Exploration of aging biomarkers such as senescence-associated secretory phenotype and epigenetic clocks can inform appropriate patient and treatment selection in the future.
It is commonly said that “all oncologists are geriatric oncologists,” and this is especially true for those who treat diffuse large B-cell lymphoma (DLBCL), which has a median age of diagnosis of 66 years, with over half of patients older than 65 years.1 Despite this, the outcomes of DLBCL in older adults are suboptimal, with a 5-year relative survival of 54.3% in patients who are older than 65 years compared with 78.4% in those younger than 55 years.1 How do we improve these outcomes and narrow the gap between our younger and older adults with DLBCL?
First, I suggest applying the Goldilocks principle by carefully choosing the dose of the available agents that is “just right”—ie, cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine (R-CHOP) vs a reduced regimen of R-CHOP, or rituximab (Rituxan) plus R-CHOP (mini R-CHOP). It is vital to remember that older adults are a unique, heterogeneous patient group and any therapeutic personalization should be based on biological age rather than chronological age. We all have had patients who are 80 years “young” who run marathons and those who are extremely frail even at 60 years of age. While most oncologists believe that an eyeball test is enough to discern a patient’s ability to tolerate chemotherapy, this was shown to be false in an Italian study almost 15 years ago, suggesting a more formal fitness assessment should be applied.2
While a comprehensive geriatric assessment (GA) is the gold standard for accurately assessing functional reserves in multiple geriatric domains, there are several barriers to its routine implementation, including lack of trained personnel, time, reimbursement, and referral services. Several abbreviated GA and screening tools have been evaluated in patients with DLBCL of which the simplified GA (sGA), which categorizes patients into fit, unfit, and frail groups, is the most widely used.3,4 Patients who are fit benefit from a full dose/curative approach, whereas for unfit patients, consideration should be made to reduce the intensity of chemotherapy. Frail patients with DLBCL are a group with major unmet need due to a lack of satisfactory treatment options. Unfit/frail patients should be referred to geriatric services where available.
Another easy intervention is to use prephase therapy with steroids with or without rituximab, which has shown to decrease early morbidity from R-CHOP and reverse the proinflammatory cytokine milieu associated with phenotypic impairments.5 Supportive measures including growth factors, allopurinol, and antinausea medication should be liberalized. There is no proven benefit of central nervous system (CNS) prophylaxis in older adults with DLBCL, and it should be avoided due to increased risk of infections.6
Mini R-CHOP is still the standard of care for a majority of older adults with DLBCL.7 Although it is tempting to use novel agents/targeted therapy to target disease biology in DLBCL, except for the addition of polatuzumab vedotin-piiq (Polivy) to R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) in high international prognostic index (IPI) score (2-5) DLBCL, according to findings from the POLARIX study (NCT03274492)8, none of the other strategies have shown benefit over R-CHOP and should be used with extreme caution.9-12
Similarly, maintenance strategies have not proven beneficial in improving outcomes.13-16 Ongoing clinical trials in older adults with DLBCL such as the SWOG 1918 study (NCT04799275), which is a phase 2/3 randomized study of mini R-CHOP with or without oral azacitidine (CC-486),17 and the POLAR-BEAR study (NCT04332822), which is a randomized, multicenter, phase 3 trial comparing mini R-CHOP with mini R-CHP plus polatuzumab have the potential to change the standard of care in the next few years. Another interesting avenue of research is incorporating immunotherapeutic agents/targeted therapies into chemotherapy-free regimens.18,19 Many of these trials are using interim PET scans and minimal residual disease assessment by circulating tumor DNA to guide therapeutic decisions in a response-adapted fashion.
In the relapsed/refractory (R/R) setting, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is now the standard of care for primary refractory disease or relapse that occurs less than 12 months after completing therapy.20 Both trial data and real-world data analyses have shown that the survival outcomes of older adults are similar to younger patients with CAR T-cell therapy with higher rates of cytokine release syndrome and neurotoxicity being offset by higher response rates; hence, all older adults eligible for CAR T-cell therapy must be offered this therapy.21,22 Data regarding impact of GA on outcomes of older adults receiving CAR T-cell therapy are emerging and will help guide patient selection.23
The recent approval of epcoritamab-bysp (Epkinly) and glofitamab-gxbm (Columvi) for R/R DLBCL is a welcome advance that will greatly benefit older adults not eligible for CAR T-cell therapy. Other drugs available for patients ineligible for CAR T-cell therapy or for those who experience disease relapse post–CAR T-cell therapy include polatuzumab-rituximab with or without bendamustine HCl (Bendeka),24 tafasitamab-cxix (Monjuvi), lenalidomide (Revlimid),25 and loncastuximab (Zynlonta),26 or chemotherapy-based approaches such as gemcitabine-oxaliplatin. Targeted drug classes such as Bruton tyrosine kinase inhibitors and lenalidomide are well tolerated and can lead to responses in patients with activated B-cell subtype of DLBCL. Exploration of aging biomarkers such as senescence-associated secretory phenotype and epigenetic clocks can inform appropriate patient and treatment selection in the future.
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program Database 2020. Cancer stat facts: NHL-diffuse large B-cell lymphoma. Accessed July 18, 2022. https://bit.ly/3Dh4ICL
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3. Akhtar OS, Huang LW, Tsang M, et al. Geriatric assessment in older adults with non-Hodgkin lymphoma: A Young International Society of Geriatric Oncology (YSIOG) review paper. J Geriatr Oncol. 2022;13(5):572-581. doi:10.1016/j.jgo.2022.02.005
4. Merli F, Luminari S, Tucci A, et al. Simplified geriatric assessment in older patients with diffuse large B-cell lymphoma: the prospective Elderly Project of the Fondazione Italiana Linfomi. J Clin Oncol. 2021;39(11):1214-1222. doi:10.1200/JCO.20.02465
5. Lin RJ, Owens CN, Drill E, et al. Prephase rituximab/prednisone therapy and aging-related, proinflammatory cytokine milieu in older, vulnerable patients with newly diagnosed diffuse large B-cell lymphoma. Haematologica. 2022;107(5):1144-1152. doi:10.3324/haematol.2021.278719
6. Eyre TA, Kirkwood AA, Wolf J, et al. Stand-alone intrathecal central nervous system (CNS) prophylaxis provide unclear benefit in reducing CNS relapse risk in elderly DLBCL patients treated with R-CHOP and is associated increased infection-related toxicity. Br J Haematol. 2019;187(2):185-194. doi:10.1111/bjh.16070
7. Wästerlid T, Murphy S, Villa D, El-Galaly TC. Diffuse large B-cell lymphoma among the elderly: a narrative review of current knowledge and future perspectives. Ann Lymphoma. 2022;6:6. doi:10.21037/aol-22-2
8. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304
9. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(5):649-662. doi:10.1016/S1470-2045(18)30935-5
10. Nowakowski GS, Chiappella A, Gascoyne RD, et al. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39(12):1317-1328. doi:10.1200/JCO.20.01366
11. Oberic L, Peyrade F, Puyade M, et al. Subcutaneous rituximab-miniCHOP compared with subcutaneous rituximab-miniCHOP plus lenalidomide in diffuse large B-cell lymphoma for patients age 80 years or older. J Clin Oncol. 2021;39(11):1203-1213. doi:10.1200/JCO.20.02666
12. Younes A, Sehn LH, Johnson P, et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(15):1285-1295. doi:10.1200/JCO.18.02403
13. Crump M, Leppä S, Fayad L, et al. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J Clin Oncol. 2016;34(21):2484-2492. doi:10.1200/JCO.2015.65.7171
14. Jaeger U, Trneny M, Melzer H, et al. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015;100(7):955-963. doi:10.3324/haematol.2015.125344
15. Thieblemont C, Howlett S, Casasnovas RO, et al. Lenalidomide maintenance for diffuse large B-cell lymphoma patients responding to R-CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study. Br J Haematol. 2020;189(1):84-96. doi:10.1111/bjh.16300
16. Witzig TE, Tobinai K, Rigacci L, et al. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. Ann Oncol. 2018;29(3):707-714. doi:10.1093/annonc/mdx764
17. Brem EA, Li H, Beaven AW, et al. SWOG 1918: A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed aggressive non-Hodgkin lymphomas - aiming to improve therapy, outcomes, and validate a prospective frailty tool. J Geriatr Oncol. 2022;13(2):258-264. doi:10.1016/j.jgo.2021.10.003
18. Westin J, Davis RE, Feng L, et al. Smart start: rituximab, lenalidomide, and ibrutinib in patients with newly diagnosed large B-cell lymphoma. J Clin Oncol. 2023;41(4):745-755. doi:10.1200/JCO.22.00597
19. Di M, Huntington SF, Olszewski AJ. challenges and opportunities in the management of diffuse large B-cell lymphoma in older patients. Oncologist. 2021;26(2):120-132. doi:10.1002/onco.13610
20. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665
21. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38(27):3119-3128. doi:10.1200/JCO.19.02104
22. Westin JR, Locke FL, Dickinson M, et al. Safety and efficacy of axicabtagene ciloleucel versus standard of care in patients 65 years of age or older with relapsed/refractory large B-cell lymphoma. Clin Cancer Res. 2023;29(10):1894-1905. doi:10.1158/1078-0432.CCR-22-3136
23. Lin RJ, Lobaugh SM, Pennisi M, et al. Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma. Haematologica. 2021;106(1):255-258. doi:10.3324/haematol.2019.243246
24. Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6(2):533-543. doi:10.1182/bloodadvances.2021005794
25. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4
26. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X