Faculty presentation — Dr DiNardo: Exploring the current management paradigm for AML in patients not eligible for intensive therapy

DR DINARDO: I am going to start and try to kind of lay a bit of the groundwork and the background for our older patients who are not eligible for intensive chemotherapy and who do not have a targetable mutation was my specific task. And so just kind of to remind you all that when we talk about AML patients who are not fit for intensive chemotherapy, this is a lot of AML patients, right?

The average age of AML is 68. And so along the bottom you can see the incidence of AML by age group, and you can see that a lot of people, right, more than half, are over 60-some years old and that the survival of patients significantly decreases with your age. And so we do a pretty good job of curing younger patients with AML — more than 50% have an improved 5-year overall survival — but by the decades, that significantly decreases. And people over the age of 65, 60, 70, whatever your specific cutoff you’re looking at is still not nearly as good as we would like it to be, with an average 5-year overall survival of about 28%. And so we’ve also in our world of AML therapy really bin people into 1 of 2 categories, right?

We have our younger, fit patients that we are treating with curative intent. We’re giving them standard intensive chemotherapy. If we feel that they’re at a high rate of relapsing, we consolidate that with a transplant, as opposed to the older, unfit patients who’ve we really been treating with palliative intent, right? The goal has never been to cure. We have always used low-dose cytarabine or, in particular in the United States, azacitidine or decitabine or clinical trials. And that was really kind of what we had available to offer these patients.

And what I would say is, it’s not so simple anymore. We have many more therapies, and we have many more nuances. And so we can’t really always bin patients into kind of young, fit or older, unfit palliative care.

And so that’s a good thing, but it makes our decision tree and our analysis much more challenging, I think. Just basically, what are our expectations, or at least what were our expectations before this kind of current era of all the approvals?

First of all, so how do we define who is unfit? And this is really kind of a moving target, and I’m sure everyone in the room probably has different opinions about this.

A lot of people will say, if you’re 75 years of age or older, probably unfit for intensive chemotherapy, performance status of 2 or higher, underlying organ dysfunction, in particular cardiomyopathy or heart disease preventing anthracycline use, but more and more is discussions of people who are maybe genomically unfit for intensive chemotherapy, right? We know they might not respond as well to intensive chemotherapy, and maybe that would sway us towards using a venetoclax or other lower intensity-based approach, and that’s people with hematological disorders, unfavorable high-risk karyotypes or other high-risk genomic mutations, maybe p53, for instance.

Expectations with low-dose cytarabine — this is a study done over a decade ago looking at the kind of improvement in survival with low-dose cytarabine versus hydroxyurea and expectations in this study, with a median overall survival of about 4 to 5 months and a 1-year overall survival of 25%. That’s kind of what the expectation was with low-dose cytarabine, which really is still the standard of care in many countries.

With hypomethylating agents on the left you can see azacitidine, and on the right is decitabine, with median overall survival with the hypomethylating agents as opposed to standard of care at that time at 10 months and 8 months. Perhaps better than low-dose cytarabine, right, 4 to 5 months, but certainly not the majority of people even living beyond 12 months.

What’s changed? This shows, since 2017, the many new approvals in AML. We have targeted therapeutics. We have gemtuzumab. We have liposomal daunorubicin and cytarabine, and the stars are the two that I’ll be talking just a little bit about in the next just few minutes. Left is glasdegib and venetoclax.

The first study of glasdegib was a randomized study. It took people who were older and unfit with those same characteristics along the bottom left that we talked about in the previous slide — high-risk MDS was also allowed, and they received low-dose cytarabine with or without glasdegib in a 2:1 randomization. This is an oral medicine. It’s given daily continuously. And the endpoint was overall survival, and overall survival was improved by about double, right? Low-dose cytarabine 5 months, as expected. Glasdegib/low-dose cytarabine double that, with a CR/CRi rate of 20% compared to 2% in low-dose cytarabine alone as in this publication. And I think it’ll be really interesting a little bit later on to get some of the opinions of the group in terms of who is using glasdegib and in what populations. Because the uptake of glasdegib I think has not been particularly well utilized.

Venetoclax, on the other hand, has really taken kind of the US older unfit population by storm. And this is just a basic mechanism of action, which I think is useful, because the antiapoptotic mechanism is a bit unusual, and so cancer cells really don’t want to die, right, so they upregulate these antiapoptotic proteins to prevent cells from dying. And so you go in with venetoclax, it binds and it releases all of these proapoptotic proteins, these prodeath proteins that had been kind of sequestered, and it allows the cells to rapidly undergo cell death like they were supposed to. And so in sensitive cells, this can happen very quickly.

Two studies have really changed the standard of care. This has led to the approval — along the top shows the schema for the hypomethylating agents, either azacitidine or decitabine, with venetoclax. There’s this daily ramp-up to prevent tumor lysis. And along the bottom is low-dose cytarabine with venetoclax, again with that daily ramp-up. They both end at different doses, so venetoclax with the hypomethylating agent we give at 400 mg — 600 with low-dose cytarabine. And again, the same kind of high-risk criteria was utilized in these clinical trials.

Shown on the left is with low-dose cytarabine. Median survival 5 months, CR/CRi of about 11% compared to what we’ve seen with the low-dose cytarabine with ven study that was published by Andrew Wei earlier this year. The median overall survival is 10 months, CR/CRi rate of over 50%, so really quite different than our historical expectations. But again, remember, this is not randomized, and so that randomized study confirming this benefit is still ongoing.

The historical comparison with azacitidine is on the left, and on the right now is what was seen with the azacitidine/venetoclax study with the CR/CRi rate over 70% and a median overall survival finally kind of surpassing that 12-month threshold that has been really hard for our field to ever surpass, a median overall survival of 16.9 months and a 1-year overall survival, again, above 50%.

What’s also notable is kind of the response rates really seem to be independent of certain high-risk factors, so looking at patients with high-risk or intermediate-risk cytogenetics, secondary or de novo AML as well as certain different genetic subtypes. All patients seemed to have a fairly good response rate, at least initially, to venetoclax-based chemotherapy. And so this is important as we’re thinking about our high-risk older AML patients. Now, that doesn’t always mean that our patients are going to have durable responses though, and I know we’ll talk about this a little bit later.

It’s a little bit hard to see, but along the top are those patients with NPM1-mutant leukemia, IDH1 and IDH2. Also, these patients are particularly sensitive to venetoclax and seemed to have really durable responses. And all along the bottom you can see p53 patients, complex cytogenetics. While they respond well, unfortunately those responses are not always particularly durable. And it may not be the curative treatment that we were hoping it may be for those particularly challenging populations.

Just 1 quick slide, some upcoming data, because a lot of people are really wondering, what do we do in patients who we’re trying to get to transplant? There’s no published data yet about transplant after hypomethylating agent or with venetoclax, and can we use this as a bridge to transplant in people who we think could be an appropriate transplant candidate? And this is just a little bit of some basic expectations and data from our institution showing that there’s really a quite impressive ability to take this patient in a response with this regimen and take them to transplant and have them do well. In conclusion, I think it is safe to say that the treatment has really evolved over the past few years and we now have pretty impressive treatment options to offer our older patients who are not candidates for intensive chemotherapy.

Case (Dr Marte): A woman in her early 80s who presented 7 years ago with t(8;21) AML is in complete remission 7 years after treatment with 7+3 chemotherapy

DR LOVE: And now we’re going to get into the granularity of how this plays out in practice. And Idelfia, I want to ask you about your patient in a second. But first, I just want to ask the 3 of you, Rich, who’s the oldest patient you’ve given 7 + 3 to?

DR STONE: In the recent past, probably midseventies.

DR LOVE: Midseventies.

DR STONE: And then way past, probably up to 80 years old.

DR LOVE: Courtney? How high will go you, even in a completely fit patient?

DR DINARDO: Low seventies is 71, 72.

DR PRATZ: Prior to aza/venetoclax, I remember giving it to a 79-year-old with a lot of concern. Since this, I haven’t given it much above age 70.

DR LOVE: Hmm. Interesting.

Idelfia, I’m just kind of curious, your patient, did you see her when she first presented, or somebody else did?

DR MARTE: Yes, I did.

DR LOVE: You saw her from the beginning.

DR MARTE: Yes.

DR LOVE: Could you, before you get into her treatment, could you kind of explain to them what her situation was when she presented, just briefly?

DR MARTE: She presented with fatigue and thrombocytopenia.

DR LOVE: And she was 79.

DR MARTE: At that time, 76.

DR LOVE: Seventy-six, okay.

DR MARTE: Yes. And bone marrow showed acute myelogenous leukemia with a t8;21 translocation. And overall she was in good shape, and she has a history of breast cancer and had just completed her 5 years of anastrozole.

DR LOVE: Hmm. Had she ever gotten chemo?

DR MARTE: No, she never got chemo.

DR LOVE: Interesting.

DR MARTE: Yes.

DR LOVE: And any other comorbidities? Cardiovascular disease?

DR MARTE: No. Overall, healthy. Just hypothyroidism.

DR LOVE: Was she a proactive patient, “give me everything you can” type patient?

DR MARTE: Definitely. Yes, very proactive.

DR LOVE: Even though she was 76 at that point.

DR MARTE: Yes.

Therapeutic options for older patients with AML without targetable mutations

DR LOVE: Rich, what would you be thinking? What would you have been thinking a couple of years ago, and what would you be thinking now?

DR STONE: This a great patient to discuss.

DR DINARDO: Yes, it is. To debate on, yes.

DR STONE: All the potential modalities. Because there’s really no wrong answer here, I think.

She’s 76, so she falls within the approved indication for aza/venetoclax, which would be a reasonable approach, even though she seems to be well otherwise. Why would it be a reasonable approach? Because I think in general, the venetoclax helps the chemotherapy work most optimally when the chemo is working a little bit anyway. It’s a chemo-responsive patient. That’s how we’d look at that patient. The patient has a history of — I don’t know, did they get radiation for the breast cancer or just the hormonal therapy?

DR MARTE: She did. Partial mastectomy.

DR LOVE: Radiation therapy?

DR MARTE: And radiation.

DR DINARDO: Anthracycline also?

DR LOVE: Would radiation therapy be like a predisposing for AML?

DR STONE: Yes. Yes.

DR LOVE: Really?

DR STONE: It is. Sure.

DR LOVE: Wow!

DR STONE: It can be. Technically, that’s tumor-related AML. The patient could get CPX-351, which would be probably a reasonable drug to give in this patient because it’s — and again, it works well when the patient’s responsive to chemo. You could give 3 + 7. I, frankly, would either give CPX or aza/ven to this patient.

DR LOVE: And what would you have done 2 years ago?

DR STONE: Before aza/ven was out?

DR LOVE: And CPX.

DR STONE: Three plus seven.

DR LOVE: You would have given her 3 + 7 even though she was 76?

DR STONE: Yes. Because she had 8;21 translocation. It’s very rare in this age group, but it’s a chemo-responsive disease. And unless she said, “I don’t want to be in the hospital for a month,” then I’m going to give her azacitidine. But, I mean, assuming she was willing to try get into a remission with 3 + 7 still is highly worthwhile. And maybe even if she was quiet for that, I would have considered a stem cell transplant. Because even though the 8;21, the inversion 16s who are older have a better response to chemo than their colleagues who are 76 and don’t have those abnormalities. They still are going to relapse, or most of them will. That’s a patient who could be cured with chemo plus a transplant, I suppose, if they were very healthy and very, very motivated.

DR LOVE: Courtney, agree or disagree?

DR DINARDO: I agree with the fact that there are many treatment options to consider.

DR LOVE: What do you think you would have done a couple of years ago, other than get her on a trial? Outside a trial.

DR DINARDO: Outside of a clinical trial, patients with 8;21 and the other core-binding factor leukemia patients are really chemotherapy sensitive. Prior to the era of venetoclax-based therapies, we would have given her probably a 7 + 3-type regimen. The other thing that we haven’t talked about yet that is important to think about in core-binding factor patients is the addition of gemtuzumab ozogamicin, right?

DR LOVE: Just out of curiosity, if she’d been 85 two years ago?

DR DINARDO: I think it would be hard for anyone to say that intensive chemotherapy is a great idea for someone in their 80s. A hypomethylating agent-based regimen a couple of years ago would have been the thing to do.

DR LOVE: Would you have presented the option of hospice? Right up front?

DR DINARDO: It is always something that I present in my initial meeting with a patient, yes. But in someone who has such as responsive leukemia, I wouldn’t.

DR LOVE: Just out of curiosity, because I was kind of curious too — when I interviewed Dan Pollyea, he showed me these numbers of supposedly people not getting treated at all. And I didn’t know if that was some function of the way they gathered data. I mean, you all could tell us 2, 3 years ago. Again, if this patient had been 85, no core binding, nothing, would you have treated her?

DR PRATZ: Probably not. Probably have a real conversation about hospice at that point. And, in fact, a lot of these 85-year-olds don’t even get a bone marrow or genetic workups when they’re found to have acute leukemia. They’re told they have a terminal illness, and they’re told to make their plans. That was all before some of the lower-intensity effective therapies, though.

DR LOVE: Yes, that’s why kind of when I started to hear this whole story I was trying to think of another situation in oncology where you went from even thinking about hospice to a therapy that really is helpful to people.

Anyhow, let’s hear about how long ago this was. This was what, 7 years ago?

DR MARTE: Seven years ago, and she’s in complete remission.

DR LOVE: Can you talk about her treatment? What treatment she got?

DR MARTE: Oh. She got 7 + 3 plus 2 doses of consolidation with high-dose ara-C.

DR LOVE: And how did she do?

DR MARTE: She did very well. She tolerated it well. And she’s still doing perfect.

DR LOVE: She’s just cruising along.

DR MARTE: She is.

DR LOVE: Rich, any comments?

DR STONE: No, I think that’s great. And I just do think that’s the way we would have probably approached her. The only issue is, as I mentioned, is the transplant. We probably would, in a patient like this, I probably would help my decision process by getting an MRD determination after 1 or 2 cycles of chemo. And if it was negative, we probably would have gone on with the Ara-C. If it was positive, I would at least discuss a stem cell transplant even though the results with stem cell transplant in patients who have MRD-positive disease aren’t great. It’s still probably better than more chemotherapy.

DR LOVE: Anyhow, I just wanted to kind of throw you all off to get started. I thought we could start out with 7 + 3. I just thought it was an incredible case. And I guess just the word that in spite of all these new things, 7 + 3 works too.

DR DINARDO: There’s some people that were cured with 7 + 3.

DR LOVE: Even if you’re 76 years old, I guess.

Genetic testing for patients with AML

DR LOVE: Here are the results of the survey. And you’ll see that this is the way we’re going to present them to you today.

There were 26 investigators, including our faculty. Each investigator is represented by a block, okay? If all the blocks are there, that means they all do it. And you can see that for these particular factors, there’s a lot of people doing them. And Keith, can you kind of just run through in how you answered this question and why for each one of these factors?

DR PRATZ: Yes. The most common cytogenetics done on most everybody with acute leukemia-specific mutation testing was the way in each we looked for mutations up until a few years ago when the multigene panels became more commonly used. In our practice we still will do rapid testing for FLT3 to make a decision whether to add in a FLT3 inhibitor on day 8, but the rest of the molecular genetics are done on an NGS panel that takes a few weeks often to come back.

Beyond that, PCR or FISH testing for the core-binding factor leukemias are important for the issue you mentioned earlier. The addition of gemtuzumab into the 7 + 3-based treatments for core-binding factor leukemia seems to have improved the outcomes in that group of patients.

And then the last panel down there mentions FISH testing for the monosomy 5 or in 7 cases, looking specifically for meaningful criteria to use liposomal cytarabine-based treatments. And I think that’s, of the group, maybe the one that’s the least consistently used for treatment decisions, but it’s still something we do.

DR LOVE: Rich, another question we asked was mutational analysis for relapsed disease, and the panel says, almost all of them said they do that. What’s the rationale there, Rich?

DR STONE: Simply that AML is an unstable disease, and mutations present at diagnosis can disappear at relapse and vice-versa. It’s important to define what the mutational spectrum is at the time of relapse. Can I just say one more thing about the prior one?

DR LOVE: Yes, sure.

DR STONE: The issue there is speed.

DR DINARDO: Right.

DR STONE: The answer is, depending upon your institution —

DR LOVE: Incidentally, which ones do you wait for?

DR STONE: I wouldn’t. That’s the point.

You can order some of these things, but you don’t need to order the FISH panel if you go, “Oh, these we should wait for, okay. Fine.” You need a rapid determination, as Keith mentioned, about whether the patient has a core-binding factor leukemia or adverse prognosis leukemia. If your cytogeneticist can deliver that information within 48 hours, which is technically possible, you don’t need to send FISH. FISH has to be quicker, because cytogenetics labs tend to be backed up.

I would argue that before treatment decisions can be made, you should have all the data, except in people that have highly proliferative disease, because the decision about whether to use CPX and gemtuzumab and FLT3 inhibitors — you don’t need to know right away — is still very helpful to know. I think you really have to work with your pathologist locally to figure out which tests you need to get and how you can get it most rapidly.

Assessment of minimal residual disease status in patients undergoing treatment for AML; selection of patients who are eligible for intensive chemotherapy

DR LOVE: Courtney, we’re hearing about the potential role of MRD in a lot of diseases, including CLL. And it looked like when we asked about this in the survey that there was mixed results. And a lot of times these kinds of surveys, the most interesting thing is when you see mixed results.

And so it looks like that maybe not everybody is on exactly the same page about MRD. Where are you, Courtney? And where do you think the field is right now?

DR DINARDO: I think the field is definitely evolving. I think more and more people are realizing the importance of MRD as kind of a prognostic variable, right? If you are MRD-negative, that’s great and we feel better, and we know our patients will do better. If the MRD is positive, then we are more concerned about relapse.

But the challenge has been that there’s not really any data yet that tells us what to do in that situation. And so I think that’s why we see such variable results is, more and more people, at least in the academic setting, that have the ability to do MRD testing are doing it, but how to actually act on those results is still in flux.

DR LOVE: Another issue is the issue of whether or not a patient fit for intensive chemotherapy, not so much necessarily by their status or age but by their clinical profile, Keith. And this is the thing that I was not aware of. I mean, I’ve done a bunch of interviews. I never thought to ask anybody this, which is, are there younger patients with AML who typically, based on their functional status, et cetera, would be candidates for 7 + 3 who are not candidates for 7 + 3 because of adverse prognosis even if you give them 7 + 3? And 10 of the 25 people said yes to TP53. Eight said yes to complex karyotype. What about this phenomenon, Courtney? Again, I wasn’t aware of it at all.

DR DINARDO: I think this is where the field is really changing, and we’re struggling a bit. And I think you ask a bunch of different people, even in this room, what they would do, and I think the answers you get will be different. But my view is that people who are maybe physically fit, right — they have a reasonable performance status to tolerate intensive chemotherapy — doesn’t mean that you should always give intensive chemotherapy if you have a pretest probably that it’s not going to work and there’s something that could work as well or better that is better tolerated.

DR LOVE: We’ll see that actually played out when we start asking specific questions. But Keith, we also asked the question, was a history of R-CHOP, and most people thought it wasn’t a contraindication. Any comments, Keith?

DR PRATZ: Yes. A lot of our acute myeloid leukemia patients have had prior chemotherapy exposures. Generally, secondary leukemias coming from prior chemotherapy/radiation, a little bit more difficult treat with standard 7 + 3-based treatments. And in the past there really wasn’t an alternative that was effective to achieve remissions.

Now we have the data that Courtney presented earlier showing that secondary leukemias have remission rates on par with the de novo acute leukemias with venetoclax-based treatments. And, as such, we have an alternative, a way of getting remission. And I think that’s what’s pushed some of the folks here to answer in the way they did.

DR LOVE: How about these other factors, medical factors? How would you feel about 7 + 3 in patients with these kinds of histories, Keith?

DR PRATZ: A lot of these are other adverse markers that would prevent us from curative therapy down the road. And I make an assessment early on in seeing a patient whether there’s a possibility of doing a transplant to cure them, because most of the adults with acute myeloid leukemia need something beyond achievement of a remission for cure. All the listed issues there would prevent consideration of transplant to a large extent. And I think, as such, would push us in the direction of a less intense induction approach.

Choice of therapy for a patient with AML and multiple comorbidities

DR LOVE: Rich, maybe you can run through this pretty common scenario? I would say an old or a young patient or whatever, 68, whatever you want to call that, a little bit of medical history behind this patient. The investigators seem generally motivated to use venetoclax plus an HMA, as you can see, but there’s a substantial number who, as we were talking about with this first case, would go for 7 + 3 or even CPX. Any comments on this scenario, Rich?

DR STONE: Sure. As Courtney mentioned in her initial remarks, the biological characteristics of the leukemic obviously are here with this CAD and the hypertension and the performance status of 2, which is not ideal. You’re also seeing the patient had anemia for 2 years with unclear etiology, which probably meant they had underlying MDS and thus not particularly chemo responsive. That’s why the preponderance of the respondents answered aza and venetoclax.

The only reason I would change my vote from the top one is if the patient had a highly chemo-responsive leukemia. Even then, I’d probably scratch my head a couple of times, and it would really depend on the conversation with the patient of what I really thought she had. I’d probably do echocardiography and maybe even a stress test to decide what’s going on. But aza/ven is totally reasonable for this patient. Probably, as a matter of fact, even if they’re very chemo responsive, aza/ven is probably good therapy.

DR LOVE: I also want to get into the issue a little bit of managing people who are getting these kinds of therapies, and specifically here venetoclax with an HMA. Courtney, can you talk about — we asked here about the issue of when you do the first bone marrow, but also your experience with cytopenias in patients with — because this seems to be one of the major issues about, like, what to do.

DR DINARDO: Yes. I think this is a really key management issue, because in our older patients with AML, or with MDS, for that matter, they get a hypomethylating agent. We’re used to seeing low counts, right? We’re used to seeing low counts throughout 3 to 4 cycles, because that’s the average time it takes to respond to these agents. And so their counts are low because they have disease. And so what has really changed is the fact that responses to venetoclax and aza or DAC or low-dose ara-C happen on average within 1 cycle. At the end of that first cycle, if your patient still has cytopenias, it might be because they still have disease, but more likely it’s because they’re in a remission and their marrow was still empty and it hasn’t recovered yet.

The end of cycle 1 marrow is critically important to figure out what the cytopenias are coming from. Because if they’re in a remission — so they’re in, like, a morphologic leukemia-free state — you have to hold the cycle for a week or so, allow counts to recover so that you’re not compounding additional therapy on an already myelo-suppressed marrow.

DR LOVE: What about cytopenias from the venetoclax itself, or from the —

DR DINARDO: Right. Yes. That’s essentially why they’re still having cytopenias if their disease is in a remission. That’s why the end of cycle 1 marrow is really important. And so what is not yet present in a lot of the peer-reviewed literature is the fact that even though it’s recommended to give venetoclax continuously for 28 days forever and ever, very few people are on that for very long, because they have these cytopenias related to the combination. And so what you frequently end up doing is shortening the venetoclax to 21 days, or sometimes even shorter, for subsequent cycles.

Prophylaxis for patients receiving venetoclax in combination with azacitidine

DR LOVE: Another issue that kind of started to come up as I was just talking to people is the issue of prophylactic strategies that would be considered in this situation. But in particular, what I heard about was the question of whether that would affect dosing of venetoclax. Can you kind of go through that, Keith?

DR PRATZ: Sure. The CYP3A enzyme is inhibited by many of the antibiotics we use. Quinolones and, to a large extent, antifungal will prevent metabolism of venetoclax and require a dose reduction according to the package insert of venetoclax down to 50% dose reduction or 75% dose reduction, depending on whether you’re on a quinolone or antifungal therapy.

Part of the debate in the field right now — because this is a new paradigm — is, do we need all the prophylaxis we’ve given historically for 7 + 3-based chemotherapy? And I will say that I think that there’s a reflection in this survey that it’s not clear that you do need it for everyone. For sure, allopurinol for the first several days to prevent tumor lysis is critically important. Acyclovir is something I do for all my patients. Quinolones with severe neutropenia is commonly used. Antifungal therapy wasn’t included in the front-line study in the form of triazole therapy, although many of those folks got some other form of antifungal therapy.

Infections with this treatment are real. Can really impact ability to stay out of the hospital. These drugs I do think are important.

DR LOVE: If you’re using all that, what’s your starting dose?

DR PRATZ: We dose escalate up to 100 mg — if you’re using triazole antifungals — of venetoclax. If you’re not, then I would still give the patient 400 mg.

Optimal duration of venetoclax therapy

DR LOVE: Rich, this would seem to be a simple question that’s been asked by a lot of people, which is, how long do you keep the venetoclax going if the patient’s doing great? The faculty says indefinitely. Do you agree?

DR STONE: Yes, but that’s only because we don’t know any better. I’ll definitely second Courtney’s comments about the fact that we may be overdosing people with venetoclax.

If you think about how the drug works, it helps — and when there’s cytotoxic stress applied in the form of chemotherapy, that’s when the Bcl-2 levels go up. It makes sense to use it with the chemo to potentiate the effects of the chemo. I’m less certain about using it as a single agent after the chemo is done. In fact, single-agent responses were pretty low, at least in relapsed/refractory patients, number 1.

Number 2, this question, how long do you give it, the question becomes, if you’ve got — and I get this question a lot — if you’re lucky enough to have a patient who’s been on this combo for a few months and you do MRD and they have very deep remission, it doesn’t mean they’re cured, but can you give them a treatment break? I think all of our patients want a treatment break, right? They hate this stuff.

DR LOVE: They hate it? Really?

DR STONE: They hate it. They hate the combination.

DR LOVE: Venetoclax?

DR DINARDO: They hate coming to the clinic.

DR LOVE: Okay, coming to the clinic.

DR STONE: They don’t mind the drug.

DR LOVE: That’s fine. I’m talking about the venetoclax.

DR STONE: No, they’ll take the pill. They’re happy with the pill. But the idea of the indefinite therapy, you’ve got to give people some hope. Really. I mean, how long do you take this? For the rest of your life. How long is that going to be? I hope it’s a long time.

DR LOVE: We heard this same thing with the ibrutinib in CLL, and then people were going, hey, they’re already taking 10 medicines. It’s just 1 other medicine.

DR STONE: That’s not true. I’ve talked to patients with CLL, which I don't take care of a lot of, who say they’d rather get BR rather than ibrutinib. They have to take it for the rest of their lives.

DR LOVE: And, of course, in CLL the exact strategy you just talked about — and your colleague Bill Wierda, he was actually the one who was here, has piloted using MRD and maybe stopping therapy. That, like you say, I guess it’s kind of a —

DR STONE: I think we’re stuck with indefinite right now.

DR LOVE: Right.

Prevention and management of tumor lysis syndrome associated with venetoclax

DR LOVE: This is another one, Keith. We ask this a lot. We’ve been asking it for the last year, because I think that everybody in the trials was admitted to the hospital.

DR PRATZ: That’s correct. And I would be in the disagree category, and I don’t believe everyone with acute myeloid leukemia, given venetoclax-based treatments, needs to be hospitalized. But I do think there are some red flags you can pick up with labs prior to therapy that may push me to put someone in the hospital: creatinines that are abnormal, high uric acid, high white blood cell count, high LDH. I look at 4 markers for folks who are going to have tumor lysis syndrome or problems with it, and I will hospitalize those patients.

DR LOVE: And it’s interesting. I got an email from a doc in practice who sent me this case, and I showed it to the faculty ahead of time, and it looked like — I mean, I don’t know how often you see tumor lysis, but he had a patient, 84 years old on aza/venetoclax and admitted to the hospital I think for the second cycle and the potassium went up to 5.4, phosphorus was 5.8, and he sent us all the labs, et cetera, and asked us, “What do you do?” And Rich, can you comment on the question you had, which I kind of didn’t even think about, makes complete sense.

DR STONE: Sure. And Keith just alluded to it. What’s the prior probability of tumor lysis syndrome here, and based here if the white count was high, if they come in with a high LDH, this patient had a cycle of azacitidine first before the aza/ven cycle. One wonders if he was cytoreduced with the aza. The patient has diastolic dysfunction, may have impaired number of nephrons in his kidney. I’m not really sure if it’s renal failure or TLS, but I’d certainly be cautious. Would I stop the venetoclax? If I really was convinced it was tumor lysis syndrome and the white count was going down precipitously and the LDH was going up, yes, I might hold it. Otherwise, I would keep giving it and try to manage the renal failure.

DR LOVE: Any comments, Courtney? Have you seen clinical tumor lysis, like dialysis and all that? I think I heard about 1 case maybe?

DR DINARDO: Yes. In our experience, we have had 3 people with pretty significant tumor lysis. One required dialysis. And so when you look back at those patients, that was kind of after it’s been approved, and we’re becoming much more confident in the use of these agents, and we’re not admitting people to the hospital as much. We’re not caring as much about making sure patients are debulked prior to starting. And so I think that has kind of swung our at least institutional pendulum back to being a little bit more cautious.

And so in patients who have a high white cell count or a high leukemia burden — circulating or in the bone marrow — or have particularly sensitive leukemias, that one slide I showed with MPN1 and also IDH-mutant patients, those patients are really sensitive to venetoclax in combination with therapy. And so if you have someone with any of those characteristics, you want to be on top of the TLS management, including checking labs 6 to 8 hours after you give the first dose, checking it again the next morning, whether or not they need to be hospitalized, probably not, but just being aware. And if you see changes like that, you need to push the next dose. Wait a day, let them calm down and then start it again.

DR LOVE: This is kind of interesting. We had somebody email us and say, “I have a patient who said they had decreased visual acuity.” I mean, it’s so hard to figure out whether stuff is related to treatment or not, so I just thought I’d put it in there. And, actually, when I first heard about it, I asked several faculty on the program and they had never heard of it, but it turns out 6 people did. Keith, do you think visual acuity is related to venetoclax, like, it gets better if you stop it, or…?

DR PRATZ: I don’t know the answer to that. We have had the opportunity to see if folks have trouble with visual acuity on my study, wasn’t clear whether it was related or related to retinal hemorrhage or macular edema. But I have seen it on venetoclax-based treatments.

Selection of therapy for a patient with AML with complex karyotype and a TP53 mutation

DR LOVE: This begins the section that really surprised me, and what I’m really curious about is whether it surprised you or I’m just the only one in the room who doesn’t know about this stuff.

Rich, here’s a case of a younger patient, 65 years old, you would think maybe would be eligible for 7 + 3 or fit, unless you see some reason based on what we put in there that they wouldn’t be, but with a complex karyotype and p53 mutation, both of which have pretty adverse factors. And the majority of the faculty says HMA/venetoclax.

DR STONE: I think the p53 mutation is key here. Without the p53 function, the cells don’t die with chemotherapy, which CPX-351 is. Technically, by the FDA label, this patient is only eligible for CPX-351. He’s not eligible for aza/ven or decitabine/ven, because he doesn’t have comorbid disease that we — let’s say he doesn’t. Yet almost everybody would give this patient —

DR LOVE: Why CPX, though?

DR STONE: Because he has a complex karyotype, so he has MDS related abnormalities, so he’s eligible for CPX. And the question is, if you give a daunorubicin/cytarabine/chemo for this type of patient, I would give CPX-351, because it’s probably not going to be any worse than 3 + 7 in this situation.

I would still give this patient HMA plus venetoclax, because the response to chemo is poor now. Do we really know that that’s a good idea? Of course not. The US Intergroup is hopefully going to be doing a trial in younger adults, under age 60, with adverse risk cytogenetics like this, and one of the arms will be aza/ven, and one of the arms will be CPX and one of the arms will be 7 + 3. Someday we’ll know. Right now we don’t, but it’s certainly the prejudice of us investigators that it would be HMA/ven.

DR LOVE: Courtney, can you comment a little bit more again on this issue of the younger patient who’s not going to get 7 + 3 and would be considered for something else, just based on their workup?

DR DINARDO: I mean, just echoing what Rich said, this patient with a complex cytogenetics and p53 mutation has, like, a, I don’t know, 30% to 40% chance maybe of having a remission with a 7 + 3-based therapy. That’s not great, right? If you can do the same or better with a well-tolerated outpatient azacitidine/venetoclax regimen, then that would seem to be a reasonable thing to do in the absence of actual randomized data telling us that one is better than the other.

And then again, to bring back that conversation of this guy isn’t unfit for a transplant, right? He has high-risk, chemotherapy-insensitive disease, but that doesn’t mean we couldn’t get him to a transplant if we were able to get him into a nice remission. What’s the best way of doing that and then consolidating him with a transplant? In my mind, again, with the limited evidence that we have, I would give an HMA/ven combination, and then if he has a nice response, pretty soon translate that into a consolidative transplant.

DR STONE: I bet you’d give like I would, decitabine plus venetoclax in this patient.

DR DINARDO: I would. Yes, that’s true. With even less data to drive that one.

Case (Dr Dandamudi): A woman in her early 80s with AML attains an excellent response to venetoclax and azacitidine

DR LOVE: What I really want to know, and I think 14 of you have used venetoclax combinations, and I’m curious about what your experience is. What I really want to understand is, for example, Dr Dandamudi, I see you had a patient, an 80-year-old woman. I guess I’m curious, because I’ve been asking them for the last year, for those of you who have used it — I know it’s very few patients — but can you see a difference? Is the clinical course different at this point if you’ve only had 1 or 2 patients compared to the old days, 2 years ago, whatever, when you used HMA alone? Uday, any thoughts about that? Do you want to talk about this patient?

DR DANDAMUDI: This is an 80-year-old patient, like, initially I started following in late 2017 with colon cancer, Stage II, and on surveillance. Like, labs showed neutropenia, and we did the bone marrow at the time, because I could not explain her neutropenia and, like, blast counts were about 60%. I started her on 5-aza/venetoclax. The patient did very well.

She started developing cytopenias. That’s when, like, I was thinking of stopping the venetoclax or doing a bone marrow biopsy for MRD to see if there is a need. This is coming back, or is it in-remission venetoclax causing the cytopenias?

DR LOVE: How long has she been under treatment now?

DR DANDAMUDI: It’s almost 10 months, 11 months.

DR LOVE: And what happened with the acute treatment? Did you admit her to the hospital?

DR DANDAMUDI: She did very well. Initially I started her, like, because that’s her first time with the 60% blasts, 80-year-old, I did not take a chance. I admitted her in the hospital, and I did the ramp-up dose while in the hospital.

Surprisingly, she did very well. And now started developing cytopenias. I saw her, had a discussion with the family to get a bone marrow biopsy to see whether I need to stop the venetoclax or not.

DR LOVE: Courtney, any thoughts about this patient?

DR DINARDO: Yes. Just a quick question, are you still doing continuous venetoclax?

DR DANDAMUDI: Yes.

DR LOVE: Incidentally, getting back to Rich’s question, how did she feel about taking indefinite therapy?

DR DANDAMUDI: She’s doing very good.

DR LOVE: Did she mind it?

DR DANDAMUDI: She was very apprehensive, like, was initially, before starting, but once we started venetoclax she’s tolerating it well. Her performance status is very good. She’s doing very well at this point of time.

DR DINARDO: I think it’s not so much the daily venetoclax that is challenging for patients to put their mind around, because most older folks are on a whole lot of medicines. It’s coming back to the clinic for the IV or subcutaneous injections on a monthly basis.

In this case, I think a bone marrow is certainly indicated. I wouldn’t be surprised if you see a hypocellular marrow that helps inform you to maybe shorten the venetoclax dose for subsequent cycles.

DR DANDAMUDI: Like, in addition to shortening the venetoclax, do you stop the 5-aza, or do we continue the 5-aza in this patient?

DR DINARDO: I’d continue the 5-aza. But I certainly have been known to extend the cycle lengths to, like, 5 weeks, sometimes even 6 weeks once they’re past a year on therapies, because I don’t know how much the hypomethylating agent is contributing. I think probably quite a bit. I don’t want to pull it off, but I’m not so convinced they need 4-week cycles forever and ever. I’ll start to space out the cycles, and I’ll shorten the venetoclax.

DR PRATZ: And I’ll echo that 5- and 6-week cycle lengths are very common in my patients. And then in someone who’s incredibly hypocellular in their bone marrow I’ll lower the dose of the azacitidine to 50 mg/m² or even as low as 25 mg/m² to allow better platelet recovery.

DR DINARDO: Yep.

DR STONE: I would send an MRD when you get the marrow, because that would influence me. Sometimes these patients, even before they show the extra blasts, their MRD is starting to go up, and that means that if you cut back the dose, you’re just going to relapse. You’re a little bit between a rock and hard place, but it would make me less interested in cutting back if they had incipient disease based on MRD.

DR LOVE: Any recommendations for type of MRD assay? Does it matter?

DR STONE: We don’t know that. And it’s an imperfect science, to say the least.

DR DANDAMUDI: And also, 1 more question. As far as the 5-aza, do you shorten the duration to 5 days instead of 7 days?

DR PRATZ: I have done that on occasion for convenience sake. I think we’ve only learned how to do this based on the one study, and we don’t really know, especially late in the treatments, whether we need all 7 days or all the doses we’re giving.

DR DANDAMUDI: The question is, do you prefer 7 days and increasing the, like, length of the cycle? Or do you decrease, like, 5 days and keeping the same?

DR PRATZ: I almost always lengthen the cycle duration before I start cutting the doses back.

DR STONE: I do too. I would start by decreasing — if the patient was in a good remission, I’d start by giving less venetoclax. Second, I would lengthen the cycle, and third, I would cut back on the chemo, which is probably the most important thing.

Case (Dr Choksi): A woman in her late 70s with myelodysplastic syndrome (MDS)/myeloproliferative neoplasm develops neutropenia after treatment with venetoclax and azacitidine

DR LOVE: DR CHOKSI, you have a patient also. I’m curious what happened with that patient and also if you have any questions for the faculty.

DR CHOKSI: My patient is 78 years old, whom I have known for almost 10 years. She was 68. Was referred to me for mild anemia, mild thrombocytosis and mild leukopenia. She had a bone marrow biopsy done I believe in 2010, which showed normal cytogenetics with hypocellular bone marrow. And without any treatment, I continued to observe her. At some point I had given her an option, “You can follow with your primary care and come back when there is further worsening.” She chose to follow with me every, like, 6 months. And I kept her in my office, because every visit she came in she brought at least 50 to 100 chemo caps. Like, she would work in the church with several other women. They sat down once every week, made, like, hundreds of chemo caps for my patients. She would come in with a big bag of those crocheted — the chemo caps — and I said, “Perfect! We love it.” She has done that for 10 years, and she’s still doing it despite getting the treatment.

In 2014 she had a second bone marrow biopsy done. She had a worsening of thrombocytosis with worsening of mild leukopenia and anemia. At that point she did have an MPR mutation that we found, and we continued to observe her until in December 2018, she had a third bone marrow biopsy done, which showed 12.5% blasts in the bone marrow. No cytogenetic changes. The FLT3-negative, IDH-negative.

At that point she also had the second opinion at Moffitt Cancer Center, and she was actively following in the leukemia department over there. Thanks to that happening, that’s how we decided to start her on a treatment. We actually started on a venetoclax treatment on Christmas Day last year, December 2018, with the azacitidine. That was the regimen we started, and we started as an outpatient treatment. She tolerated it well. When we started the treatment she had her platelet counts more than a million, almost 1.3 million. Again, she has this MDS/myeloproliferative neoplasm for which she was being followed up until now.

And she tolerated the treatments very well over a period of the last 10 months. She has lost more than 20 pounds, but she had only 1 time admission in the hospital with the febrile neutropenia. This is at that point which was treated in the hospital as well.

DR LOVE: How did she do in the beginning when you first treated her? You put her in the hospital?

DR CHOKSI: She was treated outpatient. Very close monitoring of the blood counts as an outpatient in the office.

DR LOVE: And what happened when she had the neutropenic infection? When was it, and what happened?

DR CHOKSI: That was about 5, 6 months ago, while she was on active treatment with the full dose of azacitidine and venetoclax as per the guidelines. She just had a follow-up, another bone marrow biopsy done, like, more than month ago, which shows only 2% blasts with no other cytogenetic changes. And again, as I mentioned, she is actively following at the Moffitt Cancer Center as well.

At this point she’s on venetoclax 200 mg daily for 2 weeks on/2 weeks off, and azacitidine from 7 days we cut down to 5 days. But she’s still getting it every 4 months. During the period of the 10 months her major problem is neutropenia, ongoing neutropenia, and that’s why she had to have 3 bone marrows — to see whether she had response to the leukemia or whether it’s treatment related.

DR DINARDO: Speaking specifically about the neutropenia, so there are some patients that even despite venetoclax reductions and modifications like we talked about with the last case, there are some patients that just have kind of persistent venetoclax-related neutropenia. The other kind of pearl that I’ve become much comfortable with is using GCSF. I think that was something that I think the world of myeloid malignancies, you just never wanted to give GCSF, because you were concerned about promoting a leukemic clone. And for whatever reason, patients on venetoclax seem to be particularly GCSF responsive. And I feel much more comfortable doing that now than I did 4 years ago when I first started. There are some patients that kind of 1 or 2 doses of GCSF even after the end of kind of 1 cycle will really help to keep that count up.

DR STONE: I have a question. What did you tell her the diagnosis was, and what’s the treatment goal?

DR CHOKSI:

Of course quality of life. She’s still able to go to the church every weekend, and she’s still making her chemo caps and bringing it to the office.

DR STONE: How old is she now?

DR CHOKSI: She’s 78 now.

DR STONE: Yes. You’re going to keep her on this indefinitely?

DR CHOKSI:

That was my actually next question: What was your suggestion? Right now she’s on venetoclax 200 mg, 2 weeks on/2 weeks off.

DR STONE: Is she on azole? Is that why she’s on a dose reduction?

DR CHOKSI: She’s on for 5 days instead of 7 days. She’s on an antifungal.

DR STONE: Is she on dose-reduced venetoclax because you’re concerned about cytopenias?

DR CHOKSI: Because of ongoing cytopenias.

DR STONE: Okay. I’m not sure we know that there’s a dose response between the venetoclax and the cytopenias, but —

DR LOVE: Would you go back up?

DR STONE: Yes.

DR CHOKSI: And the venetoclax?

DR LOVE: And could you answer your own question? I can only imagine making rounds with you, incidentally, but can you —

DR STONE: Would I make you cry?

DR LOVE: Maybe! But I am curious — what’s your diagnosis?

DR STONE: Secondary MDS. She had 18% blasts, and she had a myeloproliferative disorder —

DR CHOKSI: Slash MDS. Yes, she has secondary MDS.

DR STONE: I guess MDS. Or high-risk myeloproliferative disorder, for which there is no data for aza/ven yet, although it’s probably useful, as you’ve pointed out here.

I think this is just the reality of that this patient would not be able to go on any more trials. But certainly when we’re faced with a person whose myeloproliferative disorder is going bad, even somebody with MPL who should do pretty well, we’re often faced with doing something to help the patient. Did she have cytopenias when she had the 18% blasts?

DR CHOKSI: She had a thrombocytosis with mild leukopenias, yes. Neutropenia and anemia.

DR STONE: She needed to have something.

DR CHOKSI: Yes.

DR STONE: That was reasonable. Yes.

DR DINARDO: It’s a particularly interesting patient, because at least preclinically, right, the laboratory evidence suggests that patients with myeloproliferative diseases, MPNs, aren’t going to respond as well to venetoclax. Because as opposed to Bcl-2, MPNs are more BCL-XL driven, which is kind of something that venetoclax doesn’t hit. And so they weren’t allowed on the original trials. And so it’s an interesting case, because not always what we see in the preclinical is what we see in the clinic.

DR STONE: Although there is navitoclax plus ruxolitinib for MPNs.

DR DINARDO: Navitoclax being a Bcl2-xL inhibitor.

DR LOVE: Hold on. Venetoclax and ruxolitinib?

DR STONE: No. Navitoclax.

DR LOVE: Navitoclax and ruxolitinib.

DR STONE: That was a drug that they were going to dump, because it has the side effect of thrombocytopenia, but as Courtney pointed out, it’s a Bcl-x inhibitor. The cells have lots of different ways to prevent themselves from dying in response to chemotherapy or cytotoxic cell stress. Bcl-xL is one of the other moieties beside Bcl-2 that prevent cell death. And this drug navitoclax hits Bcl-x. In clinical situations, again, this is pie-in-the-sky stuff, but in clinical situations where Bcl-x is important, like the myeloproliferative disorders, it might be a useful agent.

Case (Dr Hussein): A man in his early 80s develops persistent neutropenia after receiving azacitidine for MDS, which resolves after treatment with pembrolizumab for metastatic melanoma

DR LOVE: I want to give you all a chance to make any comments, any questions about your cases. I’m particularly interested in what you’re seeing clinically in these patients.

DR HUSSEIN: I have a question, and it’s not a case I presented, but I find it an interesting case. I had a patient who didn’t have leukemia, had MDS, and I treated him with 5-aza, and, actually, he did very well. But he had this persistent leukopenia or neutropenia. No venetoclax. But asymptomatic, He’s, like, 80 years old. He also was diagnosed with melanoma, so he had resection. And because of his age, I told him, you have made MDS. What was going to happen to the melanoma? I didn’t treat him with adjuvant for melanoma. But then he had a lung lesion a few months later, and we biopsied it. It ended up to be metastatic melanoma. I got concerned. And I told him, “Your MDS is fine now. Let’s treat your melanoma.”

I started him on immune therapy with pembrolizumab. His neutropenia resolved. And his CBC went totally back to normal. And his melanoma is in remission.

DR STONE: Yes. Dr Garcia-Manero at Courtney’s institution has done a lot of work with checkpoint inhibitors in MDS, and there’s a signal. That’s a fascinating case. And I’m sure Guillermo would be very interested to hear about it.

DR DINARDO: Yes, it sounds like a good case report.

DR HUSSEIN: I mean, he feels great. That’s the other thing. He’s totally asymptomatic.

DR STONE: That’s a different topic, but it’s a great case. And I would phone up Dr Garcia-Manero —

DR HUSSEIN: Maybe I should call.

DR STONE: — he’ll be happy to hear that.

Choice of hypomethylating agent for patients with AML

DR LOVE: Any other questions or also comments about this? Zanetta?

DR LAMAR: I wonder, how do you determine which HMA to use? We always say HMA/venetoclax. And it seems like a lot of people are interested in using decitabine for TP53. How do you determine this drug use?

DR LOVE: Keith, how about you take that one?

DR PRATZ: I’m in the azacitidine camp of treatments. It’s something I’ve been comfortable with and used for many years. Although the one caveat being that TP53, if you know they have it, there’s an alternative thought that decitabine is a better HMA for that subgroup of patients. But I don’t think we’ve really have head-to-head data here. And I think they’re a tough disease to treat when they have the particular mutation, otherwise the Phase III studies using azacitidine has a little bit better count recovery, at least in the early-phase studies — meaning fewer folks with morphologic leukemia-free states and meeting remission criteria.

DR LOVE: Any other questions or comments?

DR GANDHI: I’m more decitabine camp, partly because I’ll see when people live longer, they don’t want to come for 7 days for IV therapy. And our clinics are open Monday to Friday, so Saturday/Sunday closed. You give next day Monday, Tuesday. They feel like they’re always in office kind of things. Like, also another thing for me was, like, I thought decitabine is faster onset of action. Is that true?

DR DINARDO: I mean, with venetoclax in combination, they both work well and quickly, right? The median response time is 1 cycle with either of them. It’s not so much the speed of response. And, I would say, I mean, the original clinical trial evaluated both azacitidine and decitabine with venetoclax. And, ultimately, azacitidine was chosen to move forward in the randomized Phase III, which is ongoing. I think that’s one of the major reasons for that, is because azacitidine is used outside of the US, right, so it’s just easier for all of the other kind of countries that were participating in that study to have.

I think that the data going through, it looks pretty equivalent for the 7-day aza versus the 5-day decitabine. If you’re a decitabine camp kind of guy and the patient likes the 5 days, I think that’s very reasonable. There is data on 10 days of decitabine. That’s the WashU New England paper that came out showing patients with p53 mutations had really profound p53 clearance, really deep, short-lived remissions. They didn’t last that long. And so there’s a lot of debate about the clinical relevance and importance of that. But that’s why people talk about decitabine with p53.

Case (Dr Gandhi): A man in his mid-70s with AML receives venetoclax/decitabine

DR LOVE: I did want to ask you, Dr Gandhi, you had a patient, a 76-year-old patient who got decitabine and venetoclax. What happened when you first treated this patient, this man, and what’s going on with on with him right now?

DR GANDHI: Yes. This patient had cytopenia to begin with, but his blast count was, like, 35%. It was clear-cut AML. We started on combined treatment. I told him that I would probably go with decitabine alone. He wanted a couple of weeks’ break. I said, “Fine. We’ll start later.” And that’s when venetoclax got approved. I talked him into getting venetoclax.

DR LOVE: Wow. That’s being an oncologist nowadays, right? Therapy, and there’s a new approval before you start it.

DR GANDHI: He was, like, my first patient on this. He did very well. Did not have any tumor lysis syndrome. His counts improved right away. He is doing well. Actually, he didn’t want to continue venetoclax. A couple of months ago he stopped venetoclax.

DR LOVE: Really?

DR GANDHI: He just stopped on his own. He said that that is making me very sick, doctor. I’m stopping it. That’s it.

DR LOVE: Did he notice any difference once he stopped it? No. But Rich, there’s your point again. He wouldn’t like to take therapy.

DR STONE: I mean, I think it’s usually the repetitive need for the follow-up.

DR LOVE: Having to ski into your clinic, probably.

DR STONE: Low blood counts. I’ve been wanting to go to Florida. Our patients want to come here. So we’re already here.

DR LOVE: But I’m just kind of curious, Dr Gandhi. When you look at this patient, as I guess the only one that you’ve treated, and you look at the clinical course that happened, how he tolerated therapy, et cetera, does it seem different than if you had just given him an HMA, or it could have been either way?

DR GANDHI: I had 1 other patient that I did not say, but that guy died within 2, 3 months.

DR LOVE: Oh, you didn’t include. What happened there? The AML just kept —

DR GANDHI: No, AML responded very well.

DR LOVE: He responded well.

DR GANDHI: But he had MI, and he died after. Cured of AML and died of MI.

DR LOVE: Wow! Wow.

DR GANDHI: And that was also elderly guy. So 78.

DR LOVE: You cured him, right? You die of something else. You’re cured.

DR GANDHI: Anyhow, I didn’t feel good about it, but —

DR LOVE: I’m sure.

Perspective on the use of GCSF for the management of neutropenia associated with venetoclax/azacitidine for AML

DR LOVE: Any other general comments anybody wants to — and I’m just trying to get a feel for this. To me, when I look at the numbers and I talk to them, it’s like, whoa! Is that your take, or maybe more skeptical? Zanetta, any thoughts?

DR LAMAR: I have a patient that received azacitidine and venetoclax and had neutropenia for 3 months. And I actually wasn’t aware of the GCSF data, because you would get your hand, like, chopped off if you gave GCSF in any leukemic patient. Similar to you, right now she’s getting 2 weeks of venetoclax with a dose reduction of azacitidine right now. But it’s made a lot of people in the area gun shy about what to do with these patients, because she was off therapy for 3 months. She was in and out of the hospital with neutropenic fevers.

DR LOVE: Again the cytopenias come up. We actually asked in the survey about GCSF, all 3 of you. Do you use GCSF?

DR STONE: Rarely, but I might consider it if a patient is doing well from a leukemic standpoint, has had neutropenic fever or infections. I would use it.

DR DINARDO: From some of the interactions I’ve had with other people around the country, some people still don’t like using it. Some people will use it if their patient is in a really nice remission, like MRD-negative — then they feel more comfortable. Some people, for neutropenic fevers and things, only in the setting of an infection, to improve counts quickly. And then I think Keith and I are of the group that uses it a little bit more liberally now.

DR STONE: I think the low counts with aza/ven are different than low counts with 3 + 7.

DR DINARDO: Yes.

DR LAMAR: Right. Because we repeat a marrow.

DR STONE: I mean, why do people get fevers? Neutropenia? Generally, but it’s toxicity that allows the bacteria to translocate into the blood stream when there’s no neutrophils.

I’m a little bit more willing to tolerate low blood counts in people getting aza. Now, they can still get F&N, and so you want to do something about that. I’d also be interested in how that leukemia is doing.

DR LAMAR: Oh, bone marrows were repeated, and she has no evidence of disease.

DR STONE: That’s great. She can tolerate a treatment-free interval for a while.

DR LAMAR: Yes.

DR PRATZ: I was in the same training program of losing my hand to GCSF. I think until the experience of venetoclax, we didn’t use it routinely. But I use it more to try to adhere to the 4- to 6-week window. And I do get anxious when they’re getting 8-week breaks.

It’s a use of GCSF there. And it’s a little bit different than what I think other diseases use GCSF for. I will give it the days they come in and they get their labs done and not give it every day as to try to prevent real high proliferative recoveries. That’s another pearl.

Faculty presentation — Dr Stone: Management of AML with a FLT3 mutation in older patients who are not eligible for intensive treatment

DR PRATZ: Neil asked me to talk about management of AML in older patients with a FLT3 mutation who are not eligible for intensive treatment — with all the caveats that Courtney mentioned about what that really means in terms of not eligible.

Here’s what I think we need to send on a patient right now with AML. We need to know a lot about their personal history, their family history, their cytogenetics, their molecular — what molecular? If you can get the NGS back quickly, I would send that.

There’s the FLT3, and everybody knows it’s a transmembrane tyrosine kinase. It’s mutated in about 30% AML patients. About one quarter of those with a mutation have a point mutation in the juxtamembrane region, and these quarters of those with the mutation, or about 20% overall, have a length or internal tandem duplication mutation in the juxtamembrane region just beneath the cell membrane. And both of those mutations are activating and will activate the enzyme or dimerize without regard to binding to its cognate ligand called the FLT3 ligand.

That’s the biology. We knew about inhibiting an activated kinase ABL through BCR-ABL with imatinib, et cetera. And so when FLT3 came out, people said, “Let’s inhibit that. We’re going to have great success.” It’s not that easy, because it’s a late hit in the leukemogenic hierarchy. And it does actually predict for chemo responsiveness, although obviously not for long-term chemo responsiveness, because people with FLT3 mutations, particularly the ITD subtype, tend to have a relapse rate.

Now, if you’re an older adult who is deemed to be unfit by whatever reason you’re talking, and by and large, when you have a FLT3 mutation, you’re not going to be in the adverse biology category. You might even be in the favorable biology category. A lot of these older adults with FLT3 mutations are going to have chemo-responsive disease but are really truly going to be unfit. And if you like the FDA definition, which Courtney mentioned, age greater than 75 or less than 75 with truly significant comorbid disease, there you go.

The major issue with unfit FLT3 patients is whether they should get — today they can get aza plus a FLT3 inhibitor, such as sorafenib or gilteritinib, or they can get aza plus venetoclax. Which one should they use?

Obviously, giving all 3 might be interesting, but that clinical research hasn’t been done yet. We’ll see what happens. But right now you’ve got a choice between those 2 agents if you really don’t want to give CPX or 3 + 7 to this patient or, for that matter, 3 + 7 plus midostaurin. That’s the big debate: Which would you do?

And you heard about venetoclax from Courtney. This is the data for the low-dose ara-C plus venetoclax that was published by Andrew Wei, and in there some place is the various subtypes of AML. There weren’t too many FLT3 patients here, so hard to know. We don’t usually use low-dose cytarabine in the US anymore.

And the survival curves, as Courtney showed, for the low-dose ara-C plus venetoclax don’t look as good, but it’s very important to point out that a sizable minority of the patients in Andrew Wei’s trial who got low-dose ara-C plus venetoclax had already failed an HMA when they had their MDS, before they had AML. In Courtney’s trial they weren’t allowed to get prior HMA before they had AML if they had MDS first. They could have MDS first but they could not have an HMA, right?

DR DINARDO: Right.

DR STONE: For that. This is Courtney’s study, which she showed, and she did mention that used both azacitidine plus venetoclax and decitabine plus venetoclax.

They both had pretty good outcomes. And to me, this is really the money slide of that work. This is the same study that was presented.

The CR/CRi was very high, 71% to 74%. These are bad patients. You’d never get a 71% CR rate with 3 + 7, and even in younger adults. This is really interesting. And about half the CR/CRis are actually CRs. I think that blue color there. That’s pretty impressive. This is impressive stuff, which is beginning to tip my hand as to my answer for the FLT3 patients. I would have a strong predilection now to give them ven/aza, but of course we’ll show some data for aza plus FLT3 inhibitors.

The CR rate is pretty rapid. And Courtney showed this. There’s not much data to answer this question.

The blue is aza plus ven, if you look to the second from the right. The blue is the aza plus ven in the FLT3 patients, 73% response rate, but only 11 patients. And then only 3 patients who got decitabine and venetoclax who happened to have a FLT3 mutation. What can we say about that? Nothing.

The survival Courtney showed, it’s very impressive. And as I’ve said in many venues, I said that if the aza versus aza plus venetoclax trial is negative, we’ll all look like a bunch of stupid people.

Here we have the FLT3 inhibitors. And these little red things are the dendrograms, basically midostaurin, which is approved for younger adults or any of the fit adults with a FLT3 mutation to begin with. Three plus seven is nonspecific. The second generation FLT3 inhibitors — of which there is 1 approved, gilteritinib, and a few others that are out there, crenolanib and quizartinib — are more specific. Does that mean they’re better? Maybe. We don’t know that.

What data do we have if we don’t want to use aza/ven in our FLT3 older adult who’s not fit for chemotherapy? We don’t have a lot of data. We have this data from Dr Ravandi from, now, I don’t know, a bunch of years ago. This was for both people who were deemed to be unfit and relapsed, but the response rate was pretty good, at least for sorafenib and azacitidine. You could use that. Sorafenib is not the easiest drug to take.

The data from another one of Courtney’s colleagues that was presented at ASH with quizartinib, which is a much more specific FLT3 inhibitor — and that’s the one that only works in the ITD patients — and so specifically it doesn’t hit the D835Y patients. And the response rates for either quizartinib plus aza or quizartinib plus low-dose ara-C were of similar magnitude to what we saw with the aza/ven. If this drug was around, you might use that.

I didn’t show the gilteritinib plus aza data, but I’m going to show the gilteritinib alone data. I’m sure Keith would agree, since he’s now the boss of one of the guys who did all the work with this, Dr Perl, and many others did, too. Gilteritinib is a specific FLT3 inhibitor. It inhibits both the D835Y and the ITD in the early Phase I trial that had a lot of activity.

And the big news was the Phase III randomized study that got the drug approved. It was presented by Sasha Perl, his colleague at Penn, but was at AACR and EHA.

It was a very interesting trial. Again, now we’re talking about relapsed/refractory patients, but just to show you that it’s a very active agent, 2:1 randomization, dealer’s choice chemo. Could be low-dose ara-C, could be MEK or FLAG-IDA or something big, which is a pill, once-a-day pill versus chemo.

And the pill won. Again, it didn’t cure people, but these are people with relapsed/refractory AML. To me this is extremely impressive and encouraging data for the use of gilteritinib. What I’m trying to tell you is that maybe gilteritinib plus azacitidine might be an interesting approach.

Therapeutic approach for elderly patients with FLT3-ITD AML and high allelic burden

DR STONE: Let’s go through some of the questions. And Courtney, here’s an interesting one.

DR LOVE: A 76-year-old woman, mildly symptomatic AML, normal karyotype, white count 20,000, 50% blasts. You can see the rest. FLT3 ITD mutation is detected with allele burden of 0.7. First of all, Courtney, what is the significance of the allelic burden?

DR DINARDO: The higher the allelic burden, the more unfavorable the outcome, at least based on some retrospective data that has been presented.

DR LOVE: More sensitivity also to treatment?

DR DINARDO: I don’t know about that.

DR STONE: No, I think what we can say about high allelic burden is, they’re probably more dependent upon the FLT3.

DR DINARDO: Yep.

DR STONE: In terms of the leukemic pathophysiology, but we haven’t got to the point where we can say how that really means treatment should be given.

DR LOVE: We can see, Courtney, that there’s a consensus in the panel — just kidding. There’s, like, 14 different answers given here.

DR DINARDO: Right. And, I mean, the main question is exactly what Rich got to, which he wanted to pool our opinions on, is, what do you do? You have an older patient who has — this question stem is a true FLT3 ITD patient, right? There’s a high allelic burden. They’re proliferative. The white count is over 20,000. There are circulating blasts. This is one of those proliferative FLT3-mutated patients. Do you do aza/ven? Do you do aza/FLT3 inhibitor? Which FLT3 inhibitor do you use? And there’s just not a lot of data to guide that decision, which is why you see all these different answers. We know that in limited numbers in all these different studies that it’s effective and it’s better than azacitidine alone, I would posit, but what the right combination is we don’t know yet.

DR LOVE: Where do you fit on this chart, Courtney?

DR DINARDO: I was one of the two, which is going to be, like, so I would do azacitidine/venetoclax and gilteritinib. And I wouldn’t do that all together initially. I would start with azacitidine/venetoclax.

DR STONE: Okay, would you advise these guys to do that off the cuff, outside the concept of a clinical trial?

DR DINARDO: No.

DR STONE: Let’s be careful here.

DR DINARDO: Yes. It is within a clinical trial.

DR LOVE: You would not do it outside a trial?

DR DINARDO: No, not yet.

DR LOVE: What would you do outside a trial?

DR DINARDO: I would do azacitidine and a FLT3 inhibitor now, and I would probably use gilteritinib.

DR PRATZ: And I’ll take gilteritinib.

DR PRATZ: I voted for azacitidine/venetoclax. And I think the sequencing of these therapies is a big debate in the academic community. And the data we have for the azacitidine/venetoclax is in the up-front setting. The data with the vast majority of FLT3 inhibitors are in the relapsed/refractory setting, save the midostaurin data.

As such, until we have data to say that the sequence should be different than that, I would give this patient aza/venetoclax in hopes of getting remission and one that happens quickly. It takes a little bit longer with the kinase inhibitors to get a clean remission. And that’s one of the reasons I would choose the aza/ven.

DR LOVE: Rich, would you like to make it a consensus? Just kidding. What do you do?

DR STONE: I’d use aza/ven for the reasons that Keith mentioned, but if the patient was truly proliferative and had a great performance status at 76, I would consider 7 + 3 and midostaurin.

DR LOVE: I mean, a lot of people write things down, but you actually wrote down aza/sorafenib. But there are quite a few people saying sorafenib, which surprised me. Like, why would you use sorafenib?

DR STONE: Only because the data has been around the longest, as I showed that one slide from Farhad’s paper, there isn’t any published data yet with — I mean, purity of publication that I’m aware of, Keith, correct me if I’m wrong, with aza/gilt or aza/quizartinib.

DR PRATZ: No.

DR STONE: That’s what we have on the literature.

Case (Ms Sanchez): A woman in her mid-60s with FLT3-ITD AML is enrolled on a clinical trial evaluating gilteritinib as maintenance therapy after allogeneic transplant

DR LOVE: I want to open it up a little bit and get a couple of cases and get some questions, and Ms Sanchez, you have a 64-year-old woman. She was actually the only patient in the entire group here who received gilteritinib on a trial, as you might guess, and I thought that was really interesting, because I’ve been kind of curious what people experience. Can you briefly kind of talk about what happened with this patient?

MS SANCHEZ: This is a lady who’ve I known since she was in her 50s. Actually, she presented with polycythemia vera, and she required phlebotomies. She had elevated platelets and was on anagrelide and later on hydroxyurea, but she had edema. She went on to interferon for 10 years. Yes.

Then after that she was having mini strokes, and so she was placed on aspirin and clopidogrel. And she did then go on to lenalidomide and prednisone, which was stopped in June 2018. And her counts started tanking.

She then went for a bone marrow biopsy. Previous bone marrow biopsy did not show blasts — this did have 30% blasts and normal female karyotype. Her FISH studies — let’s see — and then her molecular studies showed the FLT3 ITD mutation.

She was sent over to Moffitt. She had induction with 7 + 3 and mido, with no residual disease of AML. Then went on for consolidation with IDAC plus mido. On 4/2 of 2019 until 5/8, then she went for conditioning chemotherapy with a MUD transplant on 7/5 with graft-versus-host prophylaxis. And now she is enrolled in the gilteritinib trial.

DR LOVE: As maintenance.

DR DINARDO: As maintenance, or for relapse?

DR STONE: Yes, she hasn’t relapsed yet.

DR DINARDO: It’s maintenance. Okay.

DR LOVE: Rich, can you comment a little bit on this case?

DR STONE: Oh, it’s just a run-of-the-mill case. The real world’s a tough place. Yes, I mean, I think the management’s been fantastic. I mean, we could talk about many aspects of this case, like why she got lenalidomide if she was having strokes, but that’s another matter.

Right now, I mean, the issue is how to treat someone with a FLT3 ITD-positive leukemia when they’re doing well after transplant. And the part that this brings up to me is whether the gilteritinib versus observation trial, the so-called BMT CTN trial in which she’s on, quite appropriately, is ethical in light of the data from Dr Bircher from Europe. There was a randomized trial with 80 patients that was presented at ASH last year of sorafenib in 40 patients versus nothing in the other 40. And this is the same type of patient as yours — and the people who were on the sorafenib lived longer than the people who got observation. And work done at the Harvard Cancer Center, both at MGH and at our place at the NCI, suggested sorafenib leads to a reduction in relapses compared to historical controls.

Anyway, I’m happy that she’s on a clinical trial. I always support clinical research. If she wasn’t able to go on the clinical trial, I would give her sorafenib in the post-transplant setting, because it may reduce her risk relapse, which is certainly high, given that she had a prior stem cell disorder, presumptively with a JAK2 mutation because she had PV. Presumptively, the JAK2 mutation is gone now.

MS SANCHEZ: Correct. Yes.

DR STONE: And she had a FLT3 mutation, which is another whole interesting biological story. I think I support the trial she’s on. Off trial, we use sorafenib. That’s the short answer.

DR LOVE: How is she doing? I guess, can you tell whether she’s on placebo or not?

MS SANCHEZ: I cannot.

DR LOVE: She feels well. She feels fine?

MS SANCHEZ: She has sometimes gastro —

DR LOVE: Right, she has some GI. Because I’ve been trying to figure out, obviously, midostaurin is given with 7 + 3, it’s hard to separate out, Keith, what kind of tolerability issues there might be. But in the maintenance setting, when it’s given alone, you can see maybe a little bit more.

Activity and tolerability of gilteritinib and sorafenib in patients with AML

DR LOVE: What do you see in terms of tolerability, and how does it differ amongst the FLT3 inhibitors?

DR PRATZ: With gilteritinib, it seems to be one of the easier-to-take FLT3 inhibitors. It is a little bit more difficult in the placebo-controlled setting to know whether the patients are on it.

GI upset and diarrhea continues to be an issue. Cytopenias, a question after transplant always is, what’s caused that? But beyond that, it’s a reasonably easy-to-take medicine.

DR LOVE: Right. What about sorafenib? It kind of from our experience and general medical oncology using it kind of, like in HCC, et cetera, has “a bad name,” not that easy to utilize the drug. What about in this situation?

DR STONE: Yes, I think it’s a drug that’s favored by patients. It has a lot of GI side effects and other side effects.

DR LOVE: Hand-foot syndrome, though? Do you see that, hand-foot syndrome?

DR STONE: Yes, you can see hand-foot syndrome. Yes. I mean, that’s not too common, but you can see it.

But the thing about sorafenib in the post-transplant setting that makes it interesting is, there’s data that suggests it has pretty significant immunological effects. I mean, that’s what you want to do to prevent people relapsing after they have a stem cell transplant is magnify graft versus leukemia. And there’s data from Germany and elsewhere that suggests that sorafenib might be doing that.

Even though gilteritinib is clearly a more specific and potent FLT3 inhibitor than sorafenib is, sorafenib could have utility beyond the fact that it hits FLT3. At least in Germany, because they’re pretty tough over there, they were able to tolerate the sorafenib pretty well in that setting. That’s what they said, anyway.

DR PRATZ: But one of the key details about the use of sorafenib for FLT3 leukemias is that you don’t need to give the HCC dose of 400 twice a day. The inhibitory doses for FLT3 are adequate at 200 twice a day. And a lot of patients tolerate that just fine.

DR DINARDO: That’s a good point.

DR LOVE: Interesting.

Courtney, what about the use of FLT3 inhibitors, and particularly gilteritinib, which is approved not that long ago, in the relapsed setting?

DR DINARDO: I mean, I think the study that Rich presented of gilteritinib versus your investigator’s choice of therapy is really a profoundly important one, because even if it was a noninferiority study, right, if you were able to have a well-tolerated, as Keith just said, outpatient pill as opposed to being admitted for FLAG-IDA or MEK or any of the kind of choices that were given, I would take equivalent response. And so to be able to have improved responses and improved overall survival I think really speaks to kind of the importance of this therapy. But as Rich also said, it’s not curative, right?

Using gilteritinib as a single agent I think is critically important to get out there. And now it’s up to the academic world to do the study showing what combinations are going to make it even better.

Ongoing investigation of venetoclax in combination with a hypomethylating agent for younger/fit patients with AML

DR LOVE: I know a lot of people have questions about the use of HMA venetoclax in the relapsed setting — for example, younger patients who relapse on 7 + 3. Can you comment on that, Courtney?

DR DINARDO: Sure. We’ve published on some of the outcomes as well as other kind of institutions — City of Hope has one also — it’s about a 40% response rate. It’s not nearly as nice as it is in the front-line setting, but it can be an effective salvage strategy for patients who have relapsed disease.

DR LOVE: And we talked a little bit about the younger patient with adverse prognostic factors. But what about bringing it in, venetoclax, into the up-front setting? What are some of the trials right now that are looking at that strategy, Courtney?

DR DINARDO: There’s a Intergroup trial that’s going to be doing 7 + 3 versus 7 + 3/venetoclax.

DR STONE: It’s CPX versus 7 + 3 versus aza/ven in the adverse-risk younger adults.

DR LOVE: Hold on. I’m sorry. CPX, 7 + 3/venetoclax, you said?

DR STONE: No. Actually, we’re doing a Phase I trial along with MD Anderson right now of 7 + 3 plus venetoclax for younger adults. It’s not completely finalized, but there’ll definitely be an aza/ven arm in these bad risk younger patients. There will be a 7 + 3 arm, because that still is the standard of care. There will be a CPX-351 arm. And there may be a 3 + 7 plus venetoclax arm, too.

DR DINARDO: I think there are 2 different questions, right? One question is in people who are genomically adverse, right, should we use HMA/ven? The studies for that are kind of slowly kind of taking the age down, so looking at people 60, 65-plus who are maybe physically fit but genomically adverse in doing 7 + 3 versus HMA/ven, right? That’s a randomized study that is being developed.

And then the second question is, can you take a young patient who is fit for intensive chemotherapy, you’re going to give him a 7 + 3 regimen or 7 + 3 plus ven, even better. Just because venetoclax works in older patients, it very well might work in younger, fit patients to kind of improve upon chemotherapy in that setting as well. Those are the two different studies that are being developed.

DR LOVE: Keith, any thoughts on where this is all going to land?

DR PRATZ: I think this is going to land in us not giving 7 + 3 much in the future. And I can only hope that’s where we land. But the studies have to be done to show that that’s the right move.

DR LOVE: Do you think we’re going to use CPX more?

DR PRATZ: I think we’re going to be using HMA/ven plus whatever comes next. But the toxicity will be less lower in younger adults. The remission rates seem to be on numbers so far equivalent or better than what we’d expect with 7 + 3 across the board. I think if we had to predict, these studies are going to show either equivalence of outcomes or slightly improved outcomes with the lower-intensity ven-based treatments, but we’re going to have to do the randomized studies to prove that.

Duration of response to therapy with venetoclax and a hypomethylating agent; investigation of approaches to overcome resistance

DR LOVE: Rich, we had a couple — I think 1 or 2 cases, I wasn’t really clear whether or not they actually progressed, but earlier deaths. Do we know anything about people who don’t respond to venetoclax/HMA and why?

DR STONE: We’re beginning to learn. That’s the next frontier in this whole field. Because, as I mentioned earlier, there are other molecules which can also prevent cell death. One of them is called MCL1, and that pathway’s upregulated in people who fail HMA/ven, so we didn’t even say that. But MCL1 inhibitors are the next frontier. They may have side-effect profiles that aren’t ideal, but those are out there. Also, the MEK/ERK pathway may also result in venetoclax resistance. There’s a trial with an MDM2 inhibitor plus venetoclax trial that’s been done.

This is just the tip of the iceberg for taking advantage of the cells’ way to evade chemotherapy. Once we understand that in more detail, we’ll have other drugs to use besides venetoclax.

DR LOVE: Courtney, what’s the longest we’ve seen remissions right now with HMA/venetoclax? And do you think that we're going to see people cured?

DR DINARDO: The clinical trial started in November 2014, so we enrolled a handful of people at the very beginning. And there are a few patients at our institution that are still on study. That would be the longest people have been on.

I do think we are curing a small percentage of patients, but I don’t think it’s the majority. Most of the patients that I have treated on that initial Phase I that we’ve referenced a couple of times have relapsed. And the people that have relapsed are the people with high-risk disease that we’ve been spending a lot of time talking about today, those with adverse cytogenetics, p53 mutations, and the other population I’m starting to see more is those, like, signaling transduction mutations, things that are activating, like FLT3 ITD, also NRAS, KRAS, that pathway. And that’s why I’m a little less gung-ho aza/ven for FLT3 ITD-mutated patients because I’m just seeing that as a resistance factor. Somehow I want to fold in the FLT3 inhibitor.

Case (Dr Sullivan): A man in his mid-30s with AML with mutations in FLT3, MPN1 and ROS1 experiences disease progression after chemotherapy and FLT3 inhibitors

DR LOVE: Let’s get back to FLT3, and, actually, Dr Sullivan, you have a 36-year-old man, if you could maybe comment a little bit about what happened with him.

DR SULLIVAN: Yes. He presented with just merely fatigue. But it was to the point that he came in through the emergency room and was found to have 50,000 white count, real monocyte predominance and mild anemia, mild thrombocytopenia and was well. No fevers, no evidence of infection.

Went ahead and kept him, transferred him to a nearby academic center for obvious leukemia. Ended up being monocytic AML with a FLT3 mutation, MPN1 mutation. Had a ROS1. Normal cytogenetics and on workup had a little bit of an infiltrate in the right base, so he spent a lot of his period of 7 + 3 induction on antibiotics just for that eventuality but did well otherwise.

He got a remission with is first cycle. Put him on midostaurin and got 4 cycles of HDAC and consolidation. He was on a path for transplant. Couldn’t quit smoking. They didn’t want to transplant him, and I think he wanted to quit, frankly, but he actually really couldn’t quit as well, because he had both teams working to try to get him off the cigarettes.

Basically transplant got delayed and held and held and held. Got finished with all of it and stayed on the midostaurin and about 7 months later relapsed. He became a little bit cytopenic, and marrow showed that it was hypocellular and a clear blast population. Got FLAG-IDA.

DR STONE: Did he have a FLT3 mutation?

DR SULLIVAN: Yes. It persisted.

DR STONE: Is it still present?

DR DINARDO: It persisted.

DR SULLIVAN: None of it changed. And got FLAG-IDA and responded. But long story short, with the FLAG-IDA, by the way, he went on a research trial looking at crenolanib versus placebo. So here he ostensibly stayed on a FLT3 from all the way through relapse and then ended up with minimal residual disease. And at that point, he did stop smoking, and it held. We had a visit a month later and still had not resumed smoking. But the MRD kept him off the thought for a transplant.

DR LOVE: Could I just stop you right there, before you talk about what happened, and ask Rich what you’d be thinking at that point?

DR STONE: I would do a transplant.

DR SULLIVAN: Go ahead on with it.

DR STONE: I mean, the man’s going to die without a transplant. He has a small chance to survive with a transplant. He’s been on a weak FLT3 inhibitor. He still had a FLT3 mutation. He went on chemo plus a FLT3 inhibitor trial. I don’t know, was it a placebo control? He might not have gotten —

DR SULLIVAN: Yes. We don’t know.

DR STONE: We don't know. I mean, I would give that guy gilteritinib now. Try to reduce his MRD burden and then transplant him regardless of his response to gilteritinib. That’s what I would do, because you do want to go to the transplant with a minimal disease burden. He’s already got a ton of chemotherapy. We don’t know. But I would give him gilteritinib, which is the most potent FLT3 inhibitor you can get right now. And for whatever reason, his FLT3 cells were able to live through midostaurin and maybe crenolanib. We don’t know. But I would give gilteritinib for a couple of months and then transplant him. He’s got a donor. That’s his best chance for long-term survival.

DR LOVE: Courtney, any thoughts? And what about HMA/venetoclax to cytoreduce?

DR DINARDO: All the things I said before, which is that HMA/ven works really well. Not as well in the relapsed setting, though, and he’s already kind of a couple of salvages in. And if there is a FLT3 ITD clone that is still present, and we’re not really sure if he’s had anything other than midostaurin. I like the idea of gilteritinib. Yep.

DR LOVE: What happened?

DR SULLIVAN: He went on HMA/venetoclax.

DR DINARDO: Okay.

DR SULLIVAN: And gilteritinib.

DR DINARDO: Okay.

DR SULLIVAN: And that’s where he’s at. He’s gotten 1 cycle. His next cycle is coming up. He’s gone into this cytopenic and remains cytopenic transfusion-dependent anemia. ANC is running about 0.8 persistently. He’s well, and he stays home. We’re treating him as an outpatient. And so per some of your earlier comments, I’m full of questions right now about disease assessment explanation for the cytopenias. What do I do with cycle 2? And then where do we go from here? To Rich’s point, I’m not willing to abandon thoughts of a transplant on this guy, but he’s in a pretty bad position overall. And is it worth doing that in a guy that leans towards low-risk disease whose cytogenetics are completely normal.

DR STONE: But he’s 38, right?

DR SULLIVAN: He’s young.

DR DINARDO: He’s 38 and he’s relapsed, though, so he’s high risk. I think if he is fit for a transplant — I mean, if he’s well, performance status/organ status wise, I would take him to a transplant now. But I agree that I’d be very interested in the status of his bone marrow. I would be expecting it to be rather myeloablated right now from that combination.

DR SULLIVAN: Would you hold cycle 2 if it is?

DR DINARDO: Yes.

DR LOVE: Keith?

DR PRATZ: Specific to the question, I would take him to transplant regardless of what the counts are. Seemingly he had less than 5% blasts. We just published a paper looking at those patients going to transplant with residual disease with FLT3 mutations and the use of a FLT3 inhibitor post-transplant. About half of the patients on this study had minimal residual disease either by genetics or by blast percentage of being detectable but under 5%. While the patients who had MRD going into the transplant did worse, we still had a significant cure rate with the use of sorafenib afterwards.

I would argue that you ought to take them even if they have a few percentage of blasts and go. Give them an inhibitor afterwards. And this is one person for sure I wouldn’t put on a placebo-controlled study.

DR SULLIVAN: Right. Right.

DR LOVE: Any other questions about his case or about the management of patients with FLT3? Dr Sullivan, any questions?

DR SULLIVAN: What will happen is, I’m going to go home and try to get him marrowed and answer these questions. And then, hopefully, he will go on to transplant. And then gilteritinib or sorafenib.

DR PRATZ: I’m still a believer in sorafenib. It’s the only drug we’ve had a placebo-controlled study showing a benefit of, and the safety data post-transplant for gilteritinib is yet to be —

DR STONE: But he won’t be eligible for the gilteritinib trial, because he’s relapsed. That’s up front. I think you have to be in first remission for that one.

DR PRATZ: Right. And the question of crenolanib exposure would exclude him.

DR STONE: Yes.

DR PRATZ: Either way, I would favor sorafenib, but gilteritinib would probably be, as long as you’re giving it to him, not on a placebo-controlled study, adequate also.

DR DINARDO: And then the other thing, just while you do the bone marrow and hold, I would probably continue the gilteritinib, because I think the FLT3 inhibitor continuous therapy is probably not going to lead to additional myelosuppression and would be useful to help suppress whatever FLT3 ITD is still there and trying to come back. And then decide additional aza/ven cycles after the marrow if we’re not doing transplant. But I would continue the gilteritinib.

DR LOVE: Any other questions about FLT3 or any of these drugs or anything up to now before we move on?

DR STONE: I have one for them. Venetoclax, which we’re all using, any trouble getting it paid for? We have patients in Massachusetts who the copays are too high and they can’t afford it. It’s not a problem here? That’s good news?

DR LOVE: Copays.

Case (Dr Dandamudi): A man in his early 70s receives venetoclax and azacitidine for AML

DR DANDAMUDI: This is a 72-year-old male, originally presented to me when he was about 70 with complaints of severe anemia and, like, workup showed, like, MDS with multiple cytogenetic abnormalities.

At the time, the blast count was about 15 to 16. We started the patient on 5-aza, and he did very well. Everything recovered. He was not transfusion dependent for about 12 months. And then started again transfusion dependent. Blasts were around 15%. I switched it to decitabine to see if there is any improvement, but, like, the patient continued to be transfusion dependent.

Finally in May 2019, when we did the biopsy, it came back positive for 40% blasts. He had CPX-351 treatment at Moffitt and then developed severe cytopenias. He did not recover from the cytopenias completely. We continued to follow. He’s continued to be transfusion dependent with platelets getting almost twice weekly and blood transfusions every week also.

Finally, we did another bone marrow biopsy in July. He has been getting bone marrow biopsies sequentially, but in July, like, it definitely showed that, like, now developed again a 30% blast after the CPX-351. Jeffrey Lancet suggested that maybe adding venetoclax with the 5-aza at the time to see how he does. We did it while he’s having severe cytopenias. Then the repeat biopsy after 2 weeks showed complete, like, no evidence of blasts.

We had to hold the venetoclax and 5-aza because of the cytopenias. And then after 3 weeks when we repeated the biopsy again, the blast counts come back. What are your thoughts about it?

DR STONE: This is, unfortunately, a sad but typical story of someone who can get ablated but can’t have normal hematopoiesis restored because he’s got a lot of leukemia in the bone marrow. I mean, this patient’s not going to do well no matter what we do, unfortunately. However, I mean, if he can get to a point where he’s ablated, even temporarily, then he can be consolidated. How old? He’s 72, you said?

DR DANDAMUDI: He’s 72.

DR STONE: If he’s fit, he can be consolidated with a transplant.

DR DANDAMUDI: With all this now, his performance status is not very good.

DR STONE: He can’t. In this case, palliative care is certainly an important consideration, because you keep giving this guy more chemo, he’s just going to die one of these times with the cytopenia. I think he did respond — it sounds like he responded to the aza/ven, so maybe a little bit more aza/ven continuously — trying to keep him on it. Keep his disease at bay so he can have some extra time. But his disease is going to come back.

DR DANDAMUDI: We were thinking, like, week on/week off or 2 weeks on/2 weeks off.

DR STONE: Sure.

DR DANDAMUDI: Or something like that.

DR STONE: Give it a shot.

Faculty presentation — Dr Pratz: Therapeutic approach for older patients with AML with IDH1/2 mutations who are not eligible for intensive treatment

DR PRATZ: I’m going to review the management of AML patients with 1 of 2 mutations and isocitrate dehydrogenase in IDH1 or 2 and specifically tailor this towards folks who are not eligible for intensive chemotherapy. And as we’ve talked about earlier, the definition of what is not fit for intensive chemotherapies are a bit subjective from place to place. As you look at them, my list on the left here, some of the FDA-accepted or acceptable criteria as they were defined in several of the clinical studies that are ongoing right now or the one that led to the approval of venetoclax.

ECOG performance status, that’s 2 or beyond in an over-age-60 patient. Over age 75 is an absolute number. Prior history of congestive heart failure or ejection fraction under 50%, reduced pulmonary function is defined here on pulmonary function testing, creatinine clearance under 45 or bilirubin over 1.5 were all the laboratory endpoints that were used to define the unfit-to-treat patient population with some objectivity. That being said, the less objective definition of other comorbidities incompatible is a catch-all term that you all are probably very familiar with, and we can see what our eyes can always define with a piece of paper, but that’s the more common issue I think comes up with a lot of this age 65- to 75-year-old patients, polypharmacy and the like lead us to have concerns about putting them in the hospital for a month.

Limited anthracycline exposure for a lot of our breast cancer patients can become an issue. We see more and more of that now as we’re giving a lot more adjuvant chemotherapy to patients who have earlier stages of breast cancer. Prior chemotherapy exposure often leads patients to have refusals outright of wanting to go in the hospital to be given treatment. I’ve had to give folks less intense treatments just because of that in the past. And then as defined earlier by Dr DiNardo, this idea of genomically unfit or cytogenetically unfit patients to give intensive chemotherapy, some of the examples listed there include p53 mutations, inversion 3 and some of the other complex karyotype patients.

And Courtney pointed this out earlier, the average age being 60. But I point this table out here to show that as you get older and as your performance status declines, the likelihood of us killing you with 7 + 3-based treatments in 30 days goes up quite a bit. And you can see in the 65 and older group of patients, performance status 2 or 3 patients have a 30% or more mortality at 30 days with 7 + 3-based induction.

As we’ve got therapies now that we can give this patient group to have very low rates of treatment-related mortality, I think it’s important to keep in mind what the baseline numbers are. IDH1 and IDH2 are mutations that are were recognized as specific things found in leukemias not so long ago, in the late 2000s, and 2010 there were observations showing that these were driver mutations in a number of things, including leukemia, and that they are specific changes in the enzyme activity of IDH1 or IDH2 that confer a new biologic property of those enzymes.

This biologic property makes what we all an oncometabolite that wouldn’t otherwise be made, something called 2-hydroxyglutarate, or 2HG. 2HG is a compound that has properties that change the epigenetics of cells and can lead to the development of cancers in leukemia and then brain tissue. And as those mutations were identified as being novel things found only in the cancer cells, they became an ideal target for drug development. And 2 drugs that were developed to target these mutations we’ll talk about in the next few slides.

As a mutation in leukemia, they’re relatively uncommon. About 15% to 20% of patients with AML have 1 of the 2 mutations, IDH2 being a little bit more common than the IDH1 mutations. And they present with a somewhat consistent clinical phenotype in that they generally have a low white blood cell count, generally have a more intact platelet count than what you routinely expect to see with myeloid leukemia patients. And that’s one of the ways we can see their presentation and pick out the patients coming who may have the mutations.

The 2 drugs that are now approved for these mutations are listed here. Described here are the relapsed/refractory studies that led to their approvals. Ivosidenib is the IDH1 mutation-targeted agent, and it was originally studied in 125 relapsed/refractory acute myeloid leukemia patients. Remission rates, complete remission rates, which included those that didn’t have full count recovery or 30% in this study, the median time to response was 2.7 months with duration of response being 8 months on average.

What’s important I guess on the side to the left here is that the patients that did go in remission seemed to have more significant disease control, and some of those remissions lasted for significant periods of time. This led to the ultimate approval for ivosidenib in the relapsed/refractory setting. And we’ll talk a little bit in a moment about its up-front use. Enasidenib is the IDH2 inhibitor, also relapsed/refractory setting, 30% remission rates, similar kinetics and a little bit shorter durations of response.

Front-line ivosidenib has been described in 2 places. One is in the package insert, and two is in an abstract that’s presented, unfortunately not published yet. Twenty-eight patients were studied in the up-front setting, median age of 77, who were unfit to treat with conventional chemotherapy, which is why they were older. Of note, 7 out of the 28 developed differentiation syndrome, 36% of the patients had leukocytosis, which is also a form of side effect from this drug. And specific to ivosidenib, QT prolongation can occur, so it needs to be monitored.

Remission rates are similar in the front-line setting to those in the relapsed/refractory setting, 30% or so, and the median time to response is about 2.8 months. Similar reports from Gail Roboz abstract, just a few more patients observed there. Mutation clearance occurred in about half of the patients who went in remission.

And then enasidenib has also been presented and published now by Dr Pollyea, 39 patients treated, significantly less remissions in the up-front setting and in the relapsed/refractory setting for reasons we don’t entirely understand yet, but 18% got CR. One additional patient had a CRi. A total response rate just over 20% here. Event-free survival after therapy of 5.7 months. Enasidenib has not been approved yet in front-line setting, but it is approved for the relapsed/refractory setting patients.

And we talked a bit about venetoclax in combination therapy. Here’s the Phase II study as a single agent. Didn’t show a very good response as a single agent but in specific groups of patients with IDH mutations seemed to have a bit of a signal that there’s a remission as a single agent can occur with venetoclax, about 33% in this small group of patients.

My last slide, which is a basic comparison of the front-line use of either drugs targeting IDH1 or IDH2 and then in comparison the venetoclax hypomethylator therapy. CR/CRi rates specific to IDH mutation in the venetoclax hypomethylators are listed there on the top right. You can see there’s a significantly high remission rate here. Median time to remission shorter with ven hypomethylator-based therapy, and median overall survival is a bit higher.

As it stands right now, if you had to pick, I think most of us would pick the ven hypomethylator with the caveat being a lot of my colleagues would argue that the targeted IDH drugs don’t tend to have as much in the way cytopenias, and neutropenias being the main one there. But it is something we see more with the venetoclax-based treatments.

Selection of first-line therapy for patients with AML with an IDH mutation

DR LOVE: Let’s go through a few of the questions that we posed to the panel just to kind of dip our feet in the IDH water, so to speak. This is pretty interesting, Rich. We presented a 77-year-old lady with IDH1 mutation. Everybody says aza/venetoclax. Any comment?

DR STONE: Yes. I mean, I think that’s, based on what Keith just showed, it’s known that venetoclax is pretty active in the IDH-mutant setting. Aza plus venetoclax chemo-responsive disease, aza plus venetoclax, easy to give in the older adult with an IDH mutation. Sure, that makes sense.

I think the real question, and Courtney can comment, is aza plus ivosidenib, because only 1 person shows that, yet the responses in Courtney’s small Phase I study of aza plus ivo were quite high. Courtney?

DR DINARDO: Yep. That was going to be the one kind of trial population that I think is important to compare. Because when you look at ivo alone, right, the response rate is about 40%, and the median survival is about 11 months. And that’s very different than aza/ven. But we’re not really comparing apples to oranges. The comparison would be azacitidine with ivosidenib. And so that study has been done, but only 23 patients were enrolled. But it showed really quite impressive results. It was a 60% CR, a 60% true CR rate, over 70% CR/CRi. Kind of on par with aza/ven. And the median survival hasn’t been — not yet. There’s over 80% 12-month OS.

Super small numbers. It’s hard to really compare it, but it does look to be at least, so far, comparable. And so that is an important thing to be aware of. And there is an ongoing randomized study now, primarily outside of the US, that’s aza plus/minus ivosidenib.

DR LOVE: Just to cruise through a couple of these other ones, this is a patient, Keith, who had a history of P-vera, presents with AML with an IDH1 mutation at the time of transformation. Any comments about management of this situation?

DR PRATZ: This is, unfortunately, real-world patients that we see with P-vera do develop leukemia ultimately, and acquisition of an IDH mutation is something that often drives that. I think a lot of the options up here are always folks who manage this, but in truth, almost all of them are very hard to find good treatments here that work. I do think this patient deserves an IDH inhibitor mixed into their treatments, whether it’s with 7 + 3 or with a hypomethylating agent. I think that’s dealer’s choice.

But we’ve presented the 7 + 3 plus ivosidenib data. It seems to be very tolerable when given in combination. And the remission rates by numbers seem to be a little better than we would expect.

DR STONE: Secondary leukemias too.

DR PRATZ: We don’t know that. But several of the patients had secondary.

DR STONE: In the original Phase I trial of 3 + 7 plus the IDH inhibitors, there were problems with secondary leukemias, weren’t there?

DR DINARDO: I mean, over a quarter of the patients, I think almost even a third of the patients were patients with secondary AML for various different reasons. The median age of that study was, like, 60-something. As opposed to, like, the RATIFY study, where the age was much younger, IDH-mutant patients tend to be older.

DR PRATZ: And I think, to push back a bit, a lot of those patients were HMA failures that were secondary. And for sure we’ve always known those patients to be tough to treat.

Side effects associated with ivosidenib; management of differentiation syndrome related to IDH inhibitors

DR LOVE: Rich, any comments on this situation, the patient who’s in complete remission on ivosidenib, presents with lower extremity weakness? You can see the rest of it. Most of the people think this is Guillain-Barré. What do you think, and why?

DR STONE: I have no idea. I mean, it’s not seen as relapse. There are no mass lesions. Obviously we want to know as much neurologically as you can.

What’s the MRI with gadolinium? What does the neurologist think? I’ve never seen this from ivosidenib. I suppose it’s probably been reported at some point, but I’ve never seen it. I would think it’s unrelated. But I need more data.

DR LOVE: And also, would you stop the ivosidenib in that situation? Most people say yes. Courtney, what’s your take on this?

DR DINARDO: I mean, there are few important adverse events to be aware of. Differentiation syndrome also I’m sure we’ll talk about. Enasidenib can cause an indirect bilirubin. A lot of times if you’re on the IDH2 inhibitor, you’ll see this rise in your indirect bilirubin. It’s not clinically significant. It’s not liver toxicity. But you’ll see that in about a third of patients.

Ivosidenib, you can see QTc prolongation, so that Keith mentioned. And then there are these, I think, 3 or 4 patients that were on the original Phase I that had kind of progressive neurologic complications that I think were kind of classified as Guillain-Barré. It’s always really challenging in Phase I studies of multiply relapsed patients that have had so many different lines of therapy to be entirely convinced what is ivosidenib related and what’s not.

I think it’s still a little bit unclear. But there is this association that is worth being aware of.

DR LOVE: The thing I really wanted to get into here was this issue of differentiation syndrome and how to approach it clinically. Before we even get into this scenario, Keith, what’s the time sequence of when you see it? How often do you see differentiation syndrome? And in this situation, what’s the time sequence?

DR PRATZ: Differentiation syndrome is much like what we are more familiar with with APL and ATRA, but unlike what we see in APL and ATRA, this is the type of thing that often develops several weeks into therapy and as late as 5 months into therapy has been reported. It can present a number of ways: hypoxemia, fevers of unclear origin, leukocytosis, so a number of the constitutional symptoms that you see with differentiation syndrome. But it is something that occurs as later events on treatment.

DR LOVE: What about the issue of separating out differentiation syndrome from progressive disease, Keith?

DR PRATZ: Along with the differentiation syndrome, you often see a rising white blood cell count. And in my experience often persistent blasts in the blood, even as late as a month in. It’s not clear that it’s easy to tell what is clear progression versus what is leukocytosis/differentiation syndrome, but when it’s occurring in the first 2 months of therapy, I will often put somebody on hydroxyurea to bring their counts down and continue the IDH inhibitor even though your gut’s telling you the guy’s progressing on the inhibitor.

DR LOVE: And when it is differentiation syndrome, you start corticosteroids. How long does it take to work?

DR PRATZ: Fairly quickly as far as getting the hypoxemia and fevers to go away. Within 24 hours you usually see an improvement. But it takes a while to get these drugs out of your system. Their half-lives are measured in several days. Just stopping the inhibitor doesn’t necessarily stop the effects of the inhibitor. And when we do treat differentiation syndrome, we treat it with a very slow taper of steroids over weeks usually.

DR LOVE: How late can you see this, Keith? Do you see it like 6, 8 months later?

DR PRATZ: It’s been reported as late as 5 months into treatments. I don’t see any reason why you couldn’t see it that late if that’s all of a sudden when you’re starting to see the responses. But it’s usually in the first 2 months.

DR LOVE: Right.

Courtney, one of the key issues is whether to stop the treatment or not while you’re giving the corticosteroids. So, for example, in this situation, where the patient has shortness of breath, hypoxemia and fever and you can see the rest of the workup, would you keep it going or stop it?

DR DINARDO: I think the point is that the IDH inhibitor’s half-life is really long. You can’t just assume that by stopping the drug that everything is going to get better. I think the number 1 kind of thing to remember is to start steroids right away, and patients, if it’s differentiation syndrome, they get better usually within 24 to 48 hours.

I tend to stop the IDH inhibitor if they’re clinically unstable or particularly unwell, right? If they’re in the hospital, they’re on oxygen, I mean, there’s no need to keep them on the inhibitor at that point, so you stop it. If they are outpatient with some lower extremity edema or some shortness of breath that is not oxygen requiring and doesn’t warrant hospitalization, I can give them steroids and not feel the need to stop the inhibitor.

DR LOVE: Any questions anybody has? And then we’ll end with a couple of cases. But any questions that anyone has that they want to bring up about this?

DR MARTE: How long do you keep them on the steroids?

DR DINARDO: The recommendation is at least, like, just like you would in APL, right, to do dex, 10 mg twice a day for at least 3 days and then if they’re improving, then if it was something short you can just stop it. Some people don’t taper at all. I usually do as was mentioned, like a week or 2, just a slower taper, especially if their white count is high and we’re trying to kind of slowly calm things down.

I think the hardest thing is identifying if it’s differentiation syndrome at all, right? Because in relapsed patients only about 40% of people are responding, right? Is this a patient who is just progressing? Is this a patient with a neutropenic fever that is clinically unstable because of infection, which happens all the time in our relapsed patients? Or is it differentiation syndrome, or is it some combination of the two of them? You just have to be aware and start steroids.

Case (Dr Shah): A man in his late 80s with AML with an IDH2 mutation and multiple comorbidities receives enasidenib

DR LOVE: Dr Shah, I always like case presentations that begin “an 87-year-old man.” Maybe you can tell us what happened with this man.

DR SHAH: This is a gentleman that I have known for a number of years because of his beta thalassemia and microcytic hypogammaglobulinemia. We didn’t see him for a year, and then he was referred back because of the cytopenias. Ended up doing a flow cytometry on the peripheral blood, and it came back showing 24% blasts and IDH2 mutation and the CBM mutation. Being 87 years of age, and he has a few other comorbid conditions like dementia, depression, diabetes.

DR DINARDO: Just a few.

DR SHAH: Atrial fibrillation, GERD.

DR LOVE: Other than that, no problem.

DR SHAH: Other than that, I really elected not to treat him, and I suggested to them the hospice care. And the family ended up going to Sylvester Cancer Center in Miami, and they put him on enasidenib. Yes. He has been on that for about 5 weeks or so. I saw him just this week for follow-up. Did all the blood tests that I was supposed to do. And everything was good. He was tolerating it okay.

DR LOVE: Is he responding?

DR SHAH: It’s hard to say at this point. Only 4 weeks, 5 weeks.

DR LOVE: What are your thoughts about the case at this point, Dr Shah?

DR SHAH: Let’s see if I missed a couple of these. CDK3…

DR LOVE: Rich, any thoughts? Why are we treating and trying to make sense of this? I mean, targeted therapy.

DR STONE: This is what Keith was just talking about, the unfit patient who has an IDH mutation. They have lots of options, theoretically hospice, obviously. I mean, there’s the whole ethical thing about a demented patient who can’t possibly. If they’re really severely demented, they can’t possibly know what’s going on.

DR LOVE: Is he able to understand what’s going on?

DR SHAH: Mm-hmm. Not really, but it’s — see, the daughter and their son-in-law —

DR STONE: His daughter. Yes, the daughter.

DR LOVE: The family.

DR STONE: I mean, so there are patients like this who really you wouldn’t even think of giving a hypomethylating agent to, right? You wouldn’t give them that. Yes, I mean, it’s not unreasonable to try it. Other than the cost to society, you’re not really harming the guy. It’s well tolerated, unless he gets differentiation syndrome. You give him a couple of months on it, and then whatever. I mean, I think it’s not an unreasonable thing to do.

DR LOVE: I’m just kind of curious, Dr Shah, though. Do you think, for example, if he didn’t have the dementia or maybe had less comorbidities, would that have changed the way you think this through? Is that really what was affecting the way you saw this?

DR SHAH: Definitely. Yes.

DR LOVE: You felt the strategy theoretically was okay, just not in this patient? Is that what you’re thinking?

DR SHAH: A healthy 87 years old, I mean, they don’t have any other medical comorbidities, very likely they’re going to live 4 or 5, 7 more years, statistically.

DR LOVE: Also, as Rich said, the dementia really makes it a difficult, I guess, ethical issue.

Case (Dr Malhotra): A man in his early 60s with AML with an IDH2 mutation receives enasidenib

DR LOVE: Dr Malhotra, you had a patient also — there were very few patients that we saw who actually got IDH inhibitors and, as always, a lot of these are fairly complicated. But you had a 60-year-old man. Can you just briefly talk about what happened and particularly what happened when he got the enasidenib?

DR MALHOTRA: Yes. His background is important, because he had a small cell cancer of the bladder around 5 years ago, for which we gave him neoadjuvant cisplatin/etoposide. He had a complete response. He ended up having a cystectomy. A year later developed a brain met. We resected the brain met, radiated and then went on to live 4 more years but then developed MDS. And then we watched the MDS, and then the MDS evolved into — for a while we didn’t treat him because his counts were okay. Leukopenia and anemia later. Then we started 5-aza, and he did not respond well, and it transformed into an AML. And that’s when the bone marrow showed IDH2 mutation.

And in consultation with Moffitt, we treated him with the IDH2 inhibitor, in this case enasidenib, and he did not respond well again. There was an issue whether he was actually going into a tumor differentiation syndrome, but steroids helped him. We maintained for about 2 months, repeat bone marrow. Blast count was elevated. That’s when we ended up doing 7 + 3. And, unfortunately, went into renal failure and then he elected not to go on dialysis and he passed away.

DR LOVE: Courtney, any thoughts?

DR DINARDO: It’s a sad story. I think that IDH mutations are not super common, but the older you are, the more likely you are to have IDH mutations. It becomes kind of an important conversation. I would say about a third of older, unfit patients. And then now that we have these different therapies, the question is, do you do an IDH inhibitor alone? Do you do it with azacitidine and the IDH inhibitor? Azacitidine with venetoclax? And so I certainly don’t have all the answers. But these are kind of really important questions for our field right now, because it’s not just 1 or 2 patients. I mean, this happens fairly regularly.

DR MALHOTRA: Would you in a situation prefer venetoclax and 5-aza over an IDH inhibitor? I mean, I’m getting the sense from the data, and I wasn’t aware of the data.

DR DINARDO: The IDH mutant patients do incredibly well with either therapy. I think aza with an IDH inhibitor or aza with venetoclax seems to be pretty equivalent in terms of responses and duration so far with the limited data we have.

There’s more numbers on the aza/venetoclax, but when you look at just the IDH-mutant patients, we’re essentially looking at 20 to 30 patients in both studies. It’s really hard to make gross generalizations with that limited number of patients.

I think if speed of remission is important, then aza/ven happens faster. Time to response, but there’s more cytopenias, infections with that. There’s less of that with the aza/IDH inhibitor I think, especially in older patients who often have a lot of comorbidities, and sometimes you can choose the right therapy just based on their backstory.