Pathophysiology and Treatment Landscape of CLL

Susan M. O’Brien, MD: Probably the easiest way we have to divide patients with CLL into subgroups is both the mutation status and looking at the FISH panel for chromosome abnormalities. But even the significance of those chromosome abnormalities is changing over time because, of course, prognostic factors are related to therapy. And so, some of our newer therapies are improving the outcomes even in the high-risk subsets which traditionally had been patients with 17p deletion or 11q deletion.

The more effective drugs we have—and we’ve had several new drugs approved just in the past few years for CLL—the further into the background we relegate stem cell transplant. So, a perfect example is probably the one group where we recommended stem cell transplant in first remission previously for patients with 17p deletion because it was very hard to get them into remission. They had poor responses to chemo, and if you got a remission the first time, you probably weren’t going to get one the second time. So, generally, we recommended stem cell transplant in first remission. And that was the only group high risk enough to do that.

Well, now we have approved treatments including ibrutinib, idelalisib, and, most recently, venetoclax for patients with 17p. So, since we have all these effective targeted therapies, we’d no longer recommend stem cell transplant in first remission—although it’s still considered a high-risk group, and it’s something that can be discussed in relapsed or refractory patients.

Before the advent of the new agents, of course, everything that we did in CLL was chemotherapy-based. And, of course, one of the limitations of chemotherapy is that it tends to be myelosuppressive, and when you have myelosuppression, you have infections. And this is an immunocompromised patient population to begin with. So then when you add in myelosuppression, your likelihood of infection is much higher. One of the big advantages of some of the novel agents is that they’re not myelosuppressive, and they are, in fact, quite good at reversing cytopenias. Now, this is not to say that we don’t see any infections; we do see them, particularly in relapsed/refractory patients because they get infections even if they’re not undergoing treatment. But it has made our treatment so much safer and more effective for patients, particularly in the relapsed setting with the novel agents.

I think what the recent drugs are doing in terms of changing the therapy for CLL is making us less likely to use chemotherapy. Previously, pretty much all patients would get chemotherapy up front, and there still is a role for chemotherapy up front in some patients. But now when the patients lose their response to chemotherapy because of the novel agents, and the fact that novel agents are so good even in patients who’ve had one prior therapy, I generally don’t feel there is pretty much any role for chemotherapy outside the frontline setting. We should really be using the targeted therapies.