The Surveillance, Epidemiology and End Results (SEER) program predicted that the incidence of NHL would be estimated at around 4% of all cancer cases worldwide in 2024, with a median age at 66 years . DLBCL accounts for about 31% of NHL cases, with the majority of DLBCL patients being over 60 years [6, 22]. Therefore, measures to improve patient outcomes, individual life expectancy, and survival for this category of patients must be enhanced.
In the recent past, R-CHOP was the recommended standard regimen for the treatment DLBCL in older patients below the age of 80 years. Older patients aged 60-80 years with DLBCL could achieve a relatively high CR rate and prolonged median survival after 4-6 cycles of R-CHOP . R-miniCHOP offered an improved comprise between safety and efficiency in patients aged 80 years and older as a substantial number of older people could be cured . However, complications and adverse treatment reactions were reported to increase in patients aged 70 years and older . Several risk factors, including comorbidity, functional impairment, cognitive decline, poor performance score and social isolation, contributed to the treatment-related toxicity . Despite having R-CHOP or R-miniCHOP as treatment options in older patients, the presence of comorbidities and treatment-related toxicity, to some extent, contributes to limited available therapeutic options in real-world practice. Thus, promising regimens need to be exploited and in order to provide an optimal balance between efficiency and safety in older patients.
Several studies demonstrated that the BR regimen was a promising prospect in both indolent and aggressive lymphomas because of its modest activity and manageable toxicity profile. The BRIGHT study reported that the BR regimen had a better long-term disease control than R-CHOP regimen and therefore, should be recommended as the first-line treatment in indolent and mantel-cell lymphoma . Furthermore, a multicenter, retrospective study reported that the BR regimen was less toxic and more efficient compared to the R-CHOP regimen in patients with FL grade 3A . BR regimen demonstrated a low rate of nonhematologic adverse events in older patients with chronic lymphocytic leukemia . Moreover, BR regimen was well-tolerated and safety in indolent NHL patients with renal impairment .
In 2011, an exploratory clinical study suggested that BR may be an alternative treatment for aggressive lymphomas in older patients 80 years and older ineligible for R-CHOP therapy . To date, a few studies have demonstrated BR was a feasible option for the first-line treatment of DLBCL in elderly patients [16, 30-32]. Table 6 illustrates the different ranges of ORR, CRR and median PFS in BR groups; ORR 50-83.3%, CRR 20-54% and median progression-free survival ranged 7.7-33 months. On the contrary, results obtained by the GELA analysis, ORR in the R-miniCHOP group was 75% . BR showed nearly equivalent efficacy in this category of patients. Our study further verified the findings of the GELA analysis, the ORR was 83.3% and 75% in the BR group and R-miniCHOP group, respectively, with no statistical significance. Furthermore, in 32 patients, β2-microglobulin <3.0 mg/L was predictive of higher ORR in our univariate analyses of prognostic factors.
In the previous study, nausea and vomiting were frequently reported in older patients after BR treatment. This adverse reaction was equally commonly reported in our study (50%) . However, it was not of significance compared to R-miniCHOP group (P =0.581). Importantly, the BR group had a lower rate of leukopenia compared to the R-miniCHOP group. This result showed that BR is likely to reduce the risk of infection and febrile neutropenia. Additionally, BR had a relative low rate of cardiac events due to the absence of anthracyclines, showing that BR is safer and tolerable for unfit older patients. It's worth noting that BR had a higher incidence of transient fever which could be attributed to drug-induced fever as the inflammatory indicators such as C-reaction protein and procalcitonin maintained within normal range. Generally, the body temperature could be quickly reduced to normal after auxiliary antipyretic treatment. However, when this symptom arises at the initiation of treatment, it is difficult for physicians to determine the cause of fever which may preclude treatment.
The limitation of our study was that it was a small cohort size and short follow-up (eleven month) duration study. Bendamustine was brought to market in China on May 2019. So far, it was only used in part of first-ties cities. Furthermore, it is relatively expensive with the cost of bendamustine not being reimbursed by the national health insurance system in China. The number of elderly patients newly diagnosed with DLBCL and defined as unfit was small. Thus, it is a challenge to recruit enough unfit participants in such a short time. that was also the reason why overall survival and median progression-free survival were not analyzed in our study. For this reason, our study could not analyze overall survival and median progression-free survival. We believe that a large-scale and long-term follow-up prospective study will provide better insight into the future.
The emergence of new targeted drugs also provides more options for the treatment of DLBCL. A recent clinical trial showed that the anti-CD79b antibody polatuzumab vedotin combined with BR could reduce the risk of death in relapsed/refractory DLBCL . The novel histone deacetylases inhibitor chidamide could synergize with rituximab by upregulating CD20 expression in DLBCL and significantly inhibited the tumor growth in vitro and in vivo . The phosphoinositide 3-kinase (PI3K) inhibitor copanlisib showed high cytotoxicity in vivo and could improve survival in DLBCL model . Moreover, the Bcl-2 inhibitor venetoclax and Bruton's tyrosine kinase inhibitor ibrutinib could enhancing the sensitivity of PI3K inhibitor in actived B-cell like DLBCL [35, 36]. Thus, more clinical trials should be conducted to explore new therapeutic regimens for DLBCL.