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Therapy Options for Primary Refractory FLT3-ITD–Positive AML

In this video, Drs. Richard Stone, Courtney DiNardo, and Eunice Wang treatment options for primary refractory FLT3-ITD–positive acute myeloid leukemia (AML). The case is a 60-year-old man with a history of hypertension and hyperlipidemia who presents with fatigue. He is diagnosed with FLT3-ITD–positive AML and is enrolled in a clinical trial where he receives 7+3 (cytarabine/daunorubicin) and midostaurin; after achieving complete remission, his disease eventually recurs. The faculty discuss potential treatment options for this patient, such as FLAG-IDA-VEN and gilteritinib both alone and in combination.


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Transcript

Dr. Stone: Welcome to The ASCO Post Roundtable Series on Updates in Acute Myeloid Leukemia. I'm Dr. Richard Stone, chief of staff and director of translational research in the Leukemia Division at Dana-Farber Cancer Institute in Boston, Massachusetts. Joining me today are two of my esteemed colleagues. First, Dr. DiNardo? Dr. DiNardo: Hi, Courtney DiNardo in the Leukemia Department at MD Anderson Cancer Center in Houston, Texas. Thanks. Dr. Stone: And Dr. Eunice Wang? Dr. Wang: Hello, I'm Eunice Wang from the Roswell Park Comprehensive Cancer Center in Buffalo, New York in the Leukemia Division. Thanks so much for including me. Dr. Stone: Thank you, Courtney and Eunice. Today we'll be discussing new updates in AML, including recent data presented at the 2021 American Society of Hematology Annual Meeting. And we'll be integrating these new developments into four patient case studies. Our third installment will focus on a relatively older patient presenting with fatigue. So this is a 60-year-old male with history of hypertension and hyperlipidemia. He now has been quite fatigued over the past month or so. He goes to his doctor and is found to have a white count of 31,000, 62% blast. Hematocrit is 30%, and platelet count is 42,000. Flow cytometric evaluation of the peripheral blast shows that these are myeloid in origin (i.e., myoblast). Cytogenetics shows loss of the long arm of chromosome 17. And next-generation panel shows a RUNX1 6 base pair deletion, and a FLT3-ITD of 81 base pairs in length. He was enrolled in a clinical trial of 7+3 with either crenolanib or midostaurin. He was randomized to midostaurin. He needed two cycles because his bone marrow after the first cycle still showed blasts. But on day 60 after both of these cycles, his marrow showed complete remission. He went on to receive one cycle of high-dose cytarabine plus midostaurin with the idea that he would be transplanted when a donor could be found. Fifty-two days, however, after the start of the consolidation cycle, while awaiting allogeneic transplant, peripheral blasts were noted and a marrow done at that time showed recurrent FLT3-ITD-mutant AML. So this unfortunate gentleman still wants to be treated actively. And what should we give him? A, mitoxantrone/etoposide/cytarabine. B, fludarabine/idarubicin/cytarabine/G-CSF plus venetoclax, called FLAG-IDA-VEN. C, gilteritinib. D, gilteritinib/venetoclax/azacitidine, or E, gilteritinib and venetoclax. So Dr. DiNardo, historically we might have done salvage chemotherapy with this patient. Would you still do that? Dr. DiNardo: Well, the first thing I would do actually, which I might have missed, but I think you omitted on purpose is the sequencing of this patient as they are relapsing. And so I think one of the most important things in a patient, especially with a FLT3-ITD, where that mutation is a little bit less stable, is not to just presume that FLT3 mutation is going to be present at relapse just because it's there at diagnosis. And especially when you're using intensive chemo and FLT3 inhibitor–based frontline therapy, there is probably about like a 20%—Eunice might know the number better—incidence of that FLT3 mutation actually being gone at relapse. And so I'm couching my response to your answer with if that patient does have a FLT3 mutation still identified at relapse, then I think we have clear data from the randomized study of gilteritinib versus standard of care/investigator choice options, which included MEC and FLAG-IDA and the more intensive chemotherapy options and gilteritinib alone as a single-agent monotherapy improved outcomes. And so granted that wasn't in patients that it had prior midostaurin, but I think there is clear importance of incorporating, especially in a patient that had midostaurin-based therapy, a second-generation FLT3 inhibitor at the time of relapse. The question then is, do use just a single-agent gilteritinib, or do you try to combine that gilteritinib with other therapies such as azacitidine with venetoclax and gilteritinib—one those triplet type regimens—do you try to incorporate gilteritinib with venetoclax alone or with intensive chemo? I mean, the options are a bit endless. I think when you look at specific trial data, the ven/gilt combination has been presented now two or three different times. And the ASH data presented by Naval Daver, I think looks pretty impressive in patients that had prior FLT3 inhibitors in the ability to obtain a leukemia-free state marrow. So even the oral doublet of just venetoclax and gilteritinib, it causes a lot of myelosuppression and ongoing cytopenias, but you get deep remissions. And the goal for me for this patient is to get them into a remission so I can then follow with what is hopefully a curative transplant. Dr. Stone: Excellent. This patient, as it turns out, did still have the FLT3-ITD, but you're right, it's very important to check that because the selection pressure engendered by the FLT3 inhibitor he was taking could well have produced FLT3-ITD–negative relapse. In fact, when we looked at this on the CALGB10603 ratified trial, we found that about half the relapses were wild-type FLT3 and about half were the same FLT3, they had a diagnosis. So that's a key point, but for whatever reason, maybe because of the 17q deletion or whatever this patient had what's considered primary refractory disease, because they relapsed so quickly after their initial intensive therapy. So Eunice, Courtney said that, mentioned the ADMIRAL trial, which compared gilteritinib to whatever the doctor wanted to give in the setting of relapse. And gilteritinib beat the doctor's choice by quite a bit. Although the overall results were still pretty dismal with the 9-month median survival in the gilteritinib arm and a 4- or 5-month median survival in the chemotherapy arm. So are you satisfied with gilteritinib as a single agent to treat relapsed mutant FLT3 AML? And what do you think the results would be if they were done in the post-midostaurin era? Dr. Wang: So I do think that there were some limitations to the ADMIRAL trial. As you mentioned, when ADMIRAL trial was initially enrolling, there was no standard of care FLT3 inhibitor midostaurin, which was used for upfront therapy. So I believe only 13%, or some very small percentage, of patients on the ADMIRAL trial had had prior midostaurin. Now subsequent post hoc analysis has demonstrated that for patients who did have prior TKI, including midostaurin, that gilteritinib was still better than standard of care reinduction chemotherapy or load intensive therapy. But the gains that you're getting are potentially a little bit less than if you were FLT3 TKI naive. So that data, in addition to, as you mentioned, the relatively short overall survival benefit with gilteritinib alone of 9 months has really spurred on investigation of a combinatorial regimens. And I know Courtney's already mentioned the gilteritinib/venetoclax data looks really interesting because we know that BCL2 and FLT3 inhibitors, at least preclinically, can be synergistic in preclinical AML models. I think there's a lot of interest right now in triplet therapy, combining a FLT3 inhibitor with venetoclax and an HMA. There is the beat AML study, as well as study in MD Anderson has been looking at second-generation inhibitors, not just gilteritinib, but also quizartinib, HMAs, including decitabine as well as azacitidine in combination with venetoclax. And overall, there appears to be very, very high, I think over 90%, 100% overall response or morphological leukemic free states with that triplet therapy. So it does in both the de novo and the relapsed/refractory setting seem to be highly potent, but as Dr. DiNardo mentioned really comes at a cost. Median time for ANC 500 and platelets of 50 with a triplet regimen can be as long as 50 to 60 days. All of these triplet trials of a FLT3 inhibitor/ven and an HMA have been on at academic medical centers and largely the inpatient setting where patients can get daily blood counts, transfusions, IV antibiotics, etc. So again, I think these triplets are highly promising and may move into the upfront setting, but we clearly have much ways to go. The gilteritinib dose, for example, looks to be too high at 120. I think there's data suggesting it could be reduced to 80. We might be able to do an early bone marrow biopsy with triplet therapy at 14 days, instead of waiting for our typical 21 or 28 days that we do with ven/aza. But the benefit is that these are largely regimens which can at some point be transitioned to the outpatient setting. We do know that for fit younger patients, that regardless of how you get there, some of those patients really are going to benefit from an allogeneic stem cell transplantation as in this case in first remission. And I think there's also emerging data supporting the use of FLT3 inhibitors right now, sorafenib but potentially these newer generation inhibitors, in the posttransplant setting to ensure long-term remission in that setting. So I think we have a long way to go to try to optimize our FLT3 inhibitor therapy, particularly in the refractory setting for these patients. Dr. Stone: Now, Dr. DiNardo you have presented very interesting data using FLAG-IDA-VEN in the relapsed/refractory setting. Now, obviously you want to use a FLT3 inhibitor here, and I'm not saying you use FLAG-IDA-VEN/gilteritinib, but the question I'm really going to ask you is whether you had any FLT3-mutant patients within the relapsed/refractory group of patients get FLAG-IDA-VEN? Dr. DiNardo: We did, but they were I can count on, I think it was just two or three with very low allelic ratios where we thought that it was probably not as necessary to make sure we had that second-generation FLT3 inhibitor on board. I think, if this had been a patient that had a long remission and then relapsed more than 6 months out, I would be more excited to try to rechallenge with an even more intensive cytarabine-based therapy, but in a patient that just is relapsing after a HDAC cycle and still has a large FLT3-ITD mutation, I think, in a patient like this, you really want to prioritize that FLT3 inhibitor. But yes, I mean, you're absolutely right, not for this patient, but the FLAG-IDA-VEN salvage regimen, we are seeing, again, composite remission rates in the 60% range, which is an impressive. And most of those are MRD negative still in the relapsed setting. So again, all the caveats from an earlier case that we talked about, this is a myelosuppressive regimen. You need to be fit for intensive chemotherapy. So you have to be fit for intensive chemotherapy with the addition of venetoclax or risk of infections and things. But it is a very effective way of clearing disease and effectively getting patients to transplant. So again, it's a clinical trial right now, and I do worry about folks outside of academic centers using a lot of FLAG-IDA-VEN, but it is a very effective regimen. Dr. Stone: You show that it wasn't, unfortunately, all that effective in people with P53 mutations. Dr. DiNardo: That is true. Patients with P53 mutations, and then the other thing I should say is patients were excluded if they'd had prior venetoclax. So in this era where more and more people are getting venetoclax in frontline settings, I suspect that the outcomes in the relapsed setting with FLAG-IDA-VEN would be inferior, because you couldn't have had prior venetoclax. Dr. Stone: Whether the chromosome abnormalities this patient had, which might represent a hemizygous loss of P53 might also play a role in the – Dr. DiNardo: Yeah, that's a good point. Dr. Stone: Okay. So last thing I want to ask Eunice is the issue of doublets versus triplets. Courtney mentioned the exciting data by Perl and Daver about using the doublet of venetoclax/gilteritinib and also noted the triplet work that's going on with the three, but we know that things aren't always what they seem, right? You did a trial of gilteritinib plus aza versus aza in upfront, unfit patients, and that wasn't positive. So, I assume you're going to be in favor of doing doublets versus triplets prospectively. Dr. Wang: I think that even though the LACEWING trial randomizing newly diagnosed unfit patients for intensive chemotherapy with FLT3 mutations was a negative trial, I think it did demonstrate a couple of important points. One, it demonstrated that gilteritinib and azacitidine is very well tolerated in this older, unfit patient population, that the pharmacokinetics supported a dose as low as 80 mg potentially, and not 120 mg, in that combinatorial setting, and that there were very high overall response rates over 50% versus much lower response rates with aza alone. So I think that all of these recent studies have shown that aza alone really is out of date and really should not be something that we're offering in the era of targeted therapy. It does support us moving forward to combine FLT3 inhibitor in some sort of upfront setting for the older, unfit patients. And I do think the doublets, moving forward, the gilt/ven or the triplets of FLT3 inhibitor ven and HMA, are going to be the wave of the future and are going to offer our FLT3-mutant patients the ability to derive the greater benefit. However, I would want to highlight one point that in follow up to what Dr. DiNardo mentioned. In a lot of these older, unfit patients, patients are not receiving next-gen sequencing done at the time of their diagnosis. So in these nice case reports, we do have mutational profiles on all of these older patients, including patients 75 and above, but in order to incorporate FLT3 inhibitors in the upfront setting and IDH inhibitors in the upfront setting, we need to have the FLT3 and the IDH results. And I've found that many of my colleagues now, if they see an older, unfit patient are not performing or are waiting for the full mutational results before starting them on ven/aza. And this may be a missed opportunity for them to incorporate or derive additional prolonged event-free survival with incorporation of an upfront therapeutic agent. So again, just as it's important to do the testing at the time of relapse, moving to the future of even for older, unfit patients, it's going to be important to do that mutational testing as well. Dr. Stone: Absolutely great points. Drs. DiNardo and Wang, that was great. Just to finish the key takeaways from this case is that primary refractory disease, obviously including relapse within 6 months of diagnosis, we all know is a very devastating disease and unmet need, but in a case where the FLT3 mutation that we have here, targeted therapy is likely to be preferable to chemo alone. And we have to figure out what to combine the targeted therapy with for optimal results. So with that, I'd like to end the discussion of this case. But please see the other segments for further discussion about the latest data in AML or visit ascoplus.com. Thank you.
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