Case 3: Targeting IDH in AML

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD:Now, what aboutIDHinhibitors? Have you used these frequently? If you use them, James, are you using them as single agents in relapse? Have you tried them in combination? What’s been your experience?

James K. McCloskey II, MD:Yes, we have used them in combination in the context of clinical trials. We participated in the phase I studies withIDH1/2 inhibitors in combination with HMA [hypomethylating agent] and in combination with intensive induction therapy. Our approach for patients not on a clinical trial would be to use these as monotherapy, and in most patients, in the context of relapsed or refractory disease. I think there are those rare patients where you might consider using up front, although in that unfit, elderly patient population, upfront therapies have really blossomed, so we’re doing that less and less. Mostly, we’re using this drug as monotherapy in the relapsed setting.

Naval G. Daver, MD:Have you seen, David, any differentiation syndrome in your patients, and would you like to describe when that happened and how you managed that?

David Alan Rizzieri, MD:Yes, quite a bit, clinically. I don’t necessarily feel badly when we see it because I think of that as the responding patient and we follow them closely. We do quite a bit of combination, and of course, with some of the new approvals to allow us to use it up front, that’s been helpful. We often will have the agent plus an HMA, and then 1 to 2 months in therapy, see this leukocytosis possibly related to some pulmonary symptoms. We’re not sure. It’s very difficult for me to differentiate if that is failure versus differentiation syndrome as you’re indicating. I take the tact that the patient is otherwise doing OK, that it’s the therapy working, and flip them on some steroids, depending on the count. I’ll give some Hydrea, knock the count down, and try to get through that second, maybe third, month before I decide if it’s the drug therapy or not. That’s been our approach, anyway.

Naval G. Daver, MD:I agree, we see that quite frequently. There’s been the debate of 20% in the papers, and the FDA is saying it may be 30% or 40%. Whatever it is, it’s 20% to 30%. I agree that, most of the time if it’s early, you give them some steroids. We probably are more conservative. We don’t like the white count above 70 or 80. Others, I know, have argued it could be OK, but even if it’s neutrophils or monocytes, we’re usually giving a few days of Hydrea and it’s quite well managed. What I do see sometimes in the community, is that it can happen early. It’s a little different from the ATRA [all-trans retinoic acid], where that happens in the first 10 days. It can happen day 24 or 30, and the white count and blasts go up, and people think they’re progressing. Often that’s not the case, because you would not really expect anIDHpatient to suddenly turn on like aFLT3and go up. You can treat them with the steroids and manage them, and their response rate is about 50% if they have the differentiation. It’s overall pretty good. What about the frontline data with theIDHinhibitors? You’ve seen the data with 3+ 7/IDH[daunoribicin/cytarabine/IDHinhibitor regimen] that was presented at ASH [the American Society of Hematology meeting] by Eytan Stein [MD]. Is that something you’re considering doing off-trial? Let’s say you have a patient who has knownIDHmutation and you would give him 3+7, but you could give him 3+7/IDH. Is that something you would consider, James?

James K. McCloskey II, MD:Yes. We participated in that study. I think those data were very promising. If you look at the patient population that accrued to that trial, these were very high-risk patients, and generally, they were more high-risk than your average kind of everyday patient population. The CR [complete response] rates that we saw were certainly better than anticipated without any kind of signal that there were a lot of toxicities. I think, to be perfectly honest, outside of a clinical trial, we’d still be using 7+3 [cytarabine/daunorubicin]. That may be more of a conservative take, but until we have more data, especially thinking about young, fit transplant-eligible patients, I think we’re still a little cautious about interpreting phase I data that liberally. However, I don’t think it’s unreasonable to consider that.

Naval G. Daver, MD:OK. I’ll ask something that 2 years ago would have had a clear answer, but I think it’s changing. In an elderly patient who has anIDHmutation—David, maybe you want to take this one, or Usama—would you consider AZA/VEN [azacitidine/venetoclax] or AZA/IDH[azacitidine/IDHinhibitor], all things equal, for a 73-year-old with anIDHmutation? You have both options.

David Alan Rizzieri, MD:That’s a great question, and it’s great that we have the option. That’s very fortunate. I have to say, the answer is probably colored by the recent success. My most recent success is a wonderfully robust older woman, who did not want to keep coming back quite the distance to our center, and wanted something much easier to manage at home. She’s in full remission, doing great, and taking care of her ill husband on theIDHinhibitor with the hypomethylator. However, the venetoclax combination data are very supportive, as well. I think they’re 2 good options. I like the idea of more targeted therapy, so I tend to lean towards theIDHinhibitor.

Naval G. Daver, MD:What do you think?

Usama Gergis, MD, MBA:I second David. Since 20% or so of older patients will haveIDHmutation, I will be using a targetedIDH2 upfront for this particular patient. For the 80% who do not have that mutation, I’ll use the venetoclax.

Naval G. Daver, MD:It’s quite interesting, because a couple of years ago, when we had this, the AZA/VEN [azacitidine/venetoclax] data were earlier and more immature. Many people thought, it’s almost impossible to match this, but surprisingly it has been matched with 72% response rates. The recent median survival looks good. As you know, in theIDH-mutated especially, the AZA/VEN [azacitidine/venetoclax] and low-dose Ara-C/VEN [venetoclax] are quite good. Our group has been leaning towards the AZA/VEN [azacitidine/venetoclax], but I think what’s happening next, to plug some data that are going to come out at EHA [the European Hematology Association meeting], is combining them. There are actually studies looking at VEN/IDH1/2 [venetoclax/IDH1/2 inhibitor] that Dr [Courtney] DiNardo [MD, MSCE] from our group will be showing. The data are very striking in relapse. I think a year from now, we may be having discussion on which triplets we’re using. In myeloma, we’re catching up; we’re coming.

Transcript edited for clarity.