Transcript:Krishna V. Komanduri, MD: I actually want to turn to John. Now, obviously, aside from traditional factors like age and bulk, we have of course the things like IgVH mutation status and 17p deletion, 11q deletion. Can you talk about how you integrate those factors into treatment decisions?

John Byrd, MD: I really echo what Michael just said about not forgetting everything we’ve learned for groups of patients. If we were talking about large cell lymphoma and we were saying, “Well, we’re going to start with an oral drug that’s easier, even though CHOP is harder and would cure the disease,” we wouldn’t get any physicians to sign up or any patients to sign up because you can cure the disease. And, when the initial data from the MD Anderson on FCR (fludarabine/cyclophosphamide/rituximab) with this long-term follow-up was presented, it was a changing point for me in my practice. Then, we had 2 other groups which were followed-up that replicated the same result as in this IgVH-mutated group. The MD Anderson group has the longest follow-up, but at 13 years, as Michael said, two-thirds of the IgVH-mutated patients are in remission. There was a correlation in other work with that for minimal residual disease (MRD) negativity at the end of therapy, and the Germans have reproduced this in their CLL8 study, in their bendamustine/rituximab versus FCR study.

So, for me, the hardest counseling session is the patient who’s between or who’s under the age of 65 to 70 and who has IgVH-mutated disease. I do that in all my patients, at least at the time of therapy, and I often do it at the beginning because it gives patients help with deciding how the CLL is going to affect them and it will put them at ease. But, if they’re IgVH-mutated, then you really have to have the hard sit-down talk — the pros of FCR and really, I think, you have to talk about what are the consequences as well. And the consequences, although they’re not common, they’re real, since 3% to 5% of patients will get a treatment-related myeloid neoplasia. And, in our experience, virtually all of those patients die of that. It is a harder therapy over 6 months than doing ibrutinib.

But, I agree with Michael. You’re done then, and it’s a hard question. I’m 51 and I oscillate back and forth. If patients ask, “What would you do?”, 1 week I will say FCR, the next week I’ll say targeted therapy. The most common group that we see in our practice are the patients who are not candidates for FCR based upon the disease. There, we’ve really had 2 changes in therapy. We have obinutuzumab and chlorambucil, which is an active combination for this patient group and prolongs survival over chlorambucil, which hopefully will never be used as a control again in a randomized phase 3 study. That’s a good option for patients.

We have the RESONATE-2 study, which looked at ibrutinib in this patient population, and it is encouraging that we’re seeing that the durability of these patients, now out beyond 3 years, is holding to what Dr. O’Brien will be presenting at this meeting. To Michael’s point, most of the people that have gone off of ibrutinib in the RESONATE-2 study have gone off for side effects. It hasn’t been for progression. We only have a small number of progressions in that patient population.

IgVH mutational status is the most important thing for me deciding therapy. And 17p is probably less helpful because I’m probably not going to go the direction of FCR in my IgVH un-mutated patients, and 17p usually lies there. If they have 17p and they’re mutated, they’re really in that very uncommon group. I believe the mutation status or where the disease is born, in terms of where it originates, are probably more important than the cytogenetics.

Krishna V. Komanduri, MD: It’s remarkable to me in RESONATE-2 that with longer follow-up, this relative risk reduction of 84% of progression of death is actually improved over time and that there is this durability.

Leo I. Gordon, MD: One question for Michael actually. You mentioned that the 17p patients, maybe they don’t see it, seem as bad as we initially thought, and I’m wondering if that could be true. We’re seeing a similar story in large cell lymphoma where we’re checking MYC and BCL-2 by FISH in everybody now, and previously it was 17p. I think we probably looked at the worst patients and said, “They may be 17p,” and we checked it in them, but we checked in everybody. We dilute out the numbers a little bit. Maybe that’s why they’re looking better perhaps.

Michael J. Keating, MB, BS: I think one of the things is that you never see someone with loss of both 17p regions. I think it’s incompatible with life of the cells somehow. And for a long time now, Dan Catovsky, and his group have said about 20% of the patients that are 17p deleted will not have a mutation in the other allele, so that you will have a functional p53 mechanism. And the curves of time to progression are very rapid fall-off, but there is almost like a hockey stick that goes along so that you end up having more patients with long-term disease-free than in the 11q's. And the 11q, by and large, is a very sensitive disease in young males, and a reasonable number of them get to be MRD-negative, but every single one of them relapses. Even in our measurement of what our goal is and if they’re MRD-negative, we’d say, “Oh, that’s terrific! We achieve that in the 11q's.” And then, in the subtext, you just say, “Well, don’t expect this to last very long, like 3 or 4 years, etc. It will be coming back.”

I think that one of the nice things is we have a number of studies in both lymphomas and in CLL at the present time that are really studying subsets very well, so we get an idea of the historical basis, the expectation that we can have with new therapies over time. I think particularly in follicular lymphoma and CLL, it is really important that we keep on reporting longer and longer follow-up things because different things begin to appear. And, as time has gone on with the FCR, there are more and more patients that end up dying of other cancers. What’s the contribution of the therapy to that and what’s the contribution of the disease to the predisposition? They’re very real questions, and I’m very happy that there are talented, young investigators coming along that can actually do that follow-up.

Transcript Edited for Clarity