DR JOHL: This is a 33-year-old Hispanic female who presented with fever and oral ulcers earlier this year. Her initial white count was 34,000. Hemoglobin 11.8 and platelets of 164. The bone marrow biopsy showed 70% myeloblasts, and the flow cytometry was classic for AML. She had normal cytogenetics. She also had a FISH for a 15;17 translocation. That was negative. She was positive for FLT3-ITD, and she had also had NPM1 mutation. CEBPA was negative, and IDH mutation was negative. And she also had a CEBPA SNP, which, according to the pathologist, was associated with a poor event-free survival.

So she was given standard induction chemotherapy with 7 + 3 and, within a week after getting her bone marrow biopsy, we knew that she was FLT3-positive. So following induction chemotherapy, she was given a course of sorafenib. The day-14 marrow showed less than 5% blasts, but as soon as she recovered — and this is a month ago — basically when she recovered her marrow, it was 40% blasts. So, essentially, she relapsed pretty quickly.

So she has been referred to UCSF for discussion about clinical trials. And she’s currently being considered for a salvage regimen of either MEC or IDA-FLAG and ASP2215, which is an FLT3 inhibitor.

So the question I would have for you would be, what would you have done differently in this patient? And how would you treat her at the time she relapsed?

DR LOVE: And also, maybe, Rich, comment a little bit on some of the trials that are out there that might relate to a patient like this.

DR STONE: I think UCSF is considering those trials for her right now. And the trial that she might be eligible for is either the quizartinib versus dealer’s choice chemotherapy trial or the gilteritinib versus dealer’s choice chemotherapy trial. I believe she would meet the refractory definition by that standard. And the dealer’s choice chemo includes the choices you mentioned: midostaurin, etoposide, cytarabine, often called MEC, and FLAG-IDA.

It’s a terrible situation, obviously. She’s declaring herself as to being completely chemoresistant. The goal would be to get her disease under control then do a transplant. Some of the biologically based clinical trials with bromodomain inhibitors, with CDK inhibitors and other things like that require you to be in a better disease control situation, so you can let these things play out. So, basically, it’s either chemo or an FLT3 inhibitor. She’s already been on sorafenib, so if she has to stay in the community I would give her MEC and hope that she can achieve a remission. I have seen, sometimes, that work.

DR LOVE: Jorge, what about Jewel’s question of “Would you have done anything differently” up to this point?

DR CORTES: I mean, not really. We use higher doses of ara-C. But it’s hard to believe that that would have made a significant difference. I think that the chemotherapy plus an FLT3 inhibitor is what we would do in these patients. Again, it all depends on having access to either a clinical trial or sorafenib outside of a clinical trial. Hopefully, that issue will be solved with the approval of midostaurin in the near future.

In terms of what to do now, one of the problems that these studies are facing in terms of accrual is that, for a patient that has already had 1 treatment and not responding and then you’re going to go to the second and there’s a control arm where there’s no FLT3 inhibitors, there’s a lot of people who are hesitant, me included, on treating these patients without an FLT3 inhibitor for a second time when you have FLT3 trials, at least, that are available. And we’ve kind of adopted the notion that this is the best strategy in some settings. It’s not completely proven, but at least we’ve interpreted that that way.

So that is one of the problems. If you can get them to the arm of an FLT3 inhibitor, fantastic. If not, then is that the best you can do for the patients? And it’s not just a matter of getting them into remission, but you saw the data with the midostaurin where the patients who go in remission and then go to transplant — if transplant in first remission, at least. That’s from the midostaurin data — they do get a better outcome after transplant, probably because they get a better, deeper remission. So today, we have a bit of a problem with those patients. Hopefully little by little this will be solved, if these drugs get approved.

DR LOVE: So Rich, it’s interesting that this patient seems to be eligible for a couple of trials, one with quizartinib and the other with gilteritinib. All things considered, either one of those that you would prefer? What’s the relative toxicity/tolerability profile of the 2 agents, your excitement level of the 2 agents? Which trial would you rather see the patient get on?

DR STONE: I think it’s tough to choose a clinical trial when there’s 2 that they’re eligible for. It’s kind of like picking your favorite child. But if you put me to the wall I would say gilteritinib because of the lack of emergence of resistance in the D835 clone. And as best we can see, the toxicity is not going to be much different — maybe even less myelosuppression with gilteritinib. So that’s very, very soft data, though.

DR JOHL: Just a general question about not just this patient but just any patient in general. Because, obviously, a 15;17 translocation, APL is a unique subset of patients. And morphologically, you may not see the classic promyelocytes, or they may not have the classic DIC. But do you check at the time of diagnosis every patient for t(15;17), PCR?

DR STONE: That’s a really critical question for the reasons outlined earlier. You don’t want to miss APL. However, if the patient’s fibrinogen is normal and the platelet count’s above 50,000, it’s highly unlikely that they — and you look at the smear and there’s no malignant promyelocytes, you don’t have to do that. We have a very low threshold to look for the t(15;17) by molecular means or by FISH or by cytogenetics and a low threshold to start ATRA. But the patient you described, it didn’t smell like APL at all. The only thing she had going for APL was her young age and her Hispanic descent.

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions