Oncol. Published online December 14, 2020. doi:10.1186/s13045-020-01011-z

Kim DW, Byun JM, Lee JO, et al. Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B cell lymphomaJCI Insight. Published online January 24, 2023. doi:10.1172/jci.insight.164767