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. Dr. DiNardo?
Dr. DiNardo: Hi, Courtney DiNardo from MD Anderson in Houston, Texas, in the Leukemia Department here. Thank you so much for the invitation.
Dr. Stone: Thank you. And Dr. Wang?
Dr. Wang: Eunice Wang from the Leukemia Service here at Roswell Park Comprehensive Cancer Center in Buffalo, New York. Thank you again for the opportunity.
Dr. Stone: Thank you, Drs. DiNardo and Wong. Today we'll be discussing recent updates in AML, including recent data presented at the 2021 ASH Annual Meeting. And we'll be integrating these new developments into four patient case studies. Our first installment will focus on a young patient presenting with bleeding.
So this is a 23-year-old female with no essential past medical history, but having very heavy menstrual periods. She's also fatigued. She went to the doctor and was found to have a white count of 31,000 with 62% blast, hematocrit 23%, and platelet count 10,000. On peripheral blood flow, these blasts were found to be myeloid CD33 positive, but HLA-DR negative. These were normal on cytogenetic examination, and on next-generation sequencing, key mutations were found in DNMT3A, NPM1, and IDH2.
So we have to treat her for her AML, and I'm going to propose some choices, which we can discuss. The first is daunorubicin 60 mg for 3 days and ara-C for 7 days, so-called 7+3. B is the same plus gemtuzumab. C is the same plus all trans-retinoic acid. D is the same plus enasidenib, and E is so-called FLAG-IDA + VEN, a combination of fludarabine, cytarabine, G-CSF, idarubicin, and venetoclax.
Okay, so with that in mind, let us begin. I'll ask Dr. DiNardo first, how she should have looked at this case and what she's thinking about in deciding on initial therapy.
Dr. DiNardo: I think this is a great case example of one where there's really, I think, nothing wrong with any of these induction choices. I would say that the way I think through a newly diagnosed patient, a de novo AML patient who's favorable risk, with the NPM1 mutation and diploid cytogenetics, what we're trying to do is optimize her chance of remission and then cure without a transplant.
And so for me, I don't love the idea of a standard 7+3 alone, which is the standard of care, and that is an appropriate thing to do, but I want to improve incrementally those remission and potential curability rates. So for me—and we can get into the data a little bit—I would choose either one of the last two options, 3+7 with enasidenib with an IDH2 inhibitor, or the FLAG-IDA + VEN combination. And the reason I say that is because both of these have not been compared in a randomized head-to-head fashion. So I don't have any proof that they're better than 7+3, but when you look at the safety and the efficacy data of the phase II data coming in, the response rates are higher and the duration of remission and overall survival appear to be very favorable. So I really want to give this person a curative option.
Dr. Stone: Okay. I'd like to ask Dr. Wang what she thinks about that because as Courtney really points out, though the initial results, for example, the FLAG-IDA + VEN that Courtney herself has brought to the world, are very exciting, that is a toxic regimen and has not been compared to 3+7. And so I have a lot of trepidation about using that for a patient outside the context of the clinical trial, although many who are doing it. And secondly, while the—and I'll show the data for enasidenib plus 3+7—it's based on relatively few numbers of patients. And while the curves look pretty good, the follow-up is relatively short here. I'm looking at the presentation by Dr. Stein that updated this 3+7 plus enasidenib or ivosidenib data at ASH. I think it's too premature to initially adopt that, but what do you think, Dr. Wang, about these choices or about the specific two that Dr. DiNardo thought might be good?
Dr. Wang: Well, I think as you know, we've spent decades trying to improve upon our backbone as 7+3, and we've tried multiple different combinations increasing the anthracycline, increasing the cytarabine and etc., etc. And I think we're now moving into the modern era where we actually have multiple targeted therapies and things that we can add. So I think we are struggling in this sort of transitional period as to how best to improve upon 7+3. Should we add a BCL2 inhibitor, like for VEN-AZA, should we add enasidenib or ivosidenib for IDH? Should we add ATRA? Should we add gemtuzumab because she would technically be a favorable to intermediate risk? I think there is no straightforward answer. I think we all can agree that she should get 7+3.
I would favor, as Dr. Stone favors, a 7+3 backbone, just because of the tolerability and safety. And I think in terms of what to add, I think that adding enasidenib would be attractive because I don't think it adds that much toxicity, or we can say that even adding ATRA would be favorable, because it doesn't add toxicity. But to be honest, I think the data is still out there. I think that these are still considered largely experimental therapies.
FLAG-IDA is not a backbone that I have a lot of experience with in the upfront setting. Although one could argue, as I'm sure Dr. DiNardo was, that this is a 23-year-old, very fit young girl. So these are the types of patients that in the past have tolerated higher dose regimens in the upfront setting. So I'm not sure that there is an answer that would make all of us happy. I'm happy to think about 7+3 plus something else. But for right now, I think some of the options are a little bit premature because we don't know out of all of these, which is better, but I would want to add something. So I think I would add an enasidenib to 7+3, because I think that's relatively safe and I would want to, again, cure this individual.
Dr. DiNardo: If I can just add one quick comment. I think the point, Dr. Stone, that you raised about the toxicity of the FLAG-IDA + VEN, that is something not to be taken lightly. And so when I'm talking about these treatments, they are in the setting of a clinical trial and they are in a major academic center here. So, it is I think a very important thing to consider if you don't have a lot of resources and your patients are not able to be staying nearby so that they can be monitored very closely. I think that is definitely something to keep in mind, and a 7+3 may be more appropriate.
Dr. Stone: Right, I'm showing the data from your paper—FLAG-IDA + VEN in newly diagnosed AML—and the responses are very high. Complete remission rates in de novo AML, like this patient, is 91% and of those who achieve that, almost all of them do so at MRD-negative level. And I'd like to pick up on that. Should we be aiming our goal of therapy as an MRD-negative CR rather than just a morphologic CR?
Dr. Wang: I think that MRD negativity is becoming the new standard. We know that the majority of patients who get 7+3 backbone even without anything who are younger and fit can have high rates of morphologic remission, but about 50% chance of relapse. So I do think that MRD positivity is going to be in the newest standard moving forward, not only for favorable risk as this patient has, but also I think more importantly for intermediate risk.
I had a question for Dr. Stone. Now you said that maybe you wouldn't want to give the FLAG-IDA; that's a pretty intensive backbone. So I know that your center has actually looked at 7+3 plus venetoclax. Using venetoclax for this patient would be attractive because we know that IDH-mutant AMLs are particularly sensitive to BCL2 inhibition. So what are your thoughts on doing 7+3/VEN for this patient?
Dr. Stone: Sure. I would not do that outside the context of a clinical trial, but she would be eligible for our current trial in which we're adding 7+3 plus venetoclax to chemotherapy. We had virtually a 100% CR rate in patients who were under age 60 who got 7+3 plus venetoclax. It is toxic; they were bacteremias, there were some people got very sick, so I'm not sure it's ready for export to general centers, just as I would say for FLAG-IDA + VEN, although they're both very interesting combinations.
I think that for me, I would still give this patient 3+7, maybe with 90 mg of daunorubicin and a 100 mg of ara-C just as one would've done in the ECOG 1900 study. But I do want to come back to the ATRA business. You said you might add ATRA and that's based on, I think, the trial by Alan Burnett that looked at retinoic acid plus a 3+7-type backbone. And the results showed that in NPM1-mutant patients there was a superior overall survival, but it did not reach statistical significance. This is based on a paper back in 2010. So do you think anybody's actually using ATRA for an NPM1-mutant AML patient today? Eunice?
Dr. Wang: Well, I think that the data with the MRC or with regimens developed outside the US is a little hard to interpret because the MRC data includes two inductions. And so we would not give two inductions. So it's hard to know how the addition of ATRA, which is not statistically significant, really benefited those patients. So I think it's very hard for us to know whether the ATRA really improved the outcomes for patients that have NPM1-positive disease.
I'm actually very intrigued by another agent, the menin inhibitors, which have shown activity in early phase clinical trials for NPM1-mutant disease in the relapsed/refractory setting. And those agents are targeting the unique biology of NPM1-mutant disease. There's also SYC inhibitors, which are in clinical development here in the US again for NPM1-mutant patients in combination with 7+3 backbones. So there are a number of trials targeting the unique biology of NPM1-mutant disease. I'm not sure where ATRA fits in that, but it was an intriguing target to try to develop further.
Dr. Stone: That's a great point. And I'm sure there will be trials with the menin inhibitors plus 3+7 that'll show hopefully that they're safe to be combined, and then subsequent trials that'll show that they are better than 3+7 alone.
And finally gemtuzumab. Dr. DiNardo, there is that meta-analysis by Dr. Hills that suggests that patients with clearly CBF mutants—which this patient doesn't have—CBF, cytogenetic abnormalities and patients with intermediate cytogenetics, which this patient does have, benefit from gemtuzumab. But of course the magnitude of the benefit in the intermediate cytogenetics (i.e., normal cytogenetics) was minimal. Do you think this patient should have that as a consideration?
Dr. DiNardo: I think it's on the table, and I think for me the instances where I use gemtuzumab is primarily in patients with core-binding factor leukemia, as you mentioned, right? Because there is a far more dramatic improvement in overall survival. There is, as you mentioned, kind of about a 5% incremental improvement in survival endpoints in intermediate-risk cytogenetic patients receiving gemtuzumab, so that's not zero. So that's certainly something to put on the table.
But I find that, well, I like looking at the ALFA dataset where they tried to kind of look into those intermediate-risk patients and try to figure out who are those patients deriving benefit. And at least in that retrospective post hoc analysis, it looked like patients with signaling mutations were those that seemed to benefit the most. And so we've used it occasionally in patients with intermediate-risk cytogenetics with signaling mutations. I find that for the reasons I explained at the beginning, when I'm adding something to the standard intensive backbone, just our institution has opted more to prioritize the targeted therapeutics in this patient with an IDH2 mutation enasidenib or the venetoclax with intensive chemo. So those would be my preferences, but I think the addition of gemtuzumab is a reasonable one as well.
Dr. Stone: Excellent. So this a young lady has a number of options, hopefully she'll do well. It's important to just point out that she has favorable-risk disease because of her NPM1 mutation, also FLT3 mutation, and normal chromosomes according to the ELM classification system, but in the Hills review of the use of gemtuzumab, she would've fallen into the intermediate group because that paper did not use the ELM, which wasn't out by the time he wrote that paper. So it's a little bit of a fine point, but important to make.
So I think the clinical takeaways from this patient case is that induction therapy for younger patients with AML has evolved from 3+7 for everyone to a more personalized approach. Whether that applies particularly to this patient right now is a bit unclear. FLAG-IDA+ VEN is effective, but a little toxic, I would say, not yet ready for standard use but hopefully soon will be because the results will be hopefully repeated or confirmed in other studies and will be an exciting addition. 3+7 plus IDH inhibition in IDH-mutant patients is being studied. There's actually a phase III trial in Europe comparing 3+7 to IDH inhibitors, à la the way CALGB10603 compared chemo to chemo plus midostaurin in FLT3 patients. And 3+7 plus gemtuzumab might benefit intermediate-risk cytogenetic patients, but I would promote the statement that it's not routinely used outside of the core-binding factor setting.
So that was a great discussion, Courtney and Eunice, and this brings us to the end of this case. Please, see the other segments for the discussion about the latest data in AML or visit ascopost.com. Thank you very much.
