Case 2: Sequencing Therapies in CLL



Anthony Mato, MD, MSCE:For me the other big variable that we have more data on now than we did a few months ago—but still not a lot—is the question of sequencing therapies. We’ve talked about high response rates and high depth of response, but nobody really has dared to use the wordcurewith the current targeted therapies and the current regimens we use. We’re thinking about a long game for patients, and I’m always trying to focus as well on what information I have from prospective studies to really support what comes next. That’s always a very important question when we’re trying to decide do we start with venetoclax and go to ibrutinib? Do we start with ibrutinib or another BTK [Bruton tyrosine kinase] inhibitor and then go to venetoclax? The data are limited at this point, so there is a lot of extrapolation in order to try to support that decision. Any comment on prospective studies that have been done to support sequencing?

Sameer A. Parikh, MBBS:I don’t believe we have a lot of prospective data to support sequencing 1 agent after another. All the data are predominantly from retrospective studies, which are very important because, as you mentioned, patients will ask, “OK, if my disease stops responding to venetoclax or if it recurs after venetoclax is reintroduced, is there any efficacy for the BTK inhibitor?” At this ASH [American Society of Hematology Annual Meeting & Exposition] we saw data from at least three different data sets, including a very large study that you presented. It seems that there is a very good proportion of patients who will respond to ibrutinib if venetoclax stops working. That data are reassuring to many of us as physicians who are counseling our patients and to patients themselves, because they know that it would be OK to go with a time-limited therapy of venetoclax, knowing that ibrutinib will be available should disease recur after a period of time.

Shuo Ma, MD, PhD:There was a prospective phase II study of venetoclax to be used for patients who progressed after prior…

Anthony Mato, MD, MSCE:You’re reading my mind. That’s what I was just about to ask you about.

Shuo Ma, MD, PhD:…B-cell receptor pathway inhibitors, such as ibrutinib or PI3 kinase inhibitors. That’s a single-arm study. In that study, patients who failed the prior BTK inhibitor or PI3 kinase inhibitor can still have a pretty high response rate to venetoclax single agent. I think in that direction, actually there are probably more patients who are treated in that fashion because ibrutinib was approved several years ahead of time. Now we have venetoclax up front available, so the real question is would patients respond well to a B-cell receptor pathway inhibitor, such as a BTK inhibitor or a PI3 kinase inhibitor, after venetoclax is used up front. Sameer mentioned that your retrospective analysis probably gives the most data on the efficacy. Do you want to touch on that?

Anthony Mato, MD, MSCE:We presented a large number of patients who discontinued venetoclax, and there was a small subset—about 44 patients who had never seen ibrutinib before but went on to receive it after venetoclax—and it seemed to be quite active. Jennifer Brown had a similar experience with I think 27 or 28 patients who went into that same sequence and she did show activity. You mentioned the phase II trial looking at venetoclax after ibrutinib or idelalisib. From what I remember, there’s a fair number of patients on that trial who were actually intolerant of 1 or both agents. I was thinking maybe that’s a good segue to talk about the case I brought, which is a patient who had some intolerance issues. Why don’t we switch gears to that case.

Transcript edited for clarity.

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