Harry Erba, MD, PhD: Dan, there are a number of adverse events with the IDH inhibitors. We know about hyperbilirubinemia, typically unconjugated, from the UGT1A1 inhibition, QT prolongation, which we’re all aware of and can manage by looking at other drugs that the patients are on and monitoring the EKG [electrocardiogram]. The 1 thing you do need to comment on in this panel is differentiation syndrome.

Dan Pollyea, MD, MS: We’re finding upward of 10% or so patients experience differentiation syndrome. The important thing to recognize is that, unlike the familiarity with differentiation syndrome in APL [acute promyelocytic leukemia] with ATRA [all-trans retinoic acid]—arsenic [arsenic trioxide], it can occur much later in the disease process, so it’s not necessarily something you’ll see in the first couple of weeks or even a month. Management is important. Early recognition: it’s a diffuse clinical presentation. Almost anything can be differentiation syndrome, so you have to be very careful about watching for anything that looks like it. After recognition, initiation of steroids is very important. We try not to discontinue the inhibitors if we’re able to because there are a number of patients who go on to have very good responses.

Mark Levis, MD, PhD: And that won’t do you any good because the half-life is so long.

Dan Pollyea, MD, MS: That’s right. By the time you stop it, you’ve got to wait a week. That’s a good point. Hydroxyurea is used to bring the counts down if it’s a proliferative differentiation. There are definitely ways to manage, but it comes down to recognition.

Harry Erba, MD, PhD: For me, the key thing I hang my hat on is this: I go and look at the smear. If I see differentiation, which may be missed by the lab tech because they don’t know what to call these cells—they look very weird, so they’ll still call them blasts—you need to go look.

Dan Pollyea, MD, MS: Yeah, that’s true.

Harry Erba, MD, PhD: The other thing is that the therapeutic trial of dexamethasone is also a diagnostic trial. For differentiation syndrome, my experience is they turn around quickly with that.

Dan Pollyea, MD, MS: That’s a good point, yeah. That’s true.

Mark Levis, MD, PhD: You want to make sure and add: the differentiated neutrophils, whatever they are, are aberrantly cloning to areas of inflammation and infection. Usually, there is some underlying infection much like with APL, so you don’t want to forget to throw on antibiotics.

Dan Pollyea, MD, MS: Yeah, that’s a great point.

Harry Erba, MD, PhD: Just to come back to it for a second, gilteritinib has now been associated or has been associated with differentiation syndrome.

Mark Levis, MD, PhD: It’s less common, and the reason is that a FLT3 inhibitor debulks the disease first. It kills three-quarters of the disease in the first 2 days, so there is nothing to differentiate or there’s a lot less to differentiate. But yes, you’ve got to watch for it with gilteritinib.

Transcript Edited for Clarity