DR BROWN: This is a 64-year-old woman, first presented in 2002 with CLL. She had 11q deletion at that time. Progressed to therapy over about 2 years, received 4 cycles of FCR. And her disease progressed 14 months later after FCR, but she was able to be observed without being treated for some time. Developed autoimmune hemolytic anemia, which responded to prednisone, then went on a clinical trial of alemtuzumab and rituximab, out of which she got about a year remission. Progressed again. No response to an anti-CD19 antibody. Then went on a clinical trial of fludarabine and rituximab with the BCL-2 inhibitor obatoclax, on which she had only stable disease. And 3 months later, she went onto idelalisib on the Phase I study. She was one of the first patients on the Phase I study. And that was 5 years ago, and she’s in partial response with ongoing lymphocytosis, in fact.

She does have what I would say is a nontrivial disease burden. Her white count has come down over time to about 20, but she still has some 3-ish-cm abdominal lymph nodes. Her spleen has resolved. But she feels great and is doing great.

DR LOVE: You said her lymphocytosis is still going on 5 years later?

DR BROWN: Yes. So that’s actually not so uncommon with idelalisib as a single agent. In the Phase I study of the 50-odd CLL patients on that study, the median lymphocyte count at 12 months of the initial study was about the same as the starting lymphocyte count, after having peaked 2 months in and coming down. So we had a response rate of about 72% in that study, where about half was PR with lymphocytosis and half was PR.

DR LOVE: So she has no other evidence of disease?

DR BROWN: No. She still has some lymphadenopathy. But that shrunk progressively and now has been stable for some time without further shrinkage.

DR LOVE: So what do you know about the drug?

DR BROWN: So the drug is an inhibitor of the delta isoform of PI3 kinase, which is specifically expressed in hematopoietic cells and, in knockout mice, has a phenotype primarily affecting the B-cell compartment. And it induces the same pattern of response we talked about with ibrutinib in terms of rapid lymph node shrinkage, elevated white count, improvement in cytopenias over time, similar to what we see with ibrutinib. And as you can see from this lady, 5 years later, still in remission, you can have very durable responses.

The registration trial did not proceed as a single agent in large part because of this persistent lymphocytosis and the response criteria. So the drug’s in registration, has been studied in combination with rituximab in relapsed/refractory patients, where it had a significant progression-free and overall survival benefit compared to rituximab alone.

DR LOVE: And you don’t see lymphocytosis when you’ve used rituximab?

DR BROWN: You can see a small lymphocytosis, generally gone in a couple of weeks.

DR LOVE: What about tolerability issues and complications?

DR BROWN: Yes. So there are a couple of significant side effects to idelalisib. First one is that you do get a transaminitis, which generally occurs week 4 to 8 on therapy. Generally, you stop the drug. It resolves. Patients are asymptomatic the whole time. You can often restart at the same dose and not have it recur, or you can start at a lower dose. Even if it recurs again, you can sometimes go back and dose reduce and most patients can stay on drug despite the transaminitis. And that happens relatively early.

So the transaminitis, it depends what patient population you look in, but the Grade 3/4 rate in the relapsed/refractory CLL is probably 10% to 15%.

Now, pneumonitis that’s drug related is probably a couple of percent in the relapsed/refractory population, and so this requires a high index of suspicion when you’re evaluating a patient for infection than — turns out that, say, a pattern on CT looks more like drug and potentially treat with steroids once you’ve ruled out infection. That can happen anytime in my experience, early or descending later.

And then the colitis, which is inflammatory, similar to the pneumonitis, and possibly the hepatitis as well, though that hasn’t been well characterized yet, occurs later, at a median of about 5 to 7 months and can be quite severe.

DR LOVE: What do you do about it?

DR BROWN: So you can use budesonide. Turns out — typically, initially, use prednisone. Held drug, started prednisone, patients got better. About 50% of patients can potentially end up restarting and staying on drug after an incident of the colitis, but a lot of times what we do is use budesonide, as well as dose reduction of the drug and then taper the budesonide off over time.

DR LOVE: And have you observed that yourself, clinically, either the pneumonitis or the colitis?

DR BROWN: Yes, both.

DR LOVE: Any patients you’ve had where they’ve died or you’ve had serious complications in that regard, or usually they’re manageable?

DR BROWN: No. My patients have all been manageable.

DR LOVE: And when you use the drug in CLL, do you use it with rituximab?

DR BROWN: So I typically don’t, despite its approval.

DR KANTARJIAN: Why not, Jennifer? I mean, the combination should give you better results. And the approval is with the combination.

DR BROWN: In the relapsed/refractory setting, I just don’t think the rituximab adds very much. I’d be much more inclined to — so the ongoing registration trial in combination with ofatumumab and then also with BR, I’d be much more inclined to add ofatumumab when that becomes an approved regimen, but I just haven’t felt that the rituximab in a relapsed/refractory CLL patient adds that much. Most of them have had many lines of rituximab, including quite recently, just before, as well.

DR LOVE: What do we know about using it up front?

DR BROWN: Right. So there is not a lot known about that. There was a study led by Susan O’Brien of idelalisib/rituximab in patients over 65. And that had an extremely high response rate and progression-free survival at 24 months. It was 93%. None of the 17p patients have relapsed at 24 months. There was a higher incidence of these potentially immunologically mediated toxicities. The hepatitis was more common, pneumonitis was more common and colitis was more common. And that was very early on when we were still learning how to manage it, so there was a high rate of discontinuation of about 20% of the patients on that study.

There’s another ongoing study that was reported very early at ASH. And our institution is also doing an up-front study of idelalisib with ofatumumab. But I think the main thing to watch out about using it up front is that these toxicities do potentially appear to be greater, potentially because the patients may be more immunologically intact.

Chronic Lymphocytic Leukemia (CLL)

Chronic Myeloid Leukemia (CML)

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

Myelodysplastic Syndromes (MDS)

Acute Lymphocytic Leukemia (ALL)