DR BROWN: Right. So ibrutinib, of course, is an inhibitor of Bruton’s tyrosine kinase, which is an excellent target in CLL, because we know that if it’s mutated you lose B cells, and that serves as very good justification for the development of the drug. It’s a covalent inhibitor, and so it can be dosed once daily with complete target inhibition, sustained over time, which is very nice clinically.

The trial that led to its initial accelerated approval was a Phase IB/II study. It had multiple arms, but the initial approval was for relapsed/refractory CLL, 85 patients. Now, with both ibrutinib and idelalisib and all the inhibitors of the B-cell receptor pathway, people are probably very familiar now, but we see an unusual pattern of response when you start the drug that patients feel better immediately, their lymph nodes shrink, but the white count will go up. And this is believed to be a redistribution phenomenon from cells that are in lymph node and bone marrow into peripheral blood. But the white count can go up five-, six-, eightfold sometimes, very high, before stabilizing around month 1 to 2 and then coming down at some rate.

And so response rate had to be thought about in a somewhat different way with these drugs. And so we have partial responses, defined by traditional criteria, and then we have partial responses with lymphocytosis, where patients meet all criteria for a typical partial response except that the lymphocyte count is still elevated above the 50% reduction that would be required for a classic partial response. And so response rate in the initial report was on the order of 70%, but we now know that response rate is on the order of 90% for ibrutinib, even in relapsed/refractory CLL, including these partial responses with lymphocytosis patients who have a similar outcome to those with a full partial response.

And what’s most impressive is that in patients with a median of 4 prior regimens, the median progression-free survival in the overall cohort hasn’t been reached at a follow-up of 30 months. And, in fact, 89% of patients are still in remission at that point.

Now, the 17p-deleted patients had a median progression-free survival of 28 months. And the 11q patients, approximately 70% were still in remission at the 30-month follow-up. And so those data for that heavily pretreated population were fairly unprecedented but led to accelerated approval.

We had the randomized confirmatory trial of ibrutinib versus ofatumumab, which showed progression-free and overall survival benefits. Follow-up was still short, so it doesn’t inform us as much about expected durability of response.

DR LOVE: And right now, in what situations are you using ibrutinib in CLL?

DR BROWN: So in more or less any relapsed/refractory patient, potentially, except one who has a contraindication. The primary contraindication in my mind is patients who are on anticoagulation or have some other bleeding diathesis. We see very commonly that patients on ibrutinib have easy bruisability, delayed wound healing. And this is at least in part due to the fact that BTK is required for platelet aggregation to collagen. It may relate to ibrutinib’s effect on other kinases as well. It’s not completely understood, but that is one factor involved.

And then patients with 17p deletion, certainly ibrutinib is the most active agent that we have, and that includes in the up-front setting. And it did receive an FDA approval for up-front 17p CLL this past summer, as well as for relapsed 17p CLL.

DR LOVE: Just to pick up a little bit on a couple of those points, what do you do when you have patients who are on ibrutinib and need some kind of procedure, surgical procedure or dental procedure?

DR BROWN: So for any major procedure, which was defined in the trials as requiring stitches, you hold the drug 7 days before and restart 7 days after. For minor procedures not requiring stitches, 3 days before, 3 days after.

DR LOVE: And you mentioned the issue about anticoagulation. What do you do in those patients?

DR BROWN: So I tend to use idelalisib instead. There’s a certain amount of controversy and difference in practice amongst different people with respect to whether they will pair anticoagulation with ibrutinib. I have been very cautious about it. I have seen or heard of some concerning incidents. So I try to avoid using anticoagulation together with ibrutinib.

DR LOVE: Idelalisib or idelalisib-R?

DR BROWN: Usually just idelalisib.

DR LOVE: And we actually did a poll of 25 heme investigators for the ASH meeting and asked them about their up-front treatment for CLL, normal-risk situation but a patient who needed to be treated. And one brave soul said, “Ibrutinib.” Is that the wrong answer?

DR BROWN: So I don’t think we have enough data to really know. So the 17p setting, ibrutinib is clearly the most active drug we have for 17p patients up front. Other than that, to date we have 30 patients treated with single-agent ibrutinib up front who were part of that original Phase IB/II study. And there has, in fact, only been 1 progression on that trial, a 96% progression-free survival at approximately 3-year follow-up. That being said, most of the patients are in partial remission. We don’t know the ultimate durability. And so when we compare that, say, to the 65% chance that a mutated IgH, low-risk cytogenetic patient who gets FCR will be disease free and progression free 12 years later, to me that patient should still get FCR until we have comparable follow-up.

DR KANTARJIAN: Can I ask Jennifer, we know with idelalisib there are those issues with pneumonitis, diarrhea. With ibrutinib, is there any cardiac signal that one has to worry about? I heard there was some higher-than-expected incidence of atrial fibrillation. Is that something of concern?

DR BROWN: I definitely think it’s of concern. I think it’s becoming potentially of increasing concern as we have patients treated longer and longer. It first emerged as a signal from the randomized trial of ibrutinib versus ofatumumab, where there was about a 6% rate of atrial fibrillation in the ibrutinib arm compared to only one patient, less than 1% on the ofatumumab arm. And certainly in clinical experience, as patients are on ibrutinib for a number of years, I’m seeing a lot of atrial fibrillation coming out of the woodwork. We have also seen some suggestion of possible ventricular ectopy, which it’s hard to know how related that is to the drug. It’s purely anecdotal, but I’m a little worried about that, too. And so I think we need to be very cognizant of monitoring what emerges from the long-term safety data.

DR KANTARJIAN: So are there, then, the bleeding tendencies and atrial fibrillation, anything else coming out in the longer-term follow-up of ibrutinib? I don’t think there is, but —

DR BROWN: Not in terms of serious side effects. I find the arthralgias/myalgias actually very problematic for many patients clinically. That’s the main reason I’ve had patients discontinue ibrutinib, actually, outside a trial setting.

Chronic Lymphocytic Leukemia (CLL)

Chronic Myeloid Leukemia (CML)

Acute Myeloid Leukemia (AML) and Acute Promyelocytic Leukemia (APL)

Myelodysplastic Syndromes (MDS)

Acute Lymphocytic Leukemia (ALL)