BR is often viewed as palliative, although in a prospective sCGA\guided trial focused on frail patients, it resulted in 51% 2\year OS, comparable to 59% observed after R\mini\CHOP [89]. for stem cell transplantation can benefit from newly VU0134992 approved options including polatuzumab vedotin\based combinations or tafasitamab plus lenalidomide, which may have higher efficacy and/or lower toxicity than historical chemotherapy regimens. Chimeric antigen receptor T\cell therapy has been successfully applied to older patients outside of clinical trials. In the first\line setting, emerging immunotherapy options (bispecific antibodies) and targeted therapies (anti\CD20 antibodies combined with lenalidomide and/or B\cell receptor inhibitors) may provide chemotherapy\free approaches for DLBCL. Enrolling older patients in clinical trials will be paramount to fully examine potential efficacy and toxicity of VU0134992 these strategies. In this review, we discuss recent advances in fitness stratification and therapy that have expanded curative options for older patients, as well as future opportunities to improve outcomes in this population. Implications for Practice Management of diffuse large B\cell lymphoma in older patients poses challenges due to aggressive disease biology and geriatric vulnerability. Although R\CHOP remains standard first\line treatment, geriatric assessment may help evaluate patients’ fitness for immunochemotherapy. Corticosteroid prephase, prophylactic growth factors, and early palliative care can improve tolerance of treatment. Novel salvage options (polatuzumab vedotin\based combinations, tafasitamab plus lenalidomide) or chimeric antigen receptor T\cell therapy should be considered in the relapsed or refractory setting for patients ineligible for stem cell transplantation. Emerging immunotherapies (bispecific antibodies) and targeted therapies provide potential first\line chemotherapy\free approaches, which need to be rigorously assessed in clinical trials that involve geriatric patients. values are from MantelCHaenszel score test for trend. (D): Proportion of patients with ABC, GCB, or unclassified DLBCL; cell of origin was determined by RNA sequencing (=?744). (E): proportion of patients with high, medium, or low risk genomic mutation profile according to the classifier by Reddy et al. (=?733). (F): Prevalence of mutations in the 10 most commonly mutated genes in DLBCL (=?950), stars indicate uncorrected .05, but no difference was statistically significant after correction for multiple testing [16].and and/or rearrangements (double\ or triple\hit lymphoma; DHL) and HGBL, NOS. As subtype\specific treatment options begin to emerge, advanced molecular testing will gain importance regardless of patient age to help identify the most efficacious therapeutic approaches. (a) ABC DLBCL is distinguished from GCB by GEP indicative of postgerminal center origin; it is driven by chronic active B\cell receptor (BCR) signaling and NF\kB deregulation [12, 13]. The prevalence of ABC DLBCL increases VU0134992 continuously with age, reaching 40%C50% after age 60 (Fig. ?(Fig.1D)1D) [14, 15, 16]. This skewed distribution may hypothetically be influenced by progressive immune senescence and aging\related shifts in the B\cell repertoire [17]. The ABC subtype is characteristic of extranodal lymphomas, including primary CNS, testicular, and cutaneous leg\type DLBCL, which are enriched VU0134992 in the elderly population and harbor molecular features associated with immune evasion [18]. In many studies, ABC DLBCL displays inferior survival after immunochemotherapy [13, 14]. The emerging genomic data reveal that it encompasses a poor\prognosis subtype VU0134992 characterized by mutations (termed MCD or cluster NF-ATC C5) with frequent extranodal invasion [19, 20, 21, 22]. ABC lymphomas may respond to novel agents targeting the BCR (ibrubinib, acalabrutinib, zanubrutinib) or immunomodulatory mechanisms (lenalidomide), opening the possibility for less toxic treatment approaches suitable for older patients [23, 24]. (b) EBV\positive DLBCL is an aggressive lymphoma that occurs more frequently in elderly individuals and does not display a pathognomonic morphology or immunophenotype. Its diagnosis requires demonstration of EBV\encoded small RNA by in situ hybridization [25, 26]. Median age at diagnosis is 71, and extranodal disease is present in 70% of patients [27]. EBV\positive DLBCL has inferior survival in all IPI categories, with median OS of 24 months.