Differentiation Syndrome and IDH Inhibitors in AML

Harry Paul Erba, MD, PhD: I’ll come back to Courtney DiNardo, MD’s presentation at the randomized phase 2 of an enasidenib and AZA [azacitidine]. The azacitidine arm probably looked good because 20% of those patients got enasidenib. But that’s the only data she had. I wonder how many of those patients actually got venetoclax combinations and did well.

So your point is well taken, Amir, that, you know, I’m not saying that the survival of patients is that AZA alone was going to be 22 months. I’m saying that we now have choices for these patients, and we can add these therapies in.

Gail J. Roboz, MD: But I think it’s worth it to note that we’re probably never going to really know the answer to that study for the exact reason that choices evolved as those studies were trying to accrue. So, I mean, if it becomes really difficult, you have to go outside of the United States to complete the accrual because there was complete contamination with venetoclax. I think it’s just been; I think that those companies have had a very tough time accruing and have definitely broadened the net with respect to participating trial centers.

Harry Paul Erba, MD, PhD: Amir, I want to come back to you. You published in JAMA Oncology the enasidenib experience with differentiation syndrome [DS]. Do you want to talk about IDH DS?

Amir Fathi, MD: Thank you, Harry. So we published about 14%, 15% of patients who received enasidenib monotherapy on the original phase 1 dose expansion, dose escalation and dose expansion study.

And so differentiation syndrome in that setting mainly manifested as a vague constellation of symptoms–unexplained fever, respiratory symptoms, pleural effusions, pericardial effusions, rash, mild generally azotemia, boney pains, adenopathy. And we tried to go through every single case that had that constellation. And, as you can imagine in a patient who has AML [acute myeloid leukemia], who is marrow suppressed, who has potential cardiac pulmonary symptoms, it’s difficult to tease out what’s what.

Courtney DiNardo and Stéphane de Botton, MD, we came across approximately 15% or so of patients who we could easily or fairly well rule out other secondary causes of those symptoms and signs and could say that the likelihood of differentiation syndrome was possibly or likely related to the actual process, meaning that the differentiation syndrome was caused by the drug. There wasn’t a secondary cause for those symptoms, that it was related to differentiation syndrome.

Differentiation syndrome can be severe. It can be potentially life threatening, and so our recommendation has generally been that if you suspect it and worry about it, and secondary causes cannot be immediately and quickly ruled out, that you should start treatment with dexamethasone and we recommend 10 mg twice a day. And then once, and if, patients get better, and they should if it is differentiation syndrome, then there should be a tapering down dose over time.

On occasion, differentiation syndrome is accompanied, but not necessarily so, but on occasion it is accompanied by leukocytosis. So hydroxyurea may be necessary if there is concurrent leukocytosis. Similarly, other phenomena can be a co-occurrence such as DIC [disseminated intravascular coagulation], which can be potentially life threatening, as well as tumor lysis syndrome.

So, again, it is hard to necessarily tease out differentiation syndrome in the patients with AML. But when secondary causes are ruled out or cannot be ruled out in a timely manner, I think initiation of steroids is important because these conditions can escalate. And if you look at study after study after study with IDH inhibitors, either as monotherapy or a combination with induction for HMA [hypomethylating agents], you’ll see this weight of approximately 12% to 20% of patients getting differentiation syndrome. So it is a real entity, and it is to give up that closely in patients who get treatment.

One other important point I would just say is that the timing of developing differentiation syndrome can be somewhat delayed as opposed to a differentiation syndrome that you get with ATRA [all-trans retinoic acid]. The differentiation syndrome with IDH inhibitors, typically we found that the median time of loss was around 12 weeks. So anywhere between 10 days to 6 months, you can potentially get it. Especially if you stop treatment and resume it later, you can get recurrent episodes of differentiation syndrome.

Harry Paul Erba, MD, PhD: I agree, Amir. A couple other important distinctions between IDH and APL [acute promyelocytic leukemia] differentiation syndrome is 100% of patients with APL who developed differentiation syndrome, if they survive, will achieve a remission. That is not true with the IDH inhibitors. And partly because I think some of these patients really, truly had progression and pneumonia and heart failure and things like that. But also it may be that you’re differentiating 1 clone, but then a FLT3-positive clone grows out. And so you may see some differentiation.

Amir Fathi, MD: I completely agree with Harry on this one. APL is about the cleanest disease that we treat, right? Generally, it’s only 1 alteration that causes the disease. On occasion, you’ll get a FLT3 mutation. But with IDH mutations, you get the ugly AMLs, but you know, the multiple clones, the other mutations, you might have a potential efficacy. And training the IDH-susceptible clone with an IDH inhibitor, that might be why not everybody with treatment with IDH inhibitors gets to the differentiation syndrome and certainly not, well partly the reason why patients don’t respond, some patients don’t respond to IDH inhibitors.

But also keep in mind that about 100% of patients treated with ATRA arsenic trioxide these days also get remission anyway, so… we’re kind of comparing something that is good with something that is outstanding. So it’s a little bit challenging and not perhaps the comparison for IDH Inhibitors.

Gail J. Roboz, MD: Harry, I wanted to jump in with 1 comment that, you know, AML used to be an inpatient disease, right? And now there are lots of aspects of AML therapy that are being handled as an outpatient. And one of the things that we’ve actually worked on with the company is surrounding differentiation syndrome is I think a little bit of patients’ education and advocacy so that they understand, also, this toxicity. Now you have an APL patient coming into the hospital, you’re not necessarily giving them a lecture on differentiation therapy if you’re watching them in the hospital. If they get it, you’ll tell them about it—if they don’t, they don’t.

But a lot of these patients, we were thinking as we were trying to prepare some of the educational materials for patients, they might end up in a local emergency department where somebody has never heard of the medication that they’re on; they don’t know what to look for. And I think that there actually has been an explosion of articles for internal medicine doctors, for emergency department physicians, on various oncologic complications of therapy, both for solid tumor therapies and also increasingly for heme malignancies, to just alert doctors that if you have somebody coming in with leukocytosis and infiltrates, it may not be pneumonia. You might have differentiation. So I just think it was a whole other axis of this particular toxicity to kind of warn the public, if you will, warn the patients, warn so that people were not getting really down the wrong path as they presented to the emergency room.

Harry Paul Erba, MD, PhD: Yeah, early intervention with dexamethasone, 10 mg twice daily, is very important, admitting them for monitoring. I will say that I have a dot phrase, a smart phrase in my Epic notes that go into the patient instructions as to when to call, how to monitor their weight, if they’re getting more short of breath. And I talk to my nurses as well. If someone on an IDH inhibitor calls in with shortness of breath, yeah, most leukemia patients, that means you can set them up for a transfusion in a couple days. The IDH inhibitor patient, we need to see. And so there is a lot of education there.

I want to move on to our last topic. So, before I get there, I want to mention a couple of other important toxicities that we do manage with the IDH inhibitors—hyperbilirubinemia is seen with enasidenib. Quite frankly, I don’t do dose adjustments because of hyperbilirubinemia from inhibition of UGT1A1.

Mark J. Levis, MD, PhD: Harry, it’s a measure of patient adherence.

Harry Paul Erba, MD, PhD: Yes.

Gail J. Roboz, MD: Exactly.

Harry Paul Erba, MD, PhD: Very good point.

Gail J. Roboz, MD: But it is a mistake to stop the therapy, and I think you want to get that in your smart phrase, which, by the way, please send me because that will save me a lot of work. But I think that point also, you don’t want to stop the effective therapy for an irrelevant bilirubin value.

Mark J. Levis, MD, PhD: I want to see it, yeah.

Harry Paul Erba, MD, PhD: QT prolongation has been associated with ivosidenib, and then not many people know this, but in our phase 1 experience, you all may remember Guillain-Barre in 2 out of about 250?

Mark J. Levis, MD, PhD: I had a case; I had a case.

Transcript Edited for Clarity