Factors That Influence Up-front Therapy and Sequencing in CLL

Steven Coutre, MD: The treatment of CLL is really undergoing a transformative period, largely because of these new oral agents. They’re really targeted therapies rather than traditional chemotherapy or chemoimmunotherapy. So, in the last several years, we’ve seen an acceleration of the development of these drugs and broader use of them.

In terms of up-front therapy, we’ll often break down patients into several groups; perhaps an older patient versus a younger patient. Sometimes, we also differentiate by fitness, meaning how well they might be able to tolerate a given therapy. But one thing to keep in mind is that for CLL, the average patient at diagnosis is over 70, so I guess you’d call that older. Some would disagree. For that typical patient, in the past, perhaps we might not consider as aggressive a treatment regimen. Certainly, if patients were less fit, we would choose agents based on those criteria. I think those boundaries are blurring a bit now because newer agents, drugs like ibrutinib, are very well tolerated. And so, you could consider giving them to older patients, the patients who are less fit. And, of course, there is nothing wrong with giving it to a younger patient who’s fit either.

Our standard approach, traditionally for treating CLL, whether in the frontline setting or in the relapsed setting, has been chemotherapy or chemoimmunotherapy. Combination therapy has become much more relevant. The immunotherapy aspect is usually an antibody, like rituximab, used in combination. And so, for example, we have several very standard regimens—bendamustine and rituximab, and the FCR regimen, fludarabine/Cytoxan/rituximab. And those were often our choices. For older patients, our choices were perhaps a single-agent therapy, like chlorambucil alone or maybe chlorambucil plus rituximab. And we’ve had another antibody approved for use in CLL, as well: obinutuzumab with an older drug, ofatumumab. So, there are different choices. And how you combine those and how you sequence them is quite variable.

And I think now, with newer oral agents that are extremely effective and also very well tolerated, we’re going to see that all change. In the relapsed setting, for patients who’ve already had standard chemoimmunotherapy, there’s generally no reason not to use a drug like ibrutinib. If you repeat a chemoimmunotherapy regimen or give one that’s a little different, you often have fewer patients respond and that response duration is shorter. So, you’re still going to be facing that issue down the road. Whereas with a drug like ibrutinib, right now, we’re getting very prolonged responses, and we may be able to continue to manage patients for many years with that approach. I think, especially as we get more data in direct comparison to some of our chemoimmunotherapy regimens, we’ll see increasing use of ibrutinib, for example.