Novel Agents for Treating Older Patients With CLL

Jennifer Woyach, MD, Associate Professor of Medicine, Ohio State University, Columbus, discusses treatment options for older patients with CLL and why treating older patients differs from treating younger patients.

Transcript

My name is Jennifer Woyach. I'm an Associate Professor of Medicine at the Ohio State University. I'm going to be talking about treatment of CLL in older patients and whether that should be different than younger patients.

We all know that CLL is a disease primarily of older patients, with a median age at diagnosis between 70 and 72 years. About 3/4 of patients are diagnosed after the age of 65.

With increasing age in patients with CLL comes a number of opportunities and challenges that we really need to think about. Those are primarily due to decreases in organ function, specifically in kidney function, which may affect drug clearance and may affect toxicities. As well, changes in performance status that leads to interactions with specific toxicities from therapy.

We've known for a long time that treatment of older patients isn't the same as younger patients. That dates all the way back to the CLL5 study, which compared fludarabine to chlorambucil, specifically in older patients with CLL, and found that even though when you look at the population in general fludarabine was better than chlorambucil, in people who are older those 2 therapies were actually identical, and chlorambucil trended towards being better.

That was because a lot of the toxicities of fludarabine, while tolerable in the younger patient population, really impacted the care of patients who were older.

Now the field has really changed, and we have a lot of trials that are specifically targeting older patients. We now have a lot of data to tell us how we should be best treating our older patients. There are a lot of choices, and a lot of them are the same as therapies that we choose for our younger patients.

In the recent past, when we have been comparing targeted therapies to chemoimmunotherapy, there have been a few studies that have looked at either chronologically older patients or physiologically older patients, treating them with ibrutinib or ibrutinib plus an antibody compared with standard therapies.

The first of these was the RESONATE-2 study, which took patients aged 65 and older and treated them with either ibrutinib or chlorambucil, and found, of course, that ibrutinib was superior to chlorambucil in terms of efficacy. As well, the safety of those 2 was pretty similar.

The AL401202 study looked at bendamustine plus rituximab, which is a standard, more aggressive therapy for older patients. Compared that with ibrutinib given by itself, and compared, as well, with ibrutinib given in combination with rituximab.

This study included patients aged 65 and older. We found that progression-free survival for ibrutinib or ibrutinib plus rituximab was better than bendamustine plus rituximab. There was no advantage to adding rituximab to ibrutinib in terms of progression-free survival.

When we looked at toxicity of those regimens, hematologic toxicities were more common in patients treated with the chemotherapy, whereas non-hematologic toxicities occurred more in patients who were treated with ibrutinib.

Some of the specific toxicities that came out and seemed to be more enhanced in the older patients than when we look at trials in younger patients are things like atrial fibrillation, which happens about 10% of the time when you look at comers with CLL treated with ibrutinib, but is really more like 10-15% when you're looking at older patients.

Hypertension is pretty common with ibrutinib and seems to be more common in older patients than in younger patients. Other toxicities that are associated with ibrutinib, things like joint pains, rash, things like that don't seem to be different in the older versus younger patient population.

The other study looking at ibrutinib compared to chemoimmunotherapy in older patients was the ILLUMINATE trial, which looked at ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab, and again showed that ibrutinib combination was better than chemoimmunotherapy.

This was, again, targeting older patient population and saw a lot of similar toxicities to what I mentioned for the ALLIANCE trial. These studies show us that ibrutinib should be a standard therapy for older patients, but there are some toxicities that you need to watch out for when treating those older patients, specifically the cardiac toxicities.

Another study that came out within the past year was the CLL14 trial, which looked at venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab. Showed that venetoclax plus obinutuzumab was more effective than a chlorambucil plus obinutuzumab.

Toxicities were fairly similar between the 2 arms. Hematologic toxicities were no different between the obinutuzumab arm and the chlorambucil arm. The couple of toxicities that seemed more common with venetoclax, tumor lysis syndrome, and diarrhea was a little more common in the venetoclax treated patients.

When thinking about a therapy for older patients there are some factors that might make you choose either venetoclax or ibrutinib, or potentially acalabrutinib when that becomes FDA approved.

Patients who have underlying atrial fibrillation, patients that have uncontrolled hypertension, they may be better on a non-ibrutinib therapy. Patients who are on warfarin or otherwise have bleeding risks shouldn't be treated with a BTK inhibitor and may be better treated with venetoclax.

Those that don't mind an indefinite therapy, are at higher risk for tumor lysis syndrome, and don't want to worry about the monitoring that comes with a venetoclax, they might be better suited with a BTK inhibitor-based regimen.

All of these trials that have come out within the past couple years will have mature data presented over the next few years that hopefully will help us decide for each individual older patient what's going to be the best therapy.