The cardiac side effects associated with therapy, particularly the atrial fibrillation associated with Bruton tyrosine kinase (BTK) inhibitors, are much more likely to occur in older patients than in younger patients; for example, an 80-year-old patient is much more likely to develop atrial fibrillation while on ibrutinib than a 65-year-old patient. In addition, BTK inhibitors are associated with less serious, but annoying, side effects such as arthralgia and mouth sores that can dissuade patients from staying on the drugs.

For treatment-naive CLL, venetoclax plus obinutuzumab can be a nice option in older patients for 2 reasons: the lack of cardiovascular toxicity and the fact that it is a finite therapy. Aside from the risks of neutropenia, for which the patient should be monitored, and tumor lysis syndrome, which may not be practical in some settings, venetoclax is associated with relatively few side effects.

Regarding other combinations that are being studied as finite therapies in older patients, venetoclax plus ibrutinib was evaluated in the GLOW study, and you generally see the side effects associated with each agent. With the combination, there might be a bit more diarrhea than what we would expect to see with ibrutinib and a bit more neutropenia than what we would expect to see with venetoclax. For the most part, however, you are getting the expected side effects from each agent. I do think that this combination will have a label based on the registration trial. And if, in the future, we are trying to choose between venetoclax plus obinutuzumab vs venetoclax plus ibrutinib, a disadvantage of the venetoclax-plus-ibrutinib combination is that you are still having the cardiovascular side effects from the BTK inhibitor, which are particularly relevant in the older population.

One thing that might change that equation is if we see significantly longer progression-free survival with venetoclax plus ibrutinib with longer-term follow-up. If that happens, the increased toxicity associated with venetoclax plus ibrutinib might be justified. The GLOW trial showed somewhat lower minimal residual disease rates with venetoclax plus ibrutinib compared with what was observed with venetoclax plus obinutuzumab in the CLL14 study. However, I will point out that in the CAPTIVATE trial, in a younger population, minimal residual disease rates with venetoclax plus ibrutinib were high. Might that difference relate to the difference in the ages of those populations? It is possible. We need longer follow-up with the combined small molecules to ascertain the response durability. Thus, except in the context of P53 aberration, my current preference for older patients is to use venetoclax plus obinutuzumab in the frontline setting.

The median age at diagnosis of CLL is approximately 70 years, but patients do not require treatment for an average of approximately 5 years after that. So, by the time they require treatment, many patients may be 75 years old. We know that most 75-year-old patients generally have some other medical issues, such as hypertension and atrial fibrillation, and that they are likely on chronic medications. The combinations of fludarabine, cyclophosphamide, and rituximab (FCR) and bendamustine plus rituximab (BR) are challenging to safely deliver in that older patient population, so having novel agents for this group has been a huge advance.

However, there are differences between the novel agents in terms of their toxicity profiles. Cardiovascular comorbidities are a major factor that I consider in older patients. I am concerned that patients with a history of myocardial infarction, those who have preexisting atrial fibrillation, and, particularly, those who are on an anticoagulant will have increased cardiovascular risks with BTK inhibitor therapy. For these patients, I am often recommending venetoclax plus obinutuzumab, for which we have reassuring data on older patients from the CLL14 study. You do have to be mindful of renal function in these older individuals, but it is safe to give this combination if you monitor patients closely for tumor lysis syndrome. Another benefit is that it is a 1-year therapy, which reduces the number of co-payments associated with Medicare (ie, as opposed to indefinite therapy).

Phosphatidylinositol 3-kinase inhibitors are not used as much because of the perception that they are more toxic, but they tend to be better tolerated in older patients than in younger patients and can be highly effective, so I would encourage people to still consider prescribing these drugs in the relapsed setting.

As noted by Dr O’Brien, the CAPTIVATE and GLOW studies evaluated the combination of ibrutinib and venetoclax. CAPTIVATE included younger, fitter patients, while GLOW included older patients. A striking finding was that, even though the combination was very active in both studies, the toxicity profile was more favorable in younger and fitter patients than in older patients. I would be a bit more hesitant to use that combination in older patients, particularly if they are frail and/or have cardiovascular comorbidities.