Expanding Options in Treating CLL

Steven Coutre, MD: We have a lot of choices when we’re deciding on treatment for patients, certainly for a patient who’s never had prior treatment and also for relapsed patients. Of course, in that setting, you’re often influenced by what they received initially, how well they tolerated it, and how long they benefitted from it. And, historically, we started out with single-agent therapy like fludarabine. I think we’ve evolved to standard chemoimmunotherapy approaches like FCR or bendamustine/rituximab. And now, we have the novel agents. We have newer anti-CD20 antibodies; obinutuzumab is an example. Ofatumumab has also been an approved therapy for some time for relapsed patients. So, we have other tools like that. And, now, we have BTK inhibitors, ibrutinib. We have second-generation BTK inhibitors in development. We have PI3 kinase inhibitors; idelalisib is the example of that. We even have an oral BCL-2 inhibitor now; venetoclax for a subgroup of relapsed patients.

I think at the end of the day, you’re always looking at your individual patient, taking factors into consideration like their age, their physiologic age—meaning their fitness based on comorbidities—and the nature of their disease. Is it mostly bulky disease, or is your challenge cytopenias like anemia? And then, also, your goals of therapy are another factor. Your goal of therapy for a previously untreated patient is going to be very different probably for somebody who’s 55-years-old, who’s looking at a perspective of the next 25 years, versus somebody who’s 75 or even 80.

It’s not a one-size-fits-all. And when you look at a widely used guideline, say the NCCN Guidelines, they’re not really guidelines. They’re a list of drugs and regimens that have shown benefit, but you’re still making that individual choice for that individual patient. I think we’re fortunate though that we have a whole toolbox, if you will, to choose from when we’re making those decisions.

We’re very fortunate to have very high quality clinical trials in CLL over the last 5 to 10 years. They’ve really accelerated because of novel agents that have been developed. One of the early randomized trials was the RESONATE trial. This is in relapsed/refractory patients, and it wasn’t just somebody who’s in first relapse who had benefit from their initial therapy that lasted for 5 or 6 years. Patients were eligible only if they had short duration of therapy, for example. So, it’s a little more challenging to treat. There’s a randomization between ofatumumab, an anti-CD20 antibody a drug that was approved for such patients, and single-agent ibrutinib. And, that trial demonstrated a statistically significant benefit in the primary endpoint, progression-free survival, but also an overall survival advantage. It was a better drug than ofatumumab in controlling the disease and controlling it for a longer period of time. It was also a very well tolerated drug in that setting. That largely was responsible for the initial approval of ibrutinib as a single agent for relapsed/refractory CLL, and I think it’s changing the way we treat patients.

There’s really no reason not to consider ibrutinib in a relapsed patient compared to our other therapies. I think as physicians have gained experience using it and have gained a comfort level, they’re turning more towards a drug like ibrutinib than just repeating a chemoimmunotherapy regimen. We had a second drug, idelalisib, approved, also in the relapsed/refractory setting. Idelalisib in combination with rituximab is also a very effective drug. However, the problem that has arisen is a safety one. So, there’s safety issues. With continued treatment, we see a significant number of colitis and now more recently in some trials, higher death rate due to infections. And so, I think we’re very much limited in the use of that drug, because we can’t keep patients on it for long periods of time.