Dr Cheson Discusses Anti-CD20 Monoclonal Antibodies in Patients With CLL

Bruce Cheson, MD, FACP, FAAAS, FASCO, Scientific Advisor, Lymphoma Research Foundation, discusses anti-CD20 monoclonal antibodies for the management of patients with chronic lymphocytic leukemia (CLL); these data were presented at the virtual Lymphoma, Leukemia & Myeloma (LL&M) Congress.

Transcript

Hello, I'm Bruce Cheson, formerly Head of Hematology at Georgetown University Hospital and the Lombardi Cancer Center, and currently Scientific Advisor to the Lymphoma Research Foundation.

The question is: Do anti-CD20s add to the efficacy of targeted agents in the management of patients with CLL?

This became important a number of years ago when, in the CLL8 trial conducted by the German CLL study group demonstrated that the addition of rituximab to fludarabine and cyclophosphamide, or FC, creating the FCR regimen, prolonged progression-free (PFS) and overall survival (OS) in that setting.

Now, we're in the age of targeted agents. Do those data translate into what we would find currently? The answer is unclear.

Now, there have been 2 randomized trials combining rituximab with the BTK inhibitor ibrutinib, neither of which showed any benefit.

Maybe a year ago, one could say there is no role for the CD20s. However, now, there are newer studies with other targeted agents and other anti-CD20s that have changed our impression. For example, there are now several newer CD20s that bind to a different epitope on CD20 than does rituximab.

The ones that do bind to a same epitope bind to a different region. These antibodies, in fact, have a number of important features. For example, some of them have enhanced antibody-dependent cellular cytotoxicity, increased NK cell activation, increased cell kill, and other features which make them perhaps better candidates for combinations than with rituximab.

Now, for example, in the ELEVATE TN, or treatment-naive study, investigators explored a combination of a CD20—in this case, obinutuzumab—with acalabrutinib, the second-generation BTK inhibitor. There were 3 arms. The first was acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, and that poor sick puppy, chlorambucil/obinutuzumab, that all the studies like to beat up on.

What this showed was interesting. If you look at the recent data with a 4-year follow-up, you can see that not only was the response rate better with the combination of acalabrutinib and obinutuzumab compared with acalabrutinib alone, but the PFS was longer. Over time, between the initial publication and the current presentation, there was a widening of the difference in PFS and in OS, suggesting that there is clinical benefit with acalabrutinib, adding a different CD20, in this case, obinutuzumab. That's in the frontline setting.

In the relapse setting was the GENUINE trial. This was a combination of ibrutinib with or without ublituximab, which is another novel anti-CD20. In this case, there was a prolongation of PFS and OS, which we didn't see adding rituximab to ibrutinib.

What this suggests is that there is indeed benefit from adding an anti-CD20 to a novel agent, but it depends on which novel agent you're talking about and which anti-CD20 you're using.

All of these outcomes were surprising to me, because of the 2 studies that failed to show any benefit adding an anti-CD20 to rituximab.

Now, when you have acalabrutinib, which in my practice is preferred over ibrutinib because of its tolerability, and you can demonstrate that adding a CD20 further increases its efficacy—that is important for patients.

Now, you have to weigh the risks and benefits in the time of COVID, because when you add an anti-CD20 to a drug that's merely a pill that the patient can take at home, and the CD20 requires regular visits over a period of months to a hospital or other treating facility, you're obviously increasing the risk to the patient of COVID and what have you.

The 9 percent difference in PFS that you might see, and a smaller difference in OS, requires a discussion between the doctor and the patient, saying, "This is what we can accomplish with acalabrutinib alone, and this is the magnitude of the difference if we add the CD20, and these are the risks of you coming back and forth."

Not only risks, but nuisance of coming back and forth to the clinic, it becomes an important discussion.

In the relapse setting, the GENUINE trial is really—I hate to say it—not so relevant, because I don't use ibrutinib in the second line. I use either acalabrutinib or one of the newer BTK inhibitors, zanubrutinib, and eventually, hopefully, pirtobrutinib in the front line.

Therefore, if I use them, there's no role for ibrutinib in the second line. If I use venetoclax/obinutuzumab in the frontline, and the patient recurs, I wouldn't use ibrutinib. I would use either acalabrutinib, zanubrutinib, or a different BTK inhibitor because of their improved safety profile over ibrutinib.

The results are interesting, but they don't relate to how we tend to practice anymore, because the use of ibrutinib has and will continue to diminish considerably. We don't know how this anti-CD20 will interact with some of the newer BTK inhibitors. I suspect we'll see a positive result, but that study has not yet been conducted.

As far as the clinical implications, the combination of ibrutinib and rituximab, whereas it is FDA-approved for the frontline therapy of CLL, I don't think should be widely used, because we have better CD20s in CLL, and we have preferred BTK inhibitors in CLL.

That's one of the major frontline treatment options, and I don't think it should be considered in the vast majority of patients.

Now, on the other hand, we have acalabrutinib, where the addition of obinutuzumab appears to improve PFS and OS. Therefore, may be an advantage and a preferred treatment option for patients who decide to go the BTK route for their therapy.

You have an at least comparable, with regard to efficacy and BTK inhibitor, and one that has a preferred safety profile.

Ibrutinib/rituximab, whereas it is approved by the FDA for the frontline therapy of CLL, is not a desirable option, because rituximab in 2 randomized trials doesn't add to ibrutinib. There are other BTK inhibitors which have similar efficacy to ibrutinib but a better safety profile.

Therefore, acalabrutinib, with or without obinutuzumab, would be a preferred option in my clinic. The other option I discussed with patients is venetoclax and obinutuzumab. We weigh the risks and the benefits of the 2 options.

There is a role for a CD20, but it depends on the CD20 and the drug you're combining it with. Now, in the relapse setting, I don't use ibrutinib, so the GENUINE results are not terribly relevant to my practice.

If a patient had venetoclax and obinutuzumab as frontline, and I wanted to use a BTK inhibitor in second or subsequent lines of therapy, I would more likely pick—depending on certain patient characteristics—acalabrutinib and the other 2 that are soon to be approved, zanubrutinib and pirtobrutinib.

I think the treatment of CLL is in a state of flux. We are learning more about how to combine different drugs to the benefit of our patients, but what's important is we are getting away from chemotherapy in this disease.

Our patients should be delighted that we are now in a totally chemo-free world for patients with CLL, with improved tolerability and improved outcome.