Risks of advanced age, such as reduced renal function and reduced bone marrow reserve, render fludarabine-based therapy difficult to tolerate. Thus, for elderly patients, reduced-intensity regimens such as bendamustine plus rituximab continue to be used. It remains to be seen how clinical practice will change, however, given the increasing prominence of the novel agents. One could reason that bendamustine plus rituximab would be an appropriate starting point for a relatively fit 65-year-old patient, as the regimen could buy you approximately 4 years, followed by ibrutinib and, later, venetoclax. If you are considering bendamustine plus rituximab, it is incumbent upon you to test for 17p deletion (del[17p]) and TP53  mutation so that you do not inappropriately treat with chemoimmunotherapy.

If you have decided to start with ibrutinib in an older patient, let us say for tolerability reasons, one might argue that repeated genetic testing is not needed like it would be if you had opted for bendamustine plus rituximab, as ibrutinib is active in patients with del(17p) and TP53  mutations. Chemotherapy-free combination therapy with ibrutinib plus obinutuzumab is now a frontline treatment option as well. Data were presented at the 60th American Society of Hematology Annual Meeting & Exposition in 2018 and recently published in The Lancet Oncology  from the multicenter, randomized, open-label, phase 3 iLLUMINATE trial, which enrolled treatment-naïve patients aged 65 years and older and patients under age 65 years with coexisting medical conditions. Interestingly, the complete response rate by the investigator-initiated assessment was 41% and the rate of undetectable minimal residual disease in bone marrow was 20% in the ibrutinib plus obinutuzumab group—and that is not something that you see with ibrutinib alone. The possibility of synergy between ibrutinib and obinutuzumab is an interesting one, although we do not know definitively whether this actually occurs.

Generally, age-related comorbidities have less influence on the choice of novel agents when compared with chemoimmunotherapy, but there are age-related conditions that should be taken into consideration. I always inform patients of the potential side effects of treatment, but I also emphasize that the majority of events are mild and do not lead to treatment discontinuation. I note that treatment-emergent atrial fibrillation is a possibility with ibrutinib, but I also explain that most patients will not experience it. I also address apprehension about the need to be on life-long therapy by stressing that nothing is permanent. Patients on ibrutinib, for instance, will likely need to be on treatment for at least 2 years, and, while I do not encourage patients to discontinue treatment prematurely, I do inform them that it may be reasonable to stop treatment at some point in the future if they have minimal disease.