Case: A woman in her early 70s with a history of triple-negative breast cancer receives venetoclax/azacitidine for secondary acute myeloid leukemia (AML)

DR LOVE: I think the way you put these cases together is really great. I see you’ve got a 73-year-old woman, interestingly, with a history of breast cancer. What was the story there?

DR PERL: Just that we see this. We see patients with secondary leukemias, and our big question is, are we going to swing for the fences or are we going to just try to control the disease and make it as manageable as possible? Because with these genetics, very few long-term survivors, no matter what you do.

And so you have to be up front and frank with patients when you discuss that with them, because not everybody will want to go through the rigors or induction if it turns out that they’re just likely to wind up succumbing to their disease, or they’re not good candidates for intensive induction because they’ve had too much anthracycline. Which is why I threw this case in, in particular.

We bat these cases around in our case conference often: Should we use 7 + 3? Should we use CPX? Should we use venetoclax/azacitidine?

More and more we’re using venetoclax/azacitidine in these cases and still going to transplant even though there really aren’t data for it. The data support using ven/aza in patients who are unfit for induction, but there are patients who refuse, and this is often a reason that we might say we want to steer you away from intensive therapy. But I would qualify this case with this is certainly outside of the realm of where we have a lot of data, because these patients are usually excluded from trials.

DR LOVE: And, of course, the whole venetoclax/HMA story is just so amazing.

DR PERL: Oh, it’s wonderful. It’s totally transformed how we approach patients.

DR LOVE: And to me, it also really brings AML back into the community, I think, completely.

DR PERL: Absolutely. Yes. No, I’ll be honest with you. A lot of the community docs aren’t quite embracing it yet, but I think once they get the hang of it –– and it’s not perfect. I mean, on the studies that showed how effective it was, those were leukemia centers and leukemia doctors and people used to managing that degree of cytopenias. The cytopenias are rather significant, and you can’t give it like azacytidine. You just can’t set it and forget it and 6 months later see how well it’s working. You have to actually monitor these patients closely. You have to do regular marrows. And you have to warn patients, as that’s part of the process –– you can’t just say, “In 6 months we’ll know if you’re responding or not.”

We know in a month or two if they’re responding. And then we move onto something else if they’re not.

Nonspecific symptoms of AML at initial diagnosis

DR LOVE: Let’s dissect out all the pieces involved here, and maybe we can use this case to get into this issue of the workup of the patient.

DR PERL: Yes. Yes.

DR LOVE: Can you talk a little bit about how this patient presented and what her workup showed? How long ago did you first see her?

DR PERL: This patient I saw, this is somebody who’s new to my practice. Actually, I just evaluated a couple of months ago for initial therapy. And the initial presentation was just fatigue, nothing more than that. You get a CBC, and this is what you find. I think she’d been having some bruising as well and basically got a CBC by the doctor and said, “There’s something wrong with this picture.”

Not uncommonly, patients with AML are coming in with very nonspecific symptoms rather than “I know what’s wrong, because I can see a lump.” Or “I’ve got a” — there’s not a screening test outside of these CBCs, so it’s not like you’re getting a regular mammogram and we see a lesion we have to go after and get a biopsy. Patients don't expect to have anything wrong with their bone marrow until something is wrong with their bone marrow.

And often it can be insidious, where patients have months of just not feeling entirely right, but then suddenly something comes to a head — whether it’s an infection or they start having bleeding. They see the doctor. They get a blood count, and suddenly it’s clear that something’s wrong, and then we do a bone marrow biopsy and that tells us what’s wrong. But we don’t have all the information from the bone marrow biopsy until we actually get a lot of the genetics back in many patients. In this case, where somebody’s had prior chemotherapy, we consider that a therapy-related leukemia just from that moment forward, and that helps us in formulating a treatment plan.

DR LOVE: How long ago was she treated for breast cancer? I see she had triple-negative disease.

DR PERL: About a decade ago.

DR LOVE: Hmm. And I guess she got adjuvant therapy. She had anthracyclines.

DR PERL: Yes.

DR LOVE: It looks like AC followed by paclitaxel.

Efficacy and safety of liposomal cytarabine/daunorubicin (CPX-351) in older patients with newly diagnosed AML

DR PERL: The big therapy question that we have is, we have data from front-line studies comparing standard cytarabine and daunorubicin versus the newer version, which is a liposomal formulation of the same drugs, CPX-351. And in that study the response rates weren’t hugely different, but the survival was much better in the CPX arm, largely because these patients, if they’re treated aggressively, go to transplant, and the transplant outcomes were better in the CPX arm. And so in patients who are really being treated with the most aggressive approach, I think far and away the right answer in this setting is, CPX is the right answer.

Now, one issue with that study is, if you’d had a certain amount of anthracycline previously, you couldn’t go on the study –– and we run into this all the time –– in survivors in Hodgkin disease, non-Hodgkin lymphomas and breast cancer, because anthracyclines are very commonly used in those diseases, and sarcomas as well. We have to think about is this somebody who would see that benefit? Because we haven't studied this kind of therapy in people with a real risk of cardiotoxicity from induction therapy.

If somebody’s a candidate for induction chemotherapy, then, yes, my bias is to err on the side of giving CPX, because we know with the curative approach that leads to better survival. And those are flat survival curves. We really do lead to more cures with that approach as long as we’re going to transplant.

DR LOVE: That’s a really interesting question, though, about this issue of a total lifetime dose of anthracycline.

DR PERL: Correct.

DR LOVE: How do you factor it in with CPX?

DR PERL: Yes. We don’t have a lot of great data on this, because CPX is a new drug. And we have to assume that dose for dose it’s fairly comparable in terms of how much anthracycline exposure equals how much cardiotoxicity risk.

The rates of cardiotoxicity on the study were equal in the 2 arms, and about 5% developed a drop in EF. But that’s a question I don’t think we have great data on yet. And I think we’re going to get the right answer as time goes forward, just because the studies are fairly new –– the CPX trial was just published. We still don’t have long-term follow-up on that to see if anything changed across the arms.

Essential diagnostic workup and genetic testing in AML: Consideration of disease characteristics in treatment decision-making

DR LOVE: Can you talk about what you consider the essential or critical parts of the workup of a patient with newly diagnosed AML and what the workup in this patient showed?

DR PERL: The big question for us is, and this is true even in a therapy-related leukemia, are we going to treat this patient with intensive chemotherapy or are we going to use a low-intensity approach? If we’re using a low-intensity approach, the genetics don’t drive what we do in a huge way. If we are going to use intensive chemotherapy, however, then they actually drive what we’re doing significantly.

But the big question, and the first question I want to know is, does the patient have a translocation of the core-binding factor genes? An 8;21 translocation or inversion 16. Because those are the strongest predictors of patients who benefit from intensive chemotherapy, and those patients are actually excluded from the CPX study.

To get on the CPX study, even if you had a therapy-related leukemia, you couldn’t have core-binding factor leukemia. And that drives our practice as well. The first thing we do when a patient walks in the door and we say we’re going to treat them aggressively with intensive chemotherapy is, we actually send a FISH test so that we can tell within a few hours, does this patient have an 8;21 translocation or an inversion 16?

In our institution that’s the fastest turnaround. In some institutions it could be a molecular test with RTP-CR. But whatever it is, it should be a rapid turnaround.

And so this is what’s different about treating AML today is, we need to know what kind of AML it is, not just that it’s AML. We need to know something about the genetics before we make a treatment decision. Because if there’s an 8;21, I would use 7 + 3. I don’t think we have data that anything is better. And I would err on the side of using intensive postremission therapy with chemotherapy in the vast majority of patients, even in therapy-related leukemias.

I have a patient I follow in the practice who’s a long-term survivor of ALL whom I am treating right now for a therapy-related t(8;21) AML, and I’m treating her with standard induction and consolidation. We’re not transplanting her, because we don’t actually have data that in that setting there’s a need for a transplant. It’s kind of a wash. In an older patient we might feel differently.

The next question we need to know is, does the history suggest that this is therapy related or antecedent myelodysplastic syndrome? And then lastly, if we don’t have the history there to support that, is there anything in the genetics that would make you say this is a myelodysplasia-related disease? Because in patients who have myelodysplastic syndrome that transforms to AML, a clinical MDS that transforms or if you have genetics that show myelodysplasia-related changes, those diseases relapse fairly predictably with chemotherapy-only approaches. And the relapse rates are so high that we err on the side of giving transplant in first remission. And we do have prospective, randomized data that CPX outperforms standard 7 + 3 therapy.

Now, there’s one caveat I would throw in, which is, that study was only done in people over the age of 60. While the label allows treatment of younger patients –– and I would not say it’s wrong –– it’s not been my practice to treat patients under the age of 60 with CPX, just because we don’t have front-line data, and there is higher cost associated with that drug, plus some differences in the toxicities, including longer nadirs, longer hospitalizations. And I’m not sure that it’s worth it in the absence of randomized data outside of the over age-60 crowd.

Differentiating therapy-related AML; treatment outcomes in patients with unfavorable, complex or monosomal karyotypes

DR LOVE: It is possible that someone could have received chemotherapy previously and that the AML is not “therapy related”? How do you differentiate the presentation?

DR PERL: We really don’t have an easy way to know this. It would be nice to look at the flow pattern, the genetics or something, but we really know that if we look at patients who have leukemia following prior therapy, we see enrichment for certain genotypes, but they’re not 100%. The ones I worry about are patients who have evidence of aneuploidy, so lots of chromosomal abnormalities, particularly deletions and monosomies. Those patients often have mutations in p53 or a deletion in p53, which predicts a very poor outcome with any therapy, no matter what we give them. And those patients, we always try to get transplant even though we know even when we transplant these patients they have a high rate of relapse after transplant.

It’s an imperfect approach, but it really is the only therapy associated with long-term survival. These patients who have what we call a monosomal karyotype, which means they’ve got at least a monosomy of an autosomal chromosome or a p53 deletion or a mutation at a complex karyotype, those patients do very poorly with standard approaches. They really should be referred for transplant evaluation early in disease, because if they ever relapse we almost never get good control of their disease thereafter.

And if this were a patient as described in this case who had prior anthracycline-based therapy and I would think would be a risk for getting additional anthracycline, in a way that might complicate getting a transplant at all. I would reasonably err on the side of giving a hypomethylating agent-based strategy. And these days we’re pretty much not using a hypomethylating agent alone. We’re using them with venetoclax. There’s very few patients that I would give an HMA, hypomethylating agent, alone. I would generally give it with venetoclax, based on the single-arm data that shows substantially higher remission rates and really quite good survival long term and protection from relapse.

I think we need to wait for the randomized study to say it’s evidence based, but the available experience-based data, as well as the publications, is really quite promising. And my experience has been exactly as the papers show. The regimen works. It’s well tolerated. And it can be done in the outpatient setting once you have ensured that the patient doesn’t have tumor lysis in the first few days, which is a risk. Not a big risk, but it does exist.

Prior treatments that increase the risk of therapy-related AML; factors to consider in selecting intensive versus nonintensive treatment for therapy-related disease

DR LOVE: When you look at a patient’s history, in terms of therapy-related AML, are you mainly looking for anthracyclines or any other agents or regimens that kind of raise your level of suspicion?

DR PERL: There are 3 modalities that really increase the risk of leukemia following prior therapy for other cancers, and the agents that we worry about in this setting are anthracyclines or topoisomerase-II poisons, so that includes etoposide. We’ll see the higher rate in patients who’ve been cured of, say, testicular cancer, in women who’ve had prior breast cancer therapy. But recognizing also, those women get radiation. And radiation can also work as a TOPO-II inhibitor, or it can work like an alkylator in terms of inducing the kinds of damage that we see in alkylator-based leukemias.

Alkylator-based leukemias usually present with MDS and sometimes with AML. And there can be a very long latency between the exposure and the leukemia.

In somebody who presented 10 years after breast cancer therapy, I’m much more worried about the alkylatorand/or the radiation causing an alkylator-type injury, which often leads to p53 mutation and complex karyotype –– again, monosomal karyotype and very poor outcomes, both with induction and also postremission therapy. Really, those patients need to get transplanted if you can get them to transplant. Low CR rates to induction.

What we see with TOPO-II poisons, however, is, it looks like a de novo leukemia, and it may happen only months to a year or two after the exposure. That short latency is what leads me to say it’s more likely related to those agents.

If someone had breast cancer therapy and 6 months later they have a leukemia, we look for the translocation there or a normal karyotype –– they’re more likely to have intermediate- or favorable-risk genetics –– but we sometimes see translocations of the MLL gene in chromosome 11q23, and those can be much higher risk. Those patients, we’ll often err on the side of transplant.

DR LOVE: Another question that this cases raises, and a lot of cases raise, is intensive versus not intensive. And this comes up a lot of in oncology, mantle cell, whatever. Of course, everybody says age is not a number, but then you start asking about 90-, 95-year-olds and people kind of back off. But generally speaking, for example, how did you evaluate this woman? And how did she look? What was her performance status?

DR PERL: Fitness is a strong predictor of doing well with chemotherapy. And it’s variable. Because we’ll see patients who’ve had prior therapy for lymphoma and have had an autologous transplant and then develop leukemia, and it doesn’t take a lot of chemotherapy to tip those patients over.

One nice thing about giving induction to those patients is, you can see, can I transplant this patient or not? You’re not going to get that sense from a low-intensity approach. And you don’t want to find out during transplant that the patient really can’t tolerate chemotherapy. For that reason alone it’s sometimes worthwhile to think about, is this somebody I can offer induction to? And again, in therapy-related leukemia we err on the side of giving CPX when it’s an appropriate choice, for the reasons I mentioned before.

But low-intensity therapy is something that many patients want just because they’ve had prior chemotherapy and they know it’s hard. And they may not have in their mind okay, I need to get transplanted. They may not have expected to survive their prior cancer as long as they did, and it was a blessing that they got this far. When they get AML or MDS, they just say, “Okay. Enough. I don’t want to be in the hospital. I don’t want to be getting this therapy. I don’t want to be going through all the toxicity if there’s not a very high likelihood of payoff.” And you have to have a really informed conversation with your patient about this.

Yes, if the patient bounces back to excellent baseline of health, is doing well, has great functionality and really is, again, swinging for the fences and looking for the best treatment outcome for the longest amount of time, we treat them aggressively. We go for transplant. It’s the only way to cure that disease, with rare exceptions. And that’s how you have to look at these patients. That’s how I looked at this patient. The only complicating issue was the amount of prior anthracycline. And again, we don’t have an exact number.

Once you start adding up the numbers and you get up to around 500 mg/m² of daunorubicin equivalence, then you kind of are at the range where you have to worry about are you going to push the heart into permanent failure, where you couldn’t do a transplant necessarily if the patient winds up with bad cardiomyopathy. It can be challenging.

Considering patient needs and preferences in choosing intensive versus nonintensive treatment

DR LOVE: What was this woman’s attitude about the possibility of being treated with intensive chemo?

DR PERL: She didn’t want intensive chemo at all. It was actually pretty straightforward. You have a long conversation about just make sure you’re sure about this. Because when you step away from that, 2 things play into the decision-making. One is, yes, I can get you into remission with less-intensive therapy. With what looks like p53-mutant disease here, your likelihood of doing it is no better but, actually, probably not any worse with low-intensity therapy. But the durability is not good.

And so if we look at patients who’ve had venetoclax/azacitidine or maybe just azacitidine alone, we do get these patients into remission. There is some regularity with it. But it’s not a high likelihood of remission. It’s certainly not higher than we see with induction therapy.

There was an interesting article from the WashU group looking at 10 days of decitabine and arguing that should be the standard for patients with p53-mutated AML. But there’s actually a difficulty replicating that result in both our experience and other centers, and I have not been swayed by that study to say that should be our standard for everybody.

I tend to use venetoclax plus azacitidine here, because we could achieve faster results, do it largely in the outpatient setting and with relatively little toxicity other than myelosuppression, again with the risk of TLS in the first week of therapy in a few patients but not a lot.

But the problem with this therapy is, the relapse rate’s still very high. And when patients relapse, we don’t really have good options there.

Now, you could use that to be a reason to switch to a more intensive approach, but I don’t think we have the data now to say that’s better than just using intensive therapy from day 1. We also don’t have any head-to-head studies of intensive therapy versus venetoclax-based therapy to say what’s the right answer. I think in the future we’re hoping to have data like that after we get data of even just azacitidine alone plus venetoclax versus azacitidine alone. Those data are expected soon.

DR LOVE: I’m curious, though, the fact that she has this thought about chemotherapy being something she wants to avoid. How much of that was because of having a negative experience in the past? Was that the reason? Did she have a difficult time the first time?

DR PERL: Yes. There were certain toxicities of the therapy she was trying to avoid. And not everybody has experienced this. If you think of how AC plus radiation is tolerated, most women do get through it. It’s not easy, but they get through it.

What we outline, in terms of what intensive therapy in transplant is is just another order of magnitude for those patients. Plan on a month in the hospital for the therapy. With these genetics, the likelihood of going into remission is, on a good day, about 30% to 40%.

The majority of patients will get that therapy. They may need 2 months in the hospital, because we check a marrow part-way through and we say, “We haven't cleared out the blasts. We need to give you another round of treatment.” That means 2 months in the hospital, only to find that it didn’t work in the majority of cases. And if it works, we then line them up for a transplant. Another month back in the hospital. About 6 months of immunosuppression, all the risk associated with that, a high likelihood of relapse before the transplant or after the transplant, all the risks of transplant, including graft-versus-host-disease, serious infections, other complications, and it’s just more than some patients want to go through.

I respect that. I think you have to talk to patients frankly about the real risks of therapy, because there are alternatives. Unfortunately I think for this type of disease there’s not a good option for people who choose nontransplant therapy. You really need to make sure that if they say, “I don’t want the heavy-duty induction” that they’re really doing it for the right reasons.

Potential cure rates for patients with AML in different clinical scenarios

DR LOVE: I’m just kind of curious in this situation in her. I don’t know if she actually asked or you discussed what you thought maybe would be the potential cure rate. What number would you give a patient like that, a range of numbers? And what number would give someone with more garden-variety AML, and not therapy related, with intensive therapy?

DR PERL: The biggest problem with this is, as much as I can pick numbers for a patient, what I do tell them is, I can’t pick your number. I can give you a population of patients, and if you’re that 1 person who’s a long-term survivor and you see none of these side effects, you have done phenomenally. You’ll never know from all the things that didn’t happen. But you have to know the likelihood of that happening.

I can say overall, about, let’s say, a third of patients will go into remission, and we could cure up to half of those patients with transplant. If you do the math, you’re talking about 10% or 15% of patients overall. But people don’t necessarily think that. And if they’re in that 10% or 15% of patients, they don’t see everybody else who didn’t do so well. But you do have to realize that when you put those numbers, the flip side of that is, 85% of patients receive this therapy and don’t benefit from it, other than in terms of short-term gains, that they don’t die immediately of leukemia or its complications.

And those are real risks. They will live longer by having received therapy than not receiving it. But we don’t know that they’re going to live longer from the intensive therapy than less-intensive therapy, now that less-intensive therapy has caught up to some of those gaps that we had before, where we were just using low-dose ara-C, for example, which really is not an adequate therapy for this kind of disease.

DR LOVE: Again, those numbers would you give to someone with sort of garden-variety AML?

DR PERL: No. I would do that in this setting. In garden-variety AML –– I think this patient was in her 70s –– and the long-term survival on a good day for AML here really just depends on the genetics. Best-case scenario in patients with core-binding factor leukemias, we cure about 30% of those patients. Worst-case scenario, if you have high-risk karyotype, you’re talking about a 5% cure for everybody, but not everyone’s a transplant candidate. You have to look at that in terms of, can we take this patient to transplant if we achieve a remission?

And the interesting thing from the CPX study was, if they looked at patients over the age of 70, 70 to 75 on the study, versus those 60 to 70 on the study, the outcomes were pretty much the same.

Again, I don’t use age here if the patient’s fit and a transplant candidate. And more and more, we’re offering transplants. But as we get into the 70s, we’re very picky about who we choose here.

Again, if the patient’s a really fit 70-year-old, we’re going to be as aggressive as we can be. But older patients have more trouble tolerating this therapy. We’re really careful about whom we offer this to, because we really don’t want to harm patients and give them an unrealistic expectation of benefit here.

Diagnostic workup for AML; importance of genetic alterations in treatment selection

DR LOVE: Before you go through some of the options that you were considering discussing with her after you found out she really didn’t want to go the intensive route, can you just take a step back and talk a little bit about again what you consider the core of the workup for a patient with AML, particularly in a community-based setting?

DR PERL: Sure. The first thing to bear in mind is, even though patients are often getting worked up in the community, as an academician in a referral center, we like to be there and be able to help guide, is this something that can be managed in the community? Is this something that really we should manage in the academic setting? Because we’re offering targeted therapies earlier and earlier on trials, and in particular if patients have mutations in FLT3 or mutations in IDH1 or 2, we’re going to look at whether we can offer these patients targeted therapy from day 1 –– technically day 8 in the case of patients with FLT3 mutations. But in their front-line therapy is the point.

And increasingly we’re going to do sophisticated tests like next-gen sequencing panels that will give us more and more information that not so much guide the therapy on day 1 but might guide the therapy down the road. And so in patients who are borderline cases, is a transplant going to help or isn’t it? Or, in which we want to track mutations over the course of therapy, which is increasingly being seen as not a perfect minimal disease marker but measurable disease marker, we’re doing that more and more in terms of saying that persistence of leukemia-associated mutations is important.

At our center, we’ve been tracking every patient with next-gen sequencing since 2013. Everyone who walks in the door gets that with their initial diagnostics. And that’s becoming more standard.

The big problem with next-gen sequencing is, it just takes time. It’s hard to make treatment decisions based on a test that might have a turnaround time of 3 weeks. If you have the time to spend, yes. You can make decisions. But we don’t always want to wait 3 weeks before we come up with a management plan for a patient with AML.

As I mentioned before, if somebody has a karyotype that shows that they are likely to benefit from CPX, then we want to know that right up front. We actually, again, we will, once we make a diagnosis of AML, our knee-jerk is to send tests for a core-binding factor translocation. And if that’s negative, our next test is to say, do we see any of the common genetic deletions that predict response to CPX? And those include deletions of chromosome 5, either in the short or long arm, chromosome 7 and chromosome 17, which is where p53 is located.

We have a FISH panel that uses those, and if we see that’s the case, we will recommend CPX right from the get-go, again in patients over the age of 60, and the drug is approved for any age. But at our center we’re just treating over the age of 60. That’s the next thing we want to know.

We then send a FLT3 PCR, which is a rapid turnaround test that will tell you whether you have the presence or absence of a FLT3 mutation within a few days. We get our tests to turn around twice a week, so we know an answer within a few days of starting induction. But the important thing there is that we’ll know before the chemo is done and before day 8 if this patient would benefit from a FLT3 inhibitor added.

And the reason that that’s important is, there’s been a comparison of adding the drug midostaurin, which is not a specific FLT3 inhibitor but an inhibitor of FLT3 along with a lot of other kinases, to front-line 7 + 3 compared to placebo in patients who had FLT3-ITD mutations or FLT3-TKD mutations. And these are common. About a third of patients will have these. If you look at how many patients could benefit from that approach, it’s actually a fair number of patients.

The drug did not, obviously, increase toxicity of induction, but it improved survival. And the reason it improved survival, again, is not only were more people going into remission, but people stayed in remission better. The event-free survival was better. And also the transplant outcomes were better, particularly if patients went to transplant in first remission. For patients who are, again, on an aggressive treatment approach, we really want to know, did they have a FLT3 mutation within a few days of diagnosis?

Workup for intermediate- or favorable-risk karyotypes to guide the decision to use gemtuzumab ozogamicin in AML

DR PERL: I’m going to go back to the question of core-binding factor therapy, because that actually drives what we do as well. There are studies looking at the drug gemtuzumab ozogamicin. The name is a bit of a mouthful. I’m just going to call that GO — gemtuzumab ozogamicin. And GO is not a new drug, because it was approved around 2000 and was briefly on the market and then withdrawn out of some toxicity concerns. But then more recently reapproved based on a larger evidence base of comparison studies, mostly done in Europe, where the drug was added to front-line induction therapy. And in that setting did show an improvement in overall survival for patients with intermediate- or favorable-risk karyotypes. There were no benefits shown in the unfavorable-risk karyotype.

We’re not using the drug in adverse-risk disease. And at our center we’re trying not to use the drug in patients that we’re looking to take right to transplant, because there has been some concern that if you go to transplant soon after exposure to GO it can increase the risk of hepatic complications. And VOD has been an issue with that drug, particularly if you go to transplant soon after receiving it.

But if you look at the outcome of the patients who have a nonadverse karyotype, again, intermediate risk and favorable risk, there’s a survival benefit for giving GO. It’s small in the intermediate-risk group. It’s not small in the favorable-risk group. If we look at the outcome of patients with core-binding factor translocation, there was a 20% improvement in overall survival in this group that was associated with the use of GO front line. That’s a big improvement in a group that we already think of as being chemosensitive and a group that we’re not generally going to take to transplant.

We seek out the presence of an 8;21 translocation or an inversion 16 to say, that’s somebody that I want to treat with GO front line. I give 7 + 3 and GO to anybody who has that who’s fit for induction. And we’ve seen the best outcomes with that approach.

Integrating the FDA reapproved agent gemtuzumab ozogamicin into therapy for AML: Outcomes from the Phase III ALFA-0701 trial

DR LOVE: And exactly how is the GO integrated into the regimen?

DR PERL: We use the same regimen that was published from France, the French ALPHA study that was published in The Lancet a few years back and showed –– initially it suggested an overall survival, but longer-term follow-up showed the benefit was largely in event-free survival rather than overall survival in patients aged 50 to 70. And what’s different about that study was that the GO was given in the same dose for total administration as what had been approved for single agent, but it was fractionated. Given in 3 smaller doses of 3 mg/m², capped at 4 and a half mg, as part of induction and concurrent with induction starting on day 1. And that’s how we give the drug at our center.

We give it for just 1 course. If the patient needs a second cycle of induction, they don't get GO on the second cycle. And then we give 2 more courses of GO with consolidation. On that study they gave consolidation consisting of ara-C and idarubicin. And at our center we just give it with high-dose ara-C as has been shown by a British cooperative group study to be both tolerable and associated with better survival.

Patients ultimately receive induction and consolidation courses that include GO. And the published data suggests there’s substantially lower risks of relapse leading to both event-free survivals and overall survivals if you look at a meta-analysis of multiple studies.

Role of the hedgehog inhibitor glasdegib in front-line therapy for patients with AML not eligible for intensive induction chemotherapy

DR LOVE: We’re going to talk about venetoclax and HMA in a second, but another possible consideration, I guess, would be glasdegib, the hedgehog inhibitor. Was that something you considered in her?

DR PERL: Yes. Glasdegib is an interesting drug. It’s an inhibitor of the hedgehog pathway. It inhibits the protein smoothened, which is thought to be important for leukemic stem cell maintenance, and it’s been tested in a few different settings. There’s randomized data giving it with low-dose cytarabine to patients who are unfit for induction. And in that setting the drug was associated on a randomized Phase II study, not a Phase III but a Phase II study, with improved survival in the combination arm.

Based on those data, the drug was approved for use in patients who were unfit for induction. But there are a few things to pay attention to in that study. One is, the drug was not nontoxic. It had a significant amount of GI toxicity. It’s a little bit hard to take in terms of both anorexia and nausea. And in patients that I’ve taken care of who’ve been on that drug, that’s been an issue in terms of tolerability. But people can get through it, and people who do get through it seem to do better than low-dose ara-C.

The big question we have is, though, is this really an improvement over what they would receive with, say, a hypomethylating agent, which would be our preferred standard approach, prior to the approval of venetoclax? Because we don’t use a lot of low-dose ara-C front line. And it’s not that the low-dose ara-C is not an active regimen, it’s just not as commonly used in the US. It’s more commonly used in Europe. And in that setting, I think this may be an advance for those patients, although the approval’s in the US, because low-dose ara-C has a relatively low CR rate, and when you compared almost anything against it, there really haven’t been survival improvements, even when we see improvements in response rates.

That’s what’s notable about the study — is it actually did that. There are very few studies, if any studies, that show improvement in overall survival comparing something plus low-dose ara-C to low-dose ara-C alone. But if you look at how much low-dose ara-C these patients on the study got, it was relatively little. There’s very poor adherence to the low-dose ara-C. I wonder whether, if we really just treated those patients more aggressively, adhering to the regimens that you really need to stay on –– if there had been a placebo control on the study, we would have seen this. This was an open-label study. And again, it’s not powered for an overall survival benefit at Phase III, although it did show improvement in the randomized Phase II context. In our practice we’ve not found it to be a clear win over the results we’re seeing with venetoclax and hypomethylating agent, so we’re not using it very often.

I could imagine in a patient who’s had hypomethylating agent and venetoclax therapy previously, however. It’s important to know that there are alternatives. And we see this. We see patients with high-risk MDS who get all manner of therapy, trying to get into a response, and just don’t respond. And I think we need to try all options for these patients if, for some reason, they’re not candidates for more intensive therapy and don’t have targetable mutations. And that’s not an insubstantial number of patients who are out there.

I think the drug will be used. I just don’t know that it’s going to be front-line therapy for everybody walking in the door.

Treatment of AML with venetoclax and a hypomethylating agent: Considerations for optimizing therapeutic benefit

DR LOVE: I know that the other option, and I guess the option this lady and you decided to take was to use venetoclax/azacitidine.

DR PERL: In this case, yes.

DR LOVE: And was that what you recommended to her? And how did you come to that decision?

DR PERL: What sometimes happens is, when you meet the patient, you don’t have all the data. It’s not uncommon that we see the patient and we think they have MDS. We start on an MDS therapy. In the cases where we see the patient and it looks more like MDS than AML we might start with a cycle of hypomethylating agent and then the genetics come back and we say, “Oops, look what’s going on here.”

In this case it’s not so hard, because this patient has a therapy-related leukemia. But in some cases, they started with a hypomethylating agent. When should you add the venetoclax is a common question.

We err on the side of giving those 2 drugs together, not giving a week of azacitidine and then adding venetoclax after that. We really want to give the 2 together, because at least the in vitro data suggests there really is synergy when you coadminister these drugs. I think it’s important that you not use that as an “I can just always treat the patient with a hypomethylating agent and I’ll find out later on if they need venetoclax,” because that may actually just increase cytopenias without harnessing the synergy of the combination regimen.

Importantly, not so much in this case where I don’t need the genetics other than is this an 8;21, but evaluating a patient and saying, “I want to give venetoclax/azacitidine,” you want to start those 2 together. You don’t want to give a hypomethylating agent then follow up. Because again, you’re not going to necessarily see the synergy.

When you meet with the patient, you say, “Here are your options: intensive therapy, lead to transplant, versus lower-intensity therapy.” I don’t say low intensity, because it’s not low intensity. They really do get cytopenic. They really do need aggressive transfusion support. And if they get tumor lysis, they get very sick and they need to be in the hospital to manage that and they may even need dialysis. I’m quite frank with patients about the risks of this therapy, but I’m also realistic that they’re likely to get through and get through okay.

Prevention of tumor lysis syndrome in patients with AML receiving venetoclax-based therapy

DR LOVE: Maybe you can talk a little bit about exactly what happened to this patient, what you did?

DR PERL: We’re in the midst of therapy now, so there’s only so much I can talk about in this case.

DR PERL: But we’re administering venetoclax/azacitidine so far.

DR LOVE: Did you admit her to the hospital?

DR PERL: I did, yes.

DR LOVE: And do you admit everybody?

DR PERL: I err on the side of admitting patients to the hospital, particularly in patients who I would be very worried about monitoring them in the outpatient setting if they have any renal impairment, and generally in the older patients, that’s what I’m going to err on the side of. There’s not an exact cutoff here, but our ability to use a creatinine, to say what your creatinine clearance is, is pretty impaired in the older patients. If somebody has very low white count and they’re 61 years old but they have some degree of comorbidity that precludes induction chemotherapy or they refuse induction chemotherapy, they live 10 minutes from the hospital and they don't mind hanging out in our clinic for 8 hours on the first day of therapy, have I given the drug in that setting? I’ve given the drug in that setting.

I monitor prior to therapy tumor lysis labs. I monitor it a few hours after and 8 hours after. And they have to come into clinic the next day with predose tumor lysis labs, and we don’t give the second dose until we’ve seen that all of those labs are fine. You have to do that for 3 days running. It’s almost easier to be in the hospital.

I pitch that to the patients, and I always err on the side of safety. It’s usually easier to have them in the hospital, and they are there for 4 days and go home.

Efficacy of front-line venetoclax/azacitidine for AML

DR LOVE: And that’s what happened with this lady? She was in there for 4 days.

DR PERL: Yes.

DR LOVE: And what’s her current situation? How long has it been since she was started?

DR PERL: This patient is on I think about 9^th cycle now, still doing okay.

DR LOVE: And what’s going on with her counts, et cetera?

DR PERL: Counts normalized after 1 cycle. Went into a CR. She was lucky. Not everybody does, but she’s done well. I’ve repeatedly offered her transplant, and she said no.

DR LOVE: Can you talk a little bit about at least your overview of the data that we do have with this strategy?

DR PERL: The data with hypomethylating agents actually come from a single study. The history of venetoclax for AML goes back to a relapsed/refractory Phase I study where they looked at single-agent venetoclax and found, in patients that were very heavily previously treated, that the drug had only limited activity to induce remissions and not such a great survival that we would say that this is head and shoulders above anything else that’s available. It was steered towards combination studies, and those have been more successful.

In the front-line setting though, there’s only 1 published study to look at how well the drug works, and the Phase I was published separate from the Phase II. The Phase I was published in Lancet Oncology this past year by Courtney DiNardo and colleagues, and she also published the Phase II in Blood a couple of months thereafter. It shows up there.

There’s also a similar regimen using low-dose ara-C that Andrew Wei had published in the Journal of Clinical Oncology. All of these are within the last 6 months, so in the first 6 months of 2019. And they show very similar findings. The differences in these studies are minimal in terms of the patient populations. The low-dose ara-C study allowed patients with prior hypomethylating agent used for MDS, but nobody could have been treated for AML prior to going on the study. These are all untreated AML cases. And the response rates are very similar.

The complete remission rates, looking at either full CR with full count recovery, transfusion independence or CRi, where the CRi largely reflects ongoing neutropenia. The neutrophils didn’t go above, say, 1,000, but they were recovering. And in general these patients were transfusion independent and had platelets over 100. The CR and CRi combined rates on each of these studies were in the range of about 60%, 65%, which is very good.

Have we seen that high a response rate with lower-intensity therapy in patients like this with anything but 7 + 3? Pretty much never. The clofarabine data are about the closest we’ve seen here, using lower doses of clofarabine. And that was considerably higher than low-dose ara-C on a randomized comparison, but the survival was the same.

What we really need to see is, is that a short-term gain or a long-term gain? And that’s what we are waiting for from randomized, front-line studies. There is a Phase III study that’s completed enrollment comparing hypomethylating agent. In this case the Phase I/II study allowed either azacitidine or decitabine, but the Phase III is just azacitidine alone.

Either azacitidine as a single agent or azacitidine combined with venetoclax, head to head, in unfit patients who are untreated for AML and then all that prior hypomethylating exposure. And that study we don’t have data yet from. We’re really anxiously awaiting the results.

The reason we’re optimistic about this is that if we look at the survival from the Phase II single-arm study, that was multi-institutional trial. Not only were the remission rates quite high, but the median duration of remission was about a year, and the median overall survival was 17 and a half months. And that kind of survival has not been seen outside of intensive chemotherapy studies for AML in patients over the age of 65. Really no therapy has done that. And even if you look at patients who had prior MDS, therapy-related leukemias, the survival was maintained. The response rates were maintained. This looked actually as good as anything we’ve ever seen published from any other study in a nonrandomized comparison. And that’s always the challenge is, you’d like to compare apples to apples in a prospective, randomized trial. But it’s a very reasonable regimen in this setting to say that we’ve seen significant survival from an outpatient-based, low-intensity therapy that is at least comparable to anything we see with more intensive approaches.

Age- and fitness-based risk-benefit assessment when determining whether to administer venetoclax/azacitidine to patients with AML

DR LOVE: I wonder whether there’s ever been a situation like this in oncology.

DR PERL: I’m sure there are times like this in oncology, but in AML there hasn’t been something like this where it’s really just turned the whole therapy on its head. We’ve gone from years of highly intensive therapy, no pain/no gain. You have to be able to get the really intensive stuff to see the payoff. Anything less than that is just not good enough. Now we have a much less intensive approach for more and more patients. And we used to tell patients from day 1, “We’ll give you supportive care, but we’re not going to treat you, because we don't know how much benefit there is.”

There are very few patients that we’re saying no therapy and just supportive care is the right answer, although some. In particular, the patients I worry about are those who don’t have good social support, those who have difficulty getting into the clinic to get transfusion support and those with impaired mobility, where it’s hard to get from point A to point B if they have a problem. Those patients are very hard to treat with anything that we have.

I do not think that matches the group that was studied here, who, for the most part, had a performance status of 0 to 2. Patients who are largely bedbound, we don’t know that this approach is as good as anything else. And we do have to be careful about that, because it lends us a little bit of a false sense of security to say we can treat anybody walking in the door. That may be true for walking in the door, but rolling in the door may be different if patients have impaired mobility, poor performance status or really significant comorbidity, which wasn’t primarily the patients treated here.

These were all unfit for induction. May have been the fitter of the unfit, at least in the patients who got on the study under the age of 75, whose qualifications were lack of fitness. Over age 75, you could be fit or unfit on this trial. And in those patients, I really do think it’s the right choice. But again, many of the patients who went on the study were actually in reasonably good shape.

Monitoring for and mitigation of tumor lysis syndrome associated with venetoclax/azacitidine

DR LOVE: I’ll say, looking outside of AML, having been involved with oncology CME for more than 30 years, that I don’t think anything has ever happened like this in oncology where you go from a situation where people are getting palliative care to not only have a therapy that’s effective, at least certainly in the short run, but not that straightforward about what to do. And we’ve been just, like, trying to throw out every red flag out there for people to take notice of what’s going on here.

But let’s talk about the potential complications. You’ve talked about TLS. I have to say, your case is the first case I’ve heard of clinical TLS with hypomethylating agent with venetoclax. What happened with your patient?

DR PERL: Our patient was not the most severe and has happened at other places. I’ve had conversations with colleagues at other academic centers. They’ve all seen it. I’ve spoken with Marina Konopleva, who’s seen it at MD Anderson. Dan Pollyea has seen it at Denver. Keith Pratz, who’s a colleague of mine, when he was at Hopkins they had a case there. And everybody has, like, a case.

Our case wasn’t that severe, but our patient did need to be admitted to the hospital. Was briefly in ICU for electrolyte management.

DR LOVE: Oh, I thought you said the patient had dialysis.

DR PERL: My patient did not, but the patient at Anderson did.

DR LOVE: Really? Wow!

DR PERL: It has happened. And our patient, we gave a single dose of 100 mg of venetoclax, and the uric acid, the first one came back at 13 and a half. And that wasn’t the peak. We have to watch out for this as a real potential toxicity.

DR LOVE: What about the particulars of preventing TLS? Where does rasburicase fit in?

DR PERL: The big problem is there’s not a great way to predict who’s going to have it other than the studies all require patients to have a white count less than 25,000. And I hold to that number because I know that that, again, in CLL is a risk factor for tumor lysis syndrome, and we would expect the same in AML, even though it’s not been studied in that setting.

I think hyperleukocytosis plus venetoclax is potentially a real risk. It’s just a data-free zone where we just don’t know how high that risk is.

DR LOVE: What was your patient’s white count?

DR PERL: It was low, actually. It was less than 10.

DR LOVE: And how do you approach allopurinol versus rasburicase?

DR PERL: I always give allopurinol to these patients. I like to start, actually, a few days beforehand just so they have a good and low uric acid. And that’s actually on the label as a recommendation. But in terms of best practices, you want to be prepared.

In somebody who needs screening for G6PD deficiency, we screen them when we can. If we’re kind of stuck in the moment, we may not have that luxury, and we just have to say high-risk or nonhigh-risk patient.

But I don’t give preventive rasburicase to anybody unless they walk in the door already in tumor lysis. I would just hold off on giving that preemptively. If you need to give it, you certainly can. I think rasburicase is a wonderful medicine, because it’s prevented the need for dialysis in many patients.

I don’t see this as a very high likelihood of needing dialysis. Again, if we see this 1% of the time it would be a lot. But it’s not 0. It was not seen on the trials, but that doesn’t mean it doesn’t happen.

Management of myelosuppression associated with venetoclax in combination with a hypomethylating agent

DR LOVE: The other thing you mentioned that we’ve heard a lot about and I’m not clear at all about in terms of how you're supposed to manage this is cytopenias. What do you typically see, and what do you do?

DR PERL: I mean, the management of anemia and thrombocytopenia is no different than any other patient. We transfuse these patients until they’re either asymptomatic for — the hemoglobin ideally getting them up. Again, in older patients, pick a number in terms of where they don’t get symptoms. It could be 8. Some might be able to tolerate even lower than that. Some need 9 or 10 if they have significant cardiac disease.

For platelets, I try to keep my outpatients’ platelet counts ideally over 20 so they’re not really at risk for bleeding complications, at least between visits. If they’re under that, I’ll transfuse them on up. And if they’re less than 10, I may give them more than 1 transfusion at a spot.

For white cells, however, the issue is that venetoclax and hypomethylating agents are quite myelosuppressive, and usually after 4 weeks of therapy the bone marrow is aplastic. We always schedule a marrow at the end of the first course of therapy to see, is that indeed the case? And, more importantly, if their counts are really low then, enough, and they are, is that because of persistent disease, or is that because of aplasia? Because if their marrow is aplastic, they’re responding.

In those patients we actually can even give the growth factor GCS-F for a few days and usually boom, the white count shoots right on up and they’re able to start the next cycle within, say, a week or two. In those circumstances that’s been an approach we’ve tried. And I think improved safety in this setting with relatively little in the way of downsides.

If there’s persistent disease, however, they should not be getting growth factor. They should be getting more therapy. I think if you're not responding after a first cycle, you should try a second cycle if the patient’s well enough to receive it. If the second cycle works and the patient goes into remission, great. But, unlike azacitidine alone, we don’t see a need for 6 cycles of therapy before throwing in the towel and saying it’s not going to work.

These patients, usually you can tell within 2 cycles. And the benefit of additional cycles is very marginal. In the two studies that have been published in Blood and Lancet Oncology, the vast majority of patients responded to the first cycle and very few, if any, responses were seen after cycle 2.

Case: A man in his mid-20s presents with hyperplasia, leukocytosis and fatigue and is diagnosed with AML with a FLT3 mutation

DR LOVE: Let’s go through the rest of your cases and maybe kind of try to do a little more brief so we can kind of get through them all, because they look like really great cases. And I’d like to hear about your 25-year-old patient.

DR PERL: My area of research expertise is in FLT3 mutations and FLT3 inhibition in the treatment of a patient with AML. This, to me, is not an uncommon story in my practice.

This patient presented with gingival hyperplasia, leukocytosis, fatigue, so that he couldn’t do his work. CBC was drawn. White count very elevated. And when I hear this story, just boom! My spidey sense for FLT3 mutations goes off.

If we look at everybody with AML, particularly patients under the age of 60, because FLT3 mutations are more common in younger patients than older, though we can see them at any age, about a third of patients under the age of 60 are going to have a FLT3 mutation, with about three quarters of those being FLT3 ITD and about a quarter of them being a tyrosine kinase domain or TKD mutation, usually at position D835. And it’s the FLT3 ITD that is the one that I really worry about, because that’s the mutation that’s associated with the higher relapse rate and poor survival if the patient either doesn’t respond to induction or relapses after prior remission. Very poor survivals for anyone who has relapsed/refractory disease.

And so our approach here is, again, we want to quickly get a young patient with acute leukemia diagnosed, worked up and started on therapy. This is not somebody we’re dillydallying with in the outpatient setting. We quickly get them into the inpatient setting so that we, particularly if anybody has any bleeding tendencies or bruising, has any DIC at presentation. We can stabilize that. Get diagnostics off and get them started on intensive chemotherapy with curative intent.

If we see that there is a FLT3 mutation, then we err on the side of giving those patients a FLT3 inhibitor as part of front-line therapy. And when I say a FLT3 inhibitor, the standard right now is midostaurin, based on randomized data that it improves survival based on the RATIFY study that compared it to placebo. With that being said, there’s a lot of interest in drugs that are both more potent at inhibiting FLT3 and also more selective at inhibiting FLT3. And there is a number of studies that are ongoing right now and drugs that have been approved in the past year that do that.

What’s different about those drugs? What’s different about those drugs is, they work as single agents, whereas midostaurin as a single agent sort of was like hydroxyurea –– we controlled the white count. It wouldn’t do very much to the bone marrow blast. Patients might have felt a little bit better when they were on the medicine, but they still didn’t go into remission with really any regularity at all. They did not see complete remissions on that study. And all of the newer drugs have more potency of induced complete remission in at least a subset of patients.

And with the recently approved drug gilteritinib, actually about 20% of patients with relapsed/refractory disease will go into a full CR with blood count recovery. And that’s head and shoulders above what any other FLT3 inhibitor has done. And about half of patients treated with that drug in the relapsed/refractory setting will have a reduction in bone marrow blasts to less than 5% with variable amounts of blood count recovery and generally feel quite well.

The new FLT3 inhibitors are very exciting, but we don’t yet have front-line data to say that they’re better than midostaurin. That’s a clinical trial that a lot of centers are looking at getting open, is comparing midostaurin added to 7 + 3 versus the newer FLT3 inhibitor.

And another drug that’s on the horizon that you should pay attention to is a drug called quizartinib, because it’s been looked at in the relapsed/refractory setting, but there’s also a front-line study comparing the addition of quizartinib rather than midostaurin to front-line therapy, like the RATIFY study, compared to placebo. It’s an older trial. And that’s supposed to read out probably in the next year. It’s fully enrolled now.

Who knows? We may have more FLT3 inhibitors available in the front-line setting, either on trials or if the quizartinib study is positive, maybe even as standard therapy.

That’s something that we want to offer our patients as enrollment in a trial with this disease to see whether they can benefit from newer therapy over standard therapy. But with the FLT3 mutation, whether it’s an ITD or a TKD, we really do think that 7 + 3 is not enough. They should get 7 + 3 and FLT3 inhibitor from day 1.

Efficacy and safety results from the Phase III ADMIRAL trial of gilteritinib for relapsed or refractory AML; potential for moving gilteritinib into earlier lines of therapy

DR LOVE: Could you talk a little bit more about the data that we have with these newer FLT3 inhibitors, particularly gilteritinib?

DR PERL: Sure. Gilteritinib is a drug that again is a more selective and more potent FLT3 inhibitor. It’s not approved for front-line therapy, but it is approved in the relapsed/refractory setting. It’s approved based on results that have been released from a Phase III study that’s not yet published, so we’re looking forward to that. I was the lead investigator on that trial. I presented these data at AACR this past year. And that study used gilteritinib versus investigator’s choice of 1 of 4 options as first salvage for patients with primary refractory disease or relapsed FLT3-mutated AML, with the FLT3 mutation documented at the time of refractoriness or first relapse. They could not have had prior salvage to go on this study. And what the study showed was that the vast majority of these patients, more than 80%, had had prior intensive therapy, although that was not required — again, to allow people that had venetoclax/azacitidine, a rather low-intensity therapy, with a goal of remission to go on the study.

The response rates were higher in the gilteritinib arm, actually substantially higher in the gilteritinib arm, and not only was there higher response rates, but that translated into a better survival. The median overall survival in the gilteritinib arm was 9.3 months, and the chemotherapy arm was 5.6 months. And this was true whether patients received intensive chemotherapy or low-intensity chemotherapy. There was a benefit no matter which choice of prerandomization chemotherapy was selected for the patient. And in the intensive arm, that included standard salvage regimens like FLAG-IDA or MEK, which are what we would say are our standard approaches to try to get patients who are, in this setting, hopefully being treated with curative intent with the goal of going into a second remission, going to transplant and seeing long-term benefit.

We don’t see good response rates to standard chemotherapy. We see better response rates to a single-agent FLT3 inhibitor.

And the other area where it looked better was in terms of toxicity. It’s a much easier drug to tolerate. We don’t see serious toxicity that requires inpatient hospitalization. The majority of the therapy given to patients on the gilteritinib arm was done in the outpatient setting. It’s not to say the drug has no side effects. The main side effects we saw were cytopenias. Cytopenias are very common with the drug and mostly seen on the first cycle. But there are responding patients who have ongoing transfusion needs, and I don’t use that as a factor to determine transplant candidacy or not. If somebody has cleared their marrow blasts of their disease, then we take them on to transplant.

But one other thing the study allowed was, once they go to transplant, they can get the FLT3 inhibitor after transplant. And that’s something I encourage my patients to do, knowing that even if we do a transplant in second remission, relapse rates are very high for these patients.

One challenge in this study is that if we look at the overall survival for this study, while the median survival was better, the overall survival for the study in either arm was still low. This is a really high-risk population. And while I really think gilteritinib is the right answer in this setting, we’ve not yet transformed relapsed/refractory AML into a kinder, gentler leukemia in any way. This is still a really bad disease. The vast majority of these patients die of leukemia. We need better therapies.

Again, that behooves us to find the right front-line therapy. And to say if we’re giving drugs like gilteritinib in the relapsed/refractory setting, wouldn’t that improve outcomes front line? And we’re doing the studies to test that, both in front-line therapy and also for patients who go on to transplant to see if maintenance therapy after transplant would improve outcome.

And there are interesting data that came out in the past year that suggests that’s the case –– a study adding sorafenib, which is not approved as a leukemia agent, but does inhibit FLT3, adding that after transplant improved survival on a randomized Phase II study done in Germany compared to placebo. At least it tells us that we’re barking up the right tree here. The caveat before we can say that’s the right answer and everybody should just get sorafenib is that that study enrolled patients after transplant, not at diagnosis or not pretransplant, and it included patients that were not in remission at the time of transplant. It’s a broader group than what we’d like for a perfect assessment here.

I think if you were including patients who have relapsed/refractory disease, that kind of errs on the side of something I would do anyway as standard. But for a patient in first remission, we really want to know, is there a benefit, knowing that the outcome from the RATIFY study showed that comparing midostaurin front-line therapy to placebo front-line therapy –– if you look at the patients that went to transplant in first remission, the transplanted patients who got no further midostaurin still had better survival, suggesting they’re getting a deeper or better-quality remission when you add the FLT3 inhibitor to 7 + 3, and that may actually be all that you need.

FLT3 inhibitors as maintenance therapy: Optimal duration, quality of life and the ongoing Phase III BMT CTN 1506 trial

DR LOVE: In these strategies where you use a FLT3 inhibitor as maintenance, how long do you use it for? And are there any quality-of-life toxicities beyond cytopenias?

DR PERL: It’s a great question. We don’t know the answer in relapsed/refractory patients. I, again, was involved in the first-in-human Phase I study. I was the lead investigator of that for gilteritinib. I still have a patient who’s on gilteritinib maintenance 4 and a half years out from her transplant. She’s never relapsed.

DR LOVE: Wow! Wow! Hmm.

DR PERL: She feels fine on the drug. She has other transplant complications, but not gilteritinib complications.

Her platelet count is 120, and I don’t know whether that’s the gilteritinib or just post-transplant. But she is transfusion independent. She hasn’t gone to graft-versus-host disease. She’s otherwise living life and doing well.

I have no idea whether I should stop the drug. We have no data to say that we are at a point where we can and can’t. It would be nice to use MRD assessments to say that we can use that to decide that, but we actually don’t have those data yet.

There’s a front-line study that is ongoing that the Bone Marrow Transplant Clinical Trials Network is running and I’m an investigator on that is comparing gilteritinib versus placebo in first remission, which is a really different population. And again, many of those patients can be cured with transplant alone. And adding gilteritinib after transplant to, again, half the patients on the study –– actually, it’s a blinded study, so we don’t know the outcome on this yet, and we hope to have that answer within a few years, but we don’t have anything off of that study. That study will use extensive use of MRD assessments prior to transplant, after transplant, to track FLT3 mutation burden and see, can we say who are the patients who are going to relapse and pick them out early? And that study gives 2 years of maintenance.

The sorafenib study also gave 2 years of maintenance, and there were relapses after the 2 years. We don’t know what the right answer is there. And I think probably the right answer is, until we know better, if you’re going to give maintenance, at present do it on a study. If you can’t get your patient on the study, sorafenib does have some support for it. And I do do that in patients I can’t get on study. I give it for 2 years. We don’t have data longer than that. We don’t know the right answer, and we need to do the study to figure that out.

DR LOVE: Again, when oncologists think about sorafenib and putting somebody on it for 2 years, in terms of quality-of-life issues come up ––

DR PERL: It’s a hard drug to take. Yes.

DR LOVE: Again, what about gilteritinib? Same thing? In terms of, again, quality ––

DR PERL: There’s only so much I can say about an ongoing study that’s blinded. I can’t really say the patients I have on that study who are taking gilteritinib, because I don’t know who they are. But that tells you something important. If I can’t tell who they are, then that’s a good therapy.

DR LOVE: That’s a good point.

DR PERL: Because you want a blinded study where you really can’t tell who’s who. And that’s the nice thing with gilteritinib. There might be some laboratory hints as to who’s who, in terms of some ancillary things we see with gilteritinib –– it bumps LFTs a little bit —

DR LOVE: That’s interesting.

DR PERL: –– usually not a lot. It bumps LDH a little bit, usually not a lot. It bumps CK a little bit, usually not a lot. And that’s rarely a reason to stop the drug. But what we can say is that in patients that I’ve treated on the study, they’ve done well, and their quality of life post-transplant isn’t anything other than what we might expect.

I do not see that experience with sorafenib, where about half the patients I’ve tried to give this drug to post-transplant just simply can’t tolerate it. And so that’s my concern for the German data is, I love the outcome that it improves survival, but it’s a hard road to get to that payoff. And many patients just can’t tolerate it.

Outcomes with gilteritinib as front-line therapy for AML with a FLT3 mutation

DR LOVE: Getting back to your 25-year-old patient, what’s his current status?

DR PERL: This is an older case, so he’s actually done with all of the therapy. This is a patient who I enrolled in a study of gilteritinib added to front-line chemotherapy. He received 1 cycle, went into remission.

I think he got a cycle of high-dose ara-C with gilteritinib and then went to transplant. Got 2 years of maintenance on the study. Completed all therapy.

He’s more than a year out from completing maintenance. He hasn’t relapsed. He’s back to full-time work. Feels great and has no long-time complications.

Is that going to be everybody? No. But it certainly was the case for him. And I’m glad he had a great outcome. And if we look at patients who are 3 years out from transplant, their outcome is very good.

We are seeing a really different experience with FLT3-mutated patients now than what we saw before, because we’ve had advances in therapy. And I wouldn’t say that that’s limited to gilteritinib. We see that with midostaurin as well. There’s a better cure rate now than we’ve ever had for this disease. And what we think of, in terms of this is high-risk leukemia, is really only if you don’t treat it right.

If these patients don’t get front-line FLT3 inhibitor, I worry about them. If they don’t get transplanted, all the more.

Patients with FLT3 ITD I think do benefit from transplant. There are data from Europe suggesting there’s a subset of patients that may not need that. There are concerns that I have about those data that the PCR test that they’re using is not validated for worldwide use and/or standardized. And for that reason I’ve not used allelic ratios to largely sway one way versus the other. And similarly, if these patients ever relapse we know the outcome is very, very poor.

If they’re transplant candidates I’ve erred on the side of offering transplant to FLT3 ITD-positive patients. The TKD mutation is a little bit less sinister, and so I can be swayed by patients based on treatment response. Perhaps their MRD will be more helpful.

In Europe, they’re more likely to use MRD to guide therapy. And here in the US we’re a little bit late to the party in that management.

Treatment options for older patients with AML with FLT3 mutations who are not candidates for intensive therapy

DR LOVE: I want to hear about your patient with the IDH mutation. But one final question about FLT3. And I was just kind of flashing on this –– we did a multitumor program that we do every year in New York. And one of the modules was on acute leukemias. We had Harry Erba and Wendy Stock there.

And one of the more interesting questions we posed to the audience and to the faculty was, how do you manage a patient with a FLT3 mutation who’s not a candidate for intensive therapy, an older patient?

DR PERL: Ah! We just had one of these.

We had somebody in their 80s who presented fairly sick, actually, some degree of heart failure. I forget if he also had renal dysfunction. But was certainly, both for age and comorbidity, not an induction candidate. Do you use venetoclax/azacitidine in this patient? Do you use a FLT3 inhibitor front line? I think one problem here is, again, it’s all anecdotes and all the studies are small. There’s been about 20-something patients on the front-line venetoclax/azacitidine study that had FLT3 mutations for whom we have data.

It’s not a huge N, but the data on those patients is, they often had a comutation and nuclear phosphine. Virtually all the patients with nuclear phosphine mutation responded, to the tune of, like, 90%. The remission rate is actually quite good, and the side effects are not all that different than what I’ve just described. It’s quite manageable.

The challenge, however, is, either maybe because of the FLT3 mutation or because of development of FLT3 mutations, we’ve seen treatment failures in terms of relapses with that approach. It really gets down to do you want one therapy that just sticks and you get a very long treatment duration? Or can you sequence these?

Gilteritinib is approved as salvage therapy after prior remission or with primary refractory disease. You very reasonably could say I’m going to use venetoclax/azacitidine. If the patient responds, continue it as long as you get response and benefit from it. And at the point of relapse, switch then. That’s what the data would suggest. That’s what the label would say you should do.

I can say, again, anecdotally, before gilteritinib was approved we often would use sorafenib and azacitidine to treat patients like this, particularly when they present with really aggressive disease, hyperleukocytosis. And as I said before, that’s a risk factor for tumor lysis, and it’s hard to get their white count down without using grams and grams and grams of hydroxyureato the point that the patient can’t swallow anything. They get such bad mucositis from the hydroxyurea. That’s been an issue if we’re trying to tease somebody up for venetoclax, knowing that we have to get their white count down very low.

In this setting I have actually used sorafenib and azacitidine with very good results, again, with a small number of patients. And it’s not published yet. There is 1 paper on front-line sorafenib/azacitidine data from MD Anderson. The data looked very good. More than 70% of patients went into remission with or without full count recovery. The durability of those responses was comparable to what’s been seen on azacitidine studies for people who go into remission, but just more of the patients went into remission.

In my experience, I’ve had patients go a year or two before they relapse. And in an 80-something-year-old, that’s good if you can tolerate the sorafenib.

Now there’s an ongoing study looking at gilteritinib front line with or without azacitidine as the original question. It was a 3-arm study. They’ve condensed it just to 2 arms, azacitidine versus gilteritinib/azacitidine. We don’t have that study open, because we don’t like the control arm. We wouldn’t want to withhold venetoclax from a patient who could potentially benefit. And for that reason, I think it’s going to be hard to enroll that study in the US.

But there will be data soon about giving gilteritinib with azacitidine, more than just the safety cohort, which has been reported, and it was tolerable. And the response rate was quite high, actually not all that different from what was seen with the larger study giving sorafenib and azacitidine.

To answer your question, what’s the right answer? We don’t know. What would I do? I think it’s depends on how easily we can control the white count. If it comes down very readily with hydroxyurea, I’ve got no trouble saying our standard approach is to give venetoclax/azacytidine, and I do that. It’s on label. And we’ve had patients do very well with that. If they progress, I switch them to gilteritinib at that point. Or we look at a clinical trial if the patient, again, is very advanced in age and not a candidate for transplant, knowing that, again, in relapsed/refractory, a FLT3-mutated AML, survival is really quite poor. And while it’s longer with gilteritinib, it’s not necessarily years and years of experience in terms of saying we get lots of patients to long, long survival.

DR LOVE: I’m remembering, when we asked the audience through a poll question what they would want to do, there were a bunch of people who said the obvious thing to think about, which would be azacitidine/venetoclax plus a FLT3 inhibitor.

DR PERL: Let me put it this way: It’s planned. Everybody is talking about that’s kind of the next obvious study that we want to do.

Have we done it anecdotally? I hear anecdotes here and there. I would not want to do that off a study if I really didn’t have to, for the simple reason that you see a lot of cytopenias with gilteritinib alone. You see a lot of cytopenias with venetoclax/azacitidine.

We don’t know for how long to treat these patients. I would be very cautious about doing that triplet without at least some feasibility and toxicity data, knowing that it really could increase toxicity for infections would be my main concern, from potentially rather significant myelosuppression, which is a predicted overlapping toxicity of these therapies.

Evidence supporting the use of IDH inhibitors for older patients with AML with IDH1/2 mutations

DR LOVE: How do you approach the patient who’s older, not a candidate for intensive therapy, IDH?

DR PERL: Yes. Ivosidenib, the IDH-1 inhibitor, is actually approved as front-line therapy. And again, if we wanted to look at who might be somebody looking at this, if somebody had had prior hypomethylating agent for MDS and then progresses to AML and has an IDH-1 mutation, it’s on label if you want to try it.

What’s been the experience giving the drug? And my experience has been similar to what is out there on the trials. I’m not an author on the trials, but I’ve given plenty of these drugs postlaunch, after they were approved.

It’s an easy drug to tolerate, both ivosidenib and enasidenib. These drugs don’t have a lot in the way of side effects that compromise patients’ daily quality of life. The thing we can get into that as an issue is, it can actually work a little bit too well. It can induce differentiation of the leukemic clone, which, granted, we just need to recognize and then manage. If you see it, it can be severe. It can even be life threatening. You have to have a high index of suspicion, and you need to alert the patients to this too, because they may be sitting at home saying, “Oh, I don't feel like going in to see the doctor today. I’ve got this cough, and I don’t want to sit in the waiting room. And I’ve been having a low-grade temperature,” and they don’t know if their white count is now 25,000 and it’s all neutrophils.

Induction at differentiation can be life threatening in these patients, and they can go from being well to sick fairly quickly. We have seen cases of differentiation syndrome at our center in patients treated with these drugs. I do recommend hospitalization to manage that, at least to see what’s the pace of this and does this respond to steroids. We give dexamethasone, as we would in APL patients, based on the experience on the trial and in discussions with other people in the field. That’s basically our standard approach now.

It does control the side effects. It doesn’t necessarily control the disease in the way that we see with APL therapy. With APL, when you induce somebody with arsenic and all-trans retinoic acid, you see virtually everybody go into remission within a few weeks, and that is not necessarily the case when you treat with an IDH inhibitor.

You may tone down the differentiation syndrome. You may need to treat again and again. The pace of response is relatively slow to these drugs. The differentiation syndrome usually doesn’t happen in the first 2 weeks, but it can happen really any time after that. It may take a month or 2 before you see this. And the challenge is, sometimes it can look a lot like progressive disease. The white count shoots on up. You only see a few blasts –– 10% blasts in the periphery. You say, “Yes, let’s move on to something different here.” That may not be the right choice, because you may actually just be seeing that the clone is differentiating. It’s spitting out a few blasts as that happens. And if you continue therapy, continue these patients on steroids, they may be able to get through that.

You often, in that setting –– if they have leukocytosis –– will also have to give hydroxyurea to control the white count — we’ve done that –– and then you just kind of watch and see. If patients are feeling better on steroids and hydroxyurea, then we can usually continue the therapy in the outpatient setting after a few days and start tapering the steroids.

And importantly, these drugs are long lived. Stopping the IDH inhibitor is not adequate to say I’ll just watch this go away, because it takes weeks for that to get out of the system. I think the half-life of ivosidenib is about 5 days. If you stop the drug, it’ll take 2 to 3 weeks before the drug level has dropped enough for you to see a treatment effect that might be induced by the therapeutic change. You really need to treat that with steroids, not with stopping the drug. And only if the patient had a severe reaction that was life threatening would I hold the drug.

Evolving treatment landscape in acute lymphoblastic leukemia (ALL); management paradigm for ALL in younger versus older patients or those with Philadelphia chromosome-positive disease

DR LOVE: Maybe just make some closing comments about ALL, maybe even without going through the case. ALL is a disease that, in general, the general medical oncologist in the community is usually farming out to a tertiary care center.

DR PERL: Yes. ALL, we’re not seeing as many ALL cases treated in the community, because it’s so complicated still. And the new drugs have been really revolutionary, and the new approaches have been revolutionary, but they haven’t moved the therapy to the community oncologist.

DR LOVE: On the other hand, I think it is important for those docs to understand what’s going on and what their patients might be getting into when they go to a tertiary center. Can you just summarize from your point of view what are some of the major things that have occurred in the field that you think are important for a general oncologist to know about?

DR PERL: The big difference is, salvage therapy works. That’s the big difference. And the other big difference is, younger patients should be treated with a pediatric approach. If I had to say 2 major advances in the ALL world, those are the 2 things.

The pediatric approach was recently published. Actually, Wendy Stock was the lead author on that in Blood in the past few months, using a regimen that was literally borrowed from the Children’s Oncology Group and used to treat patients up to the age of 40 on that study, I think even for a brief period enrolled patients up to age 50.

The goal in that study was to enroll people up to the age of 30, and then they just expanded it, but using the same regimen that had been the control arm from a recent COG study. And that used a different approach to treating patients, not in terms of the drugs that it used but the duration of therapy, the intensity of therapy, primarily for the antimetabolites.

What’s different in pediatrics is, they use less myelosuppressive drugs, but they give them metronomically for a much longer period of time and keep a high dose intensity for the antimetabolites, in a way that was often not done in adult ALL –– which, quite honestly, more paralleled AML approaches: very intensive therapy for short courses, long breaks in between cycles. And the relapse rates, if you compare patients who were treated on pediatric center trials versus adult center trials at the same ages, were substantially higher in the adult centers for years across multiple, multiple, multiple comparisons. And finally we in the adult world just threw up our hands and said, “Let’s take the pediatric regimens and see if we can give them at all.”

We now give those. And the data are now published. This works as well as it does in the pediatrician’s hands. We see considerably lower rates of relapse. We see remission rates that are about 98%. Induction mortality is at 2%, which is as good as anything we’ve ever had. And we can actually predict who’s at greatest risk of relapse largely from looking at measurable residual disease by sending flow.

Now, that’s not flow to your local lab. That’s flow to a specialist who knows how to interpret the rare lymphoblasts and know the difference between that and recovering regenerating bone marrow. And that’s hard to do.

On these studies it was done in a central laboratory, and off of study we sent it to the University of Washington. They do that commercially, and they’ll test our patients. We send that out to their lab. They’re the reference lab for the Children’s Oncology Group. We get the same assessment as would be done on the COG trials.

And what we see is patients who are MRD-negative do very, very well, up to the age of 30 or 40. When you get over the age of 30 or 40, a few things happen. One is, PH positivity goes way up, and that study only had PH-negative patients. PH-positive, the big advantage is now adding TKIs from induction and continuing all the way through is leading to many more patients again becoming MRD-negative. And it’s bringing up the question of how much does transplant help those patients? And the answer is, we don’t know. We’re going to be studying that going forward.

We still think as of right now, off study, that PH-positive patients in remission should go to transplant even when they’re MRD-negative, knowing that the transplant outcomes are better in MRD-negative, but not answering the question of if you’re MRD-negative do you need the transplant or should you just stay on the TKI and get maintenance, et cetera.

For front-line therapy the big change is, for PH-positive patients there are TKIs early, give them all the way through. Check for MRD. Still do transplant. And even post-transplant tyrosine kinase inhibitor is part of our planned regimen. And again, those are not based on maintenance versus no maintenance head-to-head studies. That’s experiential. We’re just seeing better survival with that approach than has ever been reported.

Which TKI to give? There’s several that have data. There are data with imatinib, data with dasatinib, data with nilotinib, data with even ponatinib, plus chemotherapy backbone. That’s still a question to be answered, and there are arguments for and against various different TKIs.

And then for the patients who are PH-negative but over the age of 40, it’s anybody’s guess what the right answer is. Right now we’re still using intensive therapy. We’re trying to do as much of a pediatric approach in patients as they get older, as they can tolerate up to the age of perhaps 70, with some modifications. We withhold asparaginase, which is very important in younger patients, in the oldest of the adult patients, like over age 55. We still use extended maintenance. And we think about transplant, but we don’t mandate transplant in these patients, knowing that if you achieve an MRD-negative state you may do okay or we may reserve transplant for treatment failures.

Efficacy and safety of the bispecific T-cell engager blinatumomab as a salvage therapy option for relapsed or refractory ALL

DR PERL: What are the salvage options? The most important one I’d say is blinatumomab, which an antibody that is a bispecific recognizer of both CD19 on lymphoblasts and CD3 on T cells. It pulls the T cells together, and that allows the T cells to recognize the lymphoblasts, engages them in a way that activates the T cells and clears the lymphoblasts from this immunotherapy. It can be associated with significant toxicity, usually on the first cycle.

We see cytokine release syndrome with rather significant regularity. It mandates hospitalization. It can show up later than that, but it’s uncommon. And we see it mostly in people who have a high presenting white count. It’s much better tolerated when the white count is controlled prior to receiving the drug, and it also works better in that setting.

We see a large number of patients go into remission and a high likelihood of an MRD-negative remission when people respond. And again, if you go into an MRD-negative state after salvage therapy, that’s where transplant really works.

Patients who are MRD-positive after salvage, they can be transplanted, but it’s hard to cure them. What we like about blinatumomab is, we see a high likelihood of MRD-negative response when people respond, and particularly in patients that we can get the white count down prior to starting the therapy. While there is potential toxicity, we can manage that toxicity, again with very close observation in a specialized center that gives this regularly. It’s a continuous infusion that’s given for a 4-week course. And you may need several courses of it to say you’ve had full therapy.

But the drug has basically become a very welcome addition to our armamentarium in the academic centers. I would not try it necessarily in the community centers, at least for the first cycle. That’s something that I would be very cautious about, because that’s where you’re going to see cytokine release syndrome. And that’s a capillary leak syndrome. Patients can get high fevers, low blood pressure, shortness of breath. They can get really quite ill, and very rapidly this can progress to full-blown organ failure.

The drug has a very short half-life, so we stop the drug if we see this side effect. We give steroids. It usually resolves within hours. We can rechallenge, and we’re less likely to see it on rechallenge. And we start with a low dose of blinatumomab and then escalate the dose afterwards.

Now importantly, because it’s a continuous infusion, you have to expose the patient to that drug for 4 weeks solid. Even if the drug is discontinued for a few hours, we need to bring those patients back and hospitalize them for a period of time to get them back on the dose if the pump fails, if the patient gets deaccessed, if there’s some issue like that. That’s something that patients need to be aware of. They have to call the center if they’re having a problem with their pump.

And if they roll into your emergency room and the pump turns off, don’t start them the next day because they’ve been doing fine. They need to be monitored. They may need to go to the leukemia center for that monitoring, knowing how sick they can get. It’s something not to be trifled with, because people really can get very rapidly very sick.

DR LOVE: I’ve heard blinatumomab described as off-the-shelf CAR-T. I don’t know if you agree with that, but what about neurologic issues?

DR PERL: Yes. Neurologic issues are an issue with blinatumomab. All the studies require patients to not have prior strokes or seizures or CNS disease. It’s interesting. Blinatumomab does not penetrate into CNS, so it’s not active against patients who have disease there, but it can cause neurotoxicity. And the neurotoxicity can range anything from a tremor in your hand to word-finding abnormality of speech, difficult cerebella ataxia to encephalopathy. And again, it can happen rapidly, or it can be delayed. The CRS usually happens very soon after starting the drug, but the neurotoxicity can be later. And that’s true for CAR T cells as well.

Maybe this is a good time to segue to that.

Chimeric antigen receptor (CAR) T-cell therapies in the third-line setting for patients with relapsed or refractory ALL: Efficacy outcomes and tolerability

DR PERL: CAR T cells have been approved for ALL in children and adults up to the age of 25 as not second-line but third-line therapy. They need to have failed 2 prior lines of therapy. And they can be active, even in patients who relapse after prior blinatumomab. It’s an important modality to know about, either for patients who can get it on label commercially or for patients who are outside of that label who could get it through clinical trials, which we, again, we have many of these at academic centers. It’s a major reason for referral of ALL patients to our center. And working at Penn, we were one of the centers that really developed CAR T-cell technology, and the drug that was approved, tisagenlecleucel, which is very hard to pronounce, that came from the CAR T cells that we developed at our center. We have a lot of experience with this in patients even over the age of 25.

And we’ve presented that at meetings, and there will be publications forthcoming. This is not quite out just yet for the full experience, but that should be available soon.

The experience is that we do see significant cytokine release syndrome from this therapy, so it’s again nothing to be trifled with and needs to be administered in a center with expertise. The other challenge with this is that it’s not something I can just write for and hand to the patient right then and there. You have to collect the T cells in a pheresis setting. They have to grow and expand in the laboratory. Once they expand, then we infuse them back into the patient after an additional round of chemotherapy. There’s a lag time from when you want to treat the patient with the CAR T-cell therapy and when they actually receive it. And that’s been really one of the challenges with CAR-T technology in a disease like ALL, which is growing, is, can your patient remain stable enough to actually get to the point where they receive the CAR-T therapy? And usually we’re not looking for the patients to be in remission at the time of infusion, although some of the patients were in at least a morphologic remission, but usually still MRD-positive.

On the studies we cleared MRD-positive disease to MRD-negative disease with great regularity, and the real difference between CAR-T therapy and blinatumomab is, it’s one and done. Once the CAR T cells enter the body, they stay there. They expand within the body, and it’s that expansion and persistence that predicts the long-term benefit. If patients either don’t expand their CAR T cells in the patient or the cells only last a short period of time, that’s who usually relapses.

And so that’s really been our predictor of the long-term benefit and the need, potentially, for transplant afterwards. Patients who have persistent CAR T cells after infusion may or may not need a transplant. We often will still recommend it. Which brings up the question of, is this really a long-term therapy or a short-term therapy? And the answer is, again, in third-line therapy for ALL we often will still recommend transplant for patients responding to CAR-T therapy. And we can cure people who’ve had, again, more than 1 relapse of ALL. We never used to see this with any regularity. That’s what’s different now, is that we have salvage therapies that are effective for these patients.

It may not obviate the need for transplant, and it may not obviate the need for blinatumomab or other salvage therapies, but there are outcomes that we’re seeing that are different than what we saw before.

FDA approval of tisagenlecleucel for ALL; perspective on improving T-cell persistence and overcoming resistance to CAR T-cell therapy

DR LOVE: You mentioned that the approval is only in the younger patients. Is there some reason to think it wouldn’t work in older patients? Do you expect it?

DR PERL: No, it does. The difference that the FDA had was, they had the data from a large study in children. And the benefit seems to be a little bit greater in children than in adults, largely in terms of the persistence of the T cells. Whether that’s T-cell exhaustion that’s age related we can’t say. It might have had to do with the kind of therapies that the adult patients had had prior to going on the studies. But the data that led to the approval were from a pediatric study, and just without those data from adults the FDA couldn’t approve it in that setting.

DR LOVE: Do you expect that to happen in the near future?

DR PERL: I hope so. I think the 2 things we want to know is, is CAR T cells directed against CD19 the right antigen? We think that’s a very good antigen. We have different CAR T cells that we’re trying to see whether they work better than the existing ones, either because they go after more than 1 antigen, CD22 being a common one that we’re targeting, either as the single antigen on the lymphoblast or in combination with CD19.

The other thing we’re trying to look at is, are there ways that we can genetically engineer these cells for greater persistence, knowing that that’s what predicts longer-term benefit? And then lastly, are there ways we can get around the issue of resistance to CAR-T therapy, which has been commonly an issue in patients who’ve had blinatumomab, is that the leukemias will grow with both CD19-positive cells and CD19-negative cells. So there’s still lymphoblasts. They still have the genetics that are the same in terms of the leukemia-associated mutations, but they don’t have the antigen that the CAR T cells recognize. And so we’ll suppress the 19-positive cells, and the 19-negative cells will grow.

That’s one reason that we think these are good therapies but still may need some tweaks to them before we really think that they’re ready for every patient out there and earlier in therapy so we don’t have to burn the bridges of salvage therapy. Maybe there could be ultimately a first-line salvage therapy or even front line for people who aren’t MRD-negative coming out of induction.

Case: A woman in her early 60s with previously treated metastatic triple- negative breast cancer is diagnosed with AML with a FLT3-ITD mutation

DR LOVE: Okay, let’s jump into the meat of this. I thought we could start out talking about targeted therapy and maybe begin with this 61-year-old African American woman. Can you talk a little bit about how she presented?

DR WANG: Sure. This is one of the patients that I took care of when I was covering the leukemia inpatient service. She’s a 61-year-old African American woman, and she had been referred to us from our breast cancer colleagues. She had had a diagnosis of triple-negative breast cancer, which had presented a year or two earlier. She underwent bilateral mastectomies followed by adjuvant chemotherapy and unfortunately had presented with some chest pain and some respiratory symptoms, was found to have significant pulmonary and liver metastases.

She was on some maintenance therapy and was being followed closely by her oncologist when she presented to the breast clinic with easy bruising and ecchymoses on exam and just feeling very fatigued. What we found on examination was that she had a high white count. She had anemia and thrombocytopenia, which was new. And she had evidence of circulating peripheral blasts.

She was admitted to the leukemia inpatient service for further workup and diagnosis. We performed a bone marrow biopsy and determined that she unfortunately had acute myeloid leukemia, likely therapy related, we think, maybe in relation to the chemotherapy that she had gotten. But it was interesting that it was MLL translocated, consistent with the therapy related, but also was characterized by a presence of a FLT3 ITD mutation, which is found in about a third of patients with acute myeloid leukemia and can be found most commonly in normal karyotype AML as well as other cytogenetic subsets.

Molecular profiling in the diagnosis and treatment of AML

DR LOVE: Before you get into how she was treated, maybe we can just take a step back and talk about a couple of things. First of all in terms of workup. Again, from the point of view of the general medical oncologist, what do you consider the essential workup of a patient presenting with AML?

DR WANG: Alright, so I think first of all, patients who present with AML generally have some sort of hematologic compromise, cytopenias, elevated white count. The first thing I look at is to see whether there is anything diagnostic in the peripheral blood, if there are increased numbers of peripheral blasts and generally anything above 20%. You can actually perform a lot of the diagnostic testing to make a diagnosis of AML just from the peripheral blood. In other instances, you’ll need to perform a bone marrow biopsy.

And so from either the bone or the blood there’s about 4 things that absolutely need to be done in this day and age to make that diagnosis. One is the conventional hematopathologist looking at the size, the shape, the morphology of the blasts, and really distinguishing, is this an acute versus a chronic? Is it an APL? Is it an ALL? Hematopathology, including any cytochemistry or stains they have to do is essential, and blast count.

The second thing would be to look at flow cytometry, to determine that there’s myeloid versus lymphoid expression, and again to rule out APL. In particular, nowadays, with a lot of the targeted therapies, we are interested in knowing if an AML cell expresses CD33, because we have CD33-directed targets, and we have experimental agents that are targeting other antigens expressed on stem cells, which is CD123.

Following that, the third thing we look at is cytogenetic. We look at conventional cytochemistries — I mean, cytogenetics and karyotype, and we also look at fluorescence in situ hybridization for specific translocations, which are diagnostic for acute myeloid leukemia. And that includes translocation 8;21, inversion 3 for acute promyelocytic leukemia, translocation 15;17. We know that in acute myeloid leukemia the most robust and validated prognostic marker for patients with AML is really cytogenetic abnormalities and whether they fall within a favorable, intermediate or unfavorable karyotype. However, half of the patients that present with AML are going to have a normal karyotype.

The fourth and most important thing nowadays, in many people’s minds, is to do the molecular characterization. We do next-gen sequencing looking for a panel of myeloid genes that are commonly mutated in AML. But therapeutically we now have targeted agents, as you mentioned, that are direct against FLT3 mutations, IDH1 and IDH2 mutations. It’s important to recognize that the most common mutation in AML is FLT3, and that only occurs in about 25% to 37% of patients. There’s no mutation in this disease that is found in more than a third. IDH1 is probably found in 5% to 10% and IDH2 in probably 10% to 15%. Between the 2 of them, IDH1 and IDH2, really found in less than 20% of AML patients.

Activity and tolerability of midostaurin in combination with standard 7 + 3 chemotherapy for newly diagnosed AML with a FLT3 mutation

DR LOVE: Let’s get back to your patient, because it seems like a really provocative situation. She’s had metastatic triple-negative breast cancer, which has a pretty poor prognosis, coloring this. Was she symptomatic? What was her performance status?

DR WANG: She was pretty good. She was fatigued. She was tired, but she was still eating well. Obviously she was very discouraged. She had a long therapy with surgery and chemotherapy to get the metastatic breast diagnosis and then the acute myeloid leukemia diagnosis. But she wasn’t really willing to give up. And at the time that we saw her, her breast cancer was relatively stable. It was not actively spreading.

The decision was made, after consultation with her and her husband, to go forward with treatment for her acute myeloid leukemia. She went ahead and received standard what we call up-front chemotherapy, since she was fairly fit, with an intensive chemotherapy regimen, cytarabine and daunorubicin, also known as 7 + 3, with the addition of a FLT3 inhibitor, midostaurin.

DR LOVE: How did she tolerate therapy and respond to it?

DR WANG: She did alright. She certainly was not willing to give up and wanted aggressive therapy, and she initially did fairly well with it. She was a little bit depressed. She was not walking around as much as we would have liked, but she tolerated it relatively well. She had no significant life-threatening complications, although she did drop her counts and was transfusion dependent.

The most troubling thing, really, was that at the time that she started to have count recovery, about 28, 32 days after starting therapy, she started having peripheral blasts. It appeared that despite her tolerability and her willingness to undergo intensive therapy that she really had disease which was refractory to the initial FLT3 inhibitor and standard chemotherapy.

CPX-351 for secondary AML

DR LOVE: I don’t know exactly when this occurred, but it is thought that CPX-351 might have been a consideration in this woman. Was it?

DR WANG: It could have been, and definitely CPX-351 is a liposomal formulation of cytarabine and daunorubicin, really indicated for therapy-related AML. That definitely was something that we had considered. However, as of now we don’t have data, tolerability data, combining CPX-351 with a FLT3 inhibitor. In the Phase III study of older patients 60 and above that had therapy-related AML, definitely CPX-351 performed better and had improved overall survival and CR rates as compared to regular 7 + 3 or nonliposomal cytarabine/daunorubicin. But that was in the absence of a targeted inhibitor.

FLT3 patients on that study, when they went back and did subset analysis, benefited from CPX-351 and definitely did not suffer any untoward side effects or do worse with CPX in the FLT3-mutant setting. But in this situation I think, given her high white count, we did elect to do the FLT3 inhibitor, although I do agree that we could have used CPX.

DR LOVE: It’s been kind of hard for me, and I’m sure most general medical oncologists, to kind of get a feel about CPX and also why it even works. What’s your vision of it? Do you think it’s better tolerated?

DR WANG: I think that it was interesting. CPX, the liposomal formulation, was developed as a novel way to give cytarabine/daunorubicin. We’ve been struggling with trying to improve upon, as you know, Dr Love, the efficacy of 7 + 3 for over 40 years. And this was our latest attempt to do that. There’s a lot of solid tumor drugs, I believe, for breast cancer, pancreatic cancer, which are liposomal formulations. And the encapsulation of water-soluble drugs within a nanosphere liposome has allowed better penetration into the bone marrow space, which is the source of all acute leukemias, and allows better pharmacokinetics in terms of steady-state levels for 24, 48 or even a few days.

Cytarabine, as you know, has a very short half-life in the peripheral blood, only about 15 minutes. And that’s why the cytarabine that we give usually is continuous infusion, because otherwise we won’t be able to get therapeutic levels. I think personally, what is the benefit of liposomal versus standard? I think it’s in those subtypes of acute myeloid leukemia that traditionally don’t respond well to 7 + 3. I mean, if you have a favorable karyotype or even an intermediate, your cells are going to be relatively sensitive to cytarabine and daunorubicin, leading to favorable or intermediate outcomes.

But those patients that have adverse outcomes? They’re not responding. They don’t maybe get enough drug in there. And the ability to get a little bit more drug penetration into the bone marrow space potentially would lead to improvement just by getting more drug in there, getting more exposure of the cancer cells to those cytotoxic compounds. I think that is probably what is responsible for the improvement. But only in those subsets of patients that don’t typically respond.

DR LOVE: That’s very interesting.

Incidence and characterization of FLT3 mutations in AML; efficacy of midostaurin and gilteritinib

DR LOVE: Getting back to this lady, as you mentioned, she got 7 + 3 plus midostaurin. It sounds like she didn’t respond very well, but before we go on, can you just backtrack a little bit and talk about the types of FLT3 mutations that are seen, the agents that we have out there and the data that supported this initial decision to give her midostaurin?

DR WANG: Sure. As I mentioned, FLT3 mutations are found in about a third of patients with acute myeloid leukemia in the newly diagnosed space. Now, about 60% of those mutations, or two thirds of the FLT3 mutations, are going to be in the internal tandem duplication, which leads to tandem repeats within the mutated kinase. That is associated with a very poor outcome. Patients that have those ITD mutations tend to be younger patients, normal karyotype, intermediate karyotype. They present with high white counts, and they tend to have clinically aggressive disease.

Now, much of the data suggests that patients with FLT3-ITD mutations can go into remission at similar rates as FLT3 wild type, but they relapse. The typical setting is they’ll go into CR or they’ll be refractory. If they go into CR, they’ll relapse again after another 1 or 2 cycles.

FLT3 tyrosine kinase domains make up about 20% to 30% of the mutations. Less common at diagnosis. Much harder to detect. So from a diagnostic point of view we can do PCR for internal tandem duplications and for specific tyrosine kinase domain mutations, in 835 domain, for example. But many FLT3 tyrosine kinase domain mutations require next-gen sequencing for detection, so they’re a little bit more occult. Not quite as common, and when we look at prognostic studies in the absence of FLT3 inhibitors, not quite as poor prognosis.

There are some studies that say FLT3 D835 mutations really don’t affect overall prognosis. The problem with D835 mutations is that they still are driving the disease. And when we look at the array of FLT3 tyrosine kinase inhibitors that have been developed, the type of mutation makes a big difference. Certain tyrosine kinase inhibitors are only able to target and inhibit specific types of mutations. For example, midostaurin and gilteritinib, which are the 2 FLT3 inhibitors that are currently approved for both newly diagnosed and refractory/relapsed FLT3-mutant AML, respectively, really are of the type that would inhibit both ITD and D835 mutations.

On the other hand, other FLT3 tyrosine kinase inhibitors, like sorafenib, which was repurposed from its role in solid tumors to inhibit FLT3, as well as another FLT3 inhibitor, quizartinib. Those particular inhibitors only target the FLT3 ITD. And the development of D835, or tyrosine kinase domain mutations, is a very relevant therapy resistance mechanism that can develop in patients over time.

Characterization of the FLT3 mutations is important, looking at both PCR as well as next-gen sequencing. On the other hand, as we talked about, diagnostically FLT3 ITD mutations, sometimes those in tandem time to duplication mutations are very large and they’re not picked up by sequencing. Again, the importance of doing both molecular analyses for both the PCR for the ITD as well as next-gen sequencing for D835.

In terms of efficacy, there’s validation of the importance of FLT3 inhibition in how it adds to conventional chemotherapy. The addition of midostaurin to standard 7 + 3, as this patient received, has been shown to have significant benefits, about a 7% overall survival benefit at 4 years. The complete remission rate, interestingly, was the same, but it appears that the major benefit of the agent is preventing relapse. That data was a little bit skewed, because in patients in the RATIFY trial by Stone and colleagues in New England Journal of Medicine, 57% of patients in that Phase III trial did go on to transplant. We think midostaurin works best in the up-front setting in combination with 7 + 3 and ideally in combination with an allogeneic stem cell transplant.

Gilteritinib is a second-generation more potent FLT3 inhibitor, which was designed for patients who have relapsed/refractory disease, very aggressive disease. And the Phase III trial with gilteritinib compared a single drug, gilteritinib taken once a day, to high-dose chemotherapy as well as low-dose chemotherapy for relapsed/refractory leukemia. And astonishingly enough, this pill and the targeted potency of this FLT3 inhibitor outdid standard intensive chemotherapy with a few-month survival benefit. However, it must be pointed out that the only patients that had the best long-term survival, again in the FLT3-mutant setting, was those that went on to transplant.

Clinical experience with and tolerability of gilteritinib

DR LOVE: As you mentioned, this patient really didn’t respond very well. What was the next step?

DR WANG: The next step, we went on to start her on the gilteritinib. She, at that point, I think, with all of her prior medical history for the breast cancer, metastatic disease, having failed intensive chemotherapy with refractory disease — at that point she was pretty beat up, discouraged as well, mentally and physically, so we were able to initiate an outpatient tyrosine kinase inhibitor and support her well enough that she was actually able to go home from the hospital on that. She’s now been on therapy for about 2 or 3 months with the gilteritinib. We have seen recurrence of some circulating blasts, but for right now she is continuing, we think, to have clinical benefit with the drug, remaining outpatient, having some quality of life, and we’re looking for additional maybe experimental agents for her if she continues to progress.

DR LOVE: Any tolerability issues that she’s experiencing or that you’ve seen other patients experience with gilteritinib?

DR WANG: Gilteritinib in general is well tolerated. There is a pretty high incidence of cytopenias associated with that agent. One of the things that we saw was her counts were recovering with peripheral blasts, and when we started the gilteritinib they all fell again. Generally myelosuppression is something to keep an eye on. They also get some LFT abnormalities, which, in her case, we kept an eye on as well, because of the presence of her liver metastases. And some of our patients, they do get some nausea and some vomiting, but mostly the liver function test abnormalities. There can be some patients that get QTc prolongation, which is something to look at, and some patients do develop orthostatic hypotension and peripheral edema. Those are all things that we’ve kept an eye on in her case. However, in general, most patients are able to tolerate this well with some dose adjustments in the outpatient setting.

And the benefit of gilteritinib is that generally, activity of the drug occurs fairly quickly. We generally see the counts falling, and if patients are going to respond, we would tend to see a response within 4 to 8 weeks of starting the drug.

DR LOVE: From your point of view when you think about FLT3 mutations and drugs like gilteritinib, midostaurin, do you think it follows the concept of a driver mutation? When the drug is used as monotherapy, do most patients have some type of response?

DR WANG: In our study in patients who have not been heavily pretreated with FLT3 inhibitors, unlike this patient who had gotten midostaurin, we had seen about half of patients really respond to the drug. And there’s some studies that have been done at larger cancer centers, MD Anderson, saying that if you’ve been repeatedly, and this would be exposed to FLT3 inhibitor therapy, by the time you get to gilteritinib it might not work as well. I think in patients who are relatively naïve to the drug we do get probably 30% or 50% response rates. In the ADMIRAL trial, a Phase III trial, the overall CR/CRi rate was about 30%.

I would say about 30% to 50%, but then there’s some patients, like our patient, who didn’t technically get a complete remission, but the drug has kept their disease in check as an outpatient now for 2 or 3 months. I think there is also something to be said, particularly in older patients that have comorbidities or other diseases as she did, to have some clinical benefit of the drug in the absence of pure CR.

DR LOVE: When I think about a waterfall plot in a solid tumor, for example lung cancer with an EGFR tumor mutation, is getting EGFR TKIs. Most of the patients, almost all of them, go down. They don’t all fit the criteria for a response. And that’s kind of what I was getting at. How often do you see people blow right through it?

DR WANG: Occasionally we do. People that have very aggressive disease. As you said, it’s a driver mutation. I think that the reason that, for example, your original question, like, why did we use a FLT3 inhibitor and not use CPX? That’s because my preference is to use a FLT3 agent, because I feel like specifically blocking that driver mutation may be more beneficial clinically than just giving more cytotoxic. That’s just my bias, but I do feel like inhibiting that driver mutation is potentially putting the brakes on something that’s driving or propelling the disease forward, as opposed to standard cytotoxic chemotherapy, which affects everything equally, right?

Activity of midostaurin in newly diagnosed AML with a FLT3 mutation

DR LOVE: How much do you think adding midostaurin in this up-front situation is affecting long-term outcomes?

DR WANG: My preference and my bias is to use a FLT3 inhibitor in up-front therapy. First of all, as with any cancer, the best chance you have to treat the disease is in the up-front setting, okay? You don’t want to be in the relapsed/refractory setting, because by the time you’re relapsed and refractory, inevitably the feeling is that you’re going to die from your disease.

When you look at the data with RATIFY, which is a randomized Phase III trial randomizing FLT3-mutant patients to either midostaurin/7 + 3 or placebo/7 + 3, if you look at the curves, the curves separate out very early in the treatment, probably during induction. And that difference in overall survival, event-free survival, it persists through the rest of the results in that 7% difference in 4-year overall survival benefit. If you look very carefully, I think that major benefit of using the midostaurin is in the up-front setting and suppressing that clone. And I’ll tell you right now, Dr Love, people will say to me, “Maybe I don’t have to give a FLT3 inhibitor. Maybe I can get away with just standard chemotherapy in the up-front setting.”

We look at what we call allelic ratio. The allelic ratio’s really low. I don’t need to deal with a FLT3. I’ll just give them cytotoxic. My experience is that if you do not treat the FLT3 mutation up front, then when they relapse, that FLT3 mutation is there at relapse, and the variant allele frequency ratio has gone up, and it is driving the recurrence. I say if you detect the FLT3, if I see it and I have a drug for it, I’m going to use it, because you don’t say, “There’s a few leukemia cells with it. I’m not going to bother with it,” because at the time of relapse we’ve seen, like, a 1% or 5% clone make up 50% or 80% of the relapse. I think if you see it at diagnosis, you treat it.

DR LOVE: Are there ongoing Phase III trials looking at other FLT3 inhibitors, maybe more potent FLT3 inhibitors like gilteritinib in this up-front setting?

DR WANG: Yes, so the trial with midostaurin, the RATIFY trial, was done through the cooperative groups and international groups, and that was done over 10 years ago. Our site participated in that study. It took about 10 years to get that data published.

Midostaurin was not developed as a FLT3 inhibitor. It was actually developed as a VEGF inhibitor. That was in the days, remember, as you can recall, where they were developing VEGF inhibitors for renal cell, subsequently for hepatocellular carcinoma. That drug, midostaurin, or PKC412, was really a repurposed tyrosine kinase, because they noticed that when they looked at the tyrosine kinase profile it also inhibited FLT3. And when they gave it to some patients that had FLT3 mutant, they saw some peripheral blood clearance. They said, “Let’s combine it with standard chemo.”

Since that time we have developed very potent, specific drugs just to inhibit their ability to inhibit very potently and specifically FLT3 ITD and FLT3 TKD. Those drugs, gilteritinib is an example of those, really have efficacy in the relapsed/refractory setting, whereas midostaurin just caused a little bit of peripheral blood clearance. When you gave midostaurin as a single agent you saw no responses, nothing, no CR. You saw peripheral blood clearance, and that was it. Obviously now that we have gilteritinib approved in the relapsed setting, we would like to move those potent FLT3 inhibitors, as you said, up front.

Ongoing Phase III trials of crenolanib, gilteritinib and quizartinib as first-line therapy for AML with a FLT3 mutation

DR WANG: There currently are 3 Phase III trials which are ongoing looking at each one of the newer-generation FLT3 inhibitors, quizartinib, crenolanib and gilteritinib, and comparing the addition of each of those more potent FLT3 inhibitors, in combination with 7 + 3 as compared to 7 + 3 alone or 7 + 3 plus midostaurin, which is now the new standard.

Initial results in the Phase II setting have suggested that, for example, the addition of crenolanib to 7 + 3 or gilteritinib to 7 + 3, now, in contrast to midostaurin, actually increases the CR rate. When you looked at the midostaurin, midostaurin plus 7 + 3 did not improve the CR rate but improved the overall survival rate. We’re now seeing, with the newer drugs, CR rates of 80%, 90%, which are about 20% higher than the 59% we saw with midostaurin, which was the same as standard of care. Whether that 20% or 30% improvement in CR results in overall survival benefit, we’re optimistic, but we’re going to need to wait for those Phase IIIs to result.

DR LOVE: Any projections on when we will see some results?

DR WANG: I think those trials are accruing now, so I would imagine probably in a couple years. Some of the early Phase I/Phase II data has already come out with crenolanib, for example, plus 7 + 3, in about 27 months. They report an overall survival of about 70%. We’re going to need to wait and see. I mean, those were only a handful of patients. I would say about 2 or 3 years we’re going to get a sense. I think that people are already eager to move that to the up-front setting. In addition, as you mentioned, up-front setting — is there a benefit for that? We like to bring drugs into the up-front setting. If we can get more people into complete remission, maybe more people could go to transplant, and we think that transplant is something that we’re routinely offering these FLT3-mutant patients to prevent them from relapsing.

DR LOVE: Do you see FLT3 in MDS?

DR WANG: Rarely. Because FLT3 is, as you mentioned, a driver mutation, it is associated with excess proliferation. MDS is really characterized by lack of proliferation. It’s the opposite. It’s a bone marrow failure syndrome. Patients don’t present with high counts — they present with no counts. We do see it. We do look for it, but it tends to be a rare entity. What we find more often in myelodysplastic syndrome is really some of the other mutations, IDH1 and IDH2.

DR LOVE: Right.

Significance of allelic ratio in AML with a FLT3-ITD mutation

DR LOVE: You mentioned allelic ratio. Could you explain exactly what that is? I think I’ve heard about allelic burden — and how you interpret it.

DR WANG: Allelic ratio is really used to describe the frequency or the percentage of cells within the patient’s presentation that really have that mutation. It’s only used for ITD. There’s no tyrosine kinase domain or TKD mutation allelic ratio. When we look at allelic ratio, we’re really looking at FLT3 ITDs. And generally people have interpreted as taking the amount of mutant FLT3, that mutant that they’re getting in a patient, and putting it over the amount of wild-type FLT3. It’s kind of like a percentage. If you have this much mutant and this much wild type, what percentage of the total leukemic burden is really FLT3 mutant?

And people have looked at that, because in the past, in the absence of FLT3-mutant therapy, when we looked, we knew that FLT3 ITD was a poor prognostic marker. And if you looked at the allelic ratio, it just makes sense. The more FLT3-mutant cells you have, or the higher the allelic ratio or the allelic burden — it’s the same thing — the worse the prognosis, right? Because you had more of the mutant cells and less of the wild type, and so those cells are driving chemoresistance and refractoriness and aggressive disease, so they would do worse. And people use that to say if you had a very, very low allelic burden, a tiny amount, maybe you didn’t need to have a transplant to get rid of it. Maybe you could get rid of those mutant cells just with chemotherapy, whereas if you had a very high allelic ratio you were going to do poorly with chemotherapy and you needed to be transplanted.

Now, those studies were done in the absence of these newer FLT3 inhibitors. When we look at the FLT3 inhibitor data, particularly with midostaurin, that we have the most data with, midostaurin helped everybody. Does allelic ratio predict for response? No. You have high. You have low. You have almost nonexistent. You’re all going to respond. Are you going to benefit? Do the patients with more allelic burden do better in terms of their outcomes than people with low allelic ratios? Again, the answer is no. Does allelic ratio make a difference in this era of new therapy? I don’t think it makes a difference prognostically or response wise.

The way that we’re now looking at this allelic ratio is to use it as a measure of minimal residual disease. There are people that say if you’re able to eradicate all of the mutant allelic ratio with your FLT3 inhibitor or with your chemotherapy, your outcome is going to be better. The mutant allelic ratio, or tumor burden, has gone from being a poor prognostic thing, now, in the era of targeted therapy, not be prognostic but really to be a marker of measurable residual disease.

DR LOVE: When you put a patient on a FLT3 inhibitor, does it go away? Does the allelic ratio go to zero, or…?

DR WANG: It can go to zero, and in early studies using an assay that’s still not commercially available but in development, patients who cleared their allelic ratio, independent of whether it was high or low, had better outcomes than those that didn’t.

DR LOVE: But from your point of view, if a patient has 1% or 2%, are you still going to treat?

DR WANG: Yes. Yes. Because as I mentioned, particularly in the up-front setting, if I say I’m not going to do anything about it now, then what’s going to happen is, a few months later they’re going to relapse, and then they’re going to have 50%. And I’m going to say, “Oops! Maybe I really should have done something up front.”

And I think that our experience is that if you have a FLT3 clone, they tend to be chemoresistant, and so you may not necessarily benefit the patient. You may give them chemotherapy, and you may get rid of all the FLT3 wild-type cells, and the cells that remain are the chemoresistant FLT3. And those are responsible for relapse. If you have an agent and you can add it up front, as I said, your best chance to get rid of the disease and cure the patient is in the up-front setting.

Therapeutic options for patients with relapsed/refractory AML and metastatic triple-negative breast cancer

DR LOVE: What do you see in this woman’s future, if she does have progression? What do you think her next therapy is? Putting trials aside.

DR WANG: I’m not sure. I think that she’s weighing how much more she wants to do. I think that unfortunately with the presence of the metastatic breast cancer, she’s not a candidate for transplantation. With 2 active malignancies, the options certainly aren’t good. We are going to try to maintain her. We’re going to try to get her on a clinical trial that’ll allow her to have treatment, even though she has a second malignancy. We may try some off-label agents. And we’re really focusing on quality of life and duration of life, particularly as an outpatient, for her.

DR LOVE: What about venetoclax combinations in her?

DR WANG: Certainly we could look at that. Venetoclax in the relapsed/refractory setting has been somewhat disappointing. I know that some centers have reported venetoclax in the relapsed/refractory setting with response rates as low as 20%. Certainly we could consider that.

What we’d love to do would be is to, again, in the context of a clinical trial, combine a FLT3 inhibitor with something else. We know the gilteritinib is controlling her disease. Do we want to layer a hypomethylating agent on with it? We’d love to be able to add venetoclax to it, again, something outpatient. I think the future for her is to see whether there’s other regimens that we could add on to a FLT3 inhibitor to give her more time.

DR LOVE: It’s interesting, when you see patients who have 2 cancers like this, it also kind of brings up the opportunity to see whether the treatment of one affects the treatment of the other.

DR WANG: Right.

DR LOVE: Occasionally you see cases like that that are kind of interesting.

Activity and safety of immune checkpoint inhibitors in patients with AML

DR LOVE: And so I was flashing on the fact that I would guess she probably has had a checkpoint inhibitor. She’s got metastatic triple-negative disease. Right now, standard-of-care first-line therapy would be to get a checkpoint inhibitor. I don’t know, and I’ve heard a little bit about checkpoint inhibitors in AML. What do we know about checkpoint inhibitors in AML?

DR WANG: We have done some trials with checkpoint inhibitors. We do know that when we give checkpoint inhibitors to patients with AML that about 20% or 30% of them are going to have some side effects. We do know that they’re active in these patients. We’ve done studies combining checkpoint inhibitors in combination with chemotherapy, in combination with low-dose/high-dose chemotherapy.

In general we have not seen, in the myeloid diseases overall, the remarkable responses that we’ve seen in lymphoid diseases or in solid tumors. There just doesn’t seem to be a huge immune component to the disease, so we’re not seeing 70%, 80%, 90% response rates. We do see some patients have stable disease with the checkpoint inhibitors. We think that maybe over the long term a subset of these patients may have prolonged event- or progression-free survival.

But we’re not seeing differences in remission rates. And we are seeing about 20% or 30% of them having some immune toxicity — pneumonitis, colitis. In fact, there was a trial of checkpoint inhibitors added to epigenetic therapy for older unfit patients with AML and patients with MDS, and a couple of those trials in those older, unfit patients were actually held, because a few of those patients died because of the immune toxicities associated with that. I do think that immune checkpoint inhibitors, they appear to work in a select population of leukemia patients that maybe have immune priming or an immune microenvironment, and we do see maybe some stable disease. But it really hasn’t been the home run that we’ve seen in other cancers, unfortunately.

DR LOVE: Yes, I’m not exactly sure it’s a home run in all the other cancers but maybe sounds a little bit more active.

Biologic rationale for and activity of venetoclax in combination with a hypomethylating agent for patients with AML

DR LOVE: The other flipside that I was kind of thinking about, with her breast cancer, I was recalling an interview I did with Dan Pollyea, and he was talking about venetoclax, venetoclax combinations, venetoclax/HMA, and his theory, and other people have thought about the possibility it’s affecting stem cells. And he was mentioning that there are other cancers that have similar stem cell biology. He mentioned breast cancer, and I was just curious whether venetoclax or venetoclax combinations have ever been used in breast cancer.

DR WANG: I’m not sure. I mean, it is an intriguing possibility. Most of the data suggests venetoclax works best in AML in combination with a hypomethylating agent. So I think that it would be intriguing to think about that in her case. I don’t know. I mean, is Bcl-2 expression important for maintenance of leukemic stem cells? Yes. There’s preclinical data to support that. Does Bcl-2 overexpression play a role in breast cancer stem cell biology? I don’t know. I think that would be very intriguing to think about that. I think that that’s certainly something we could consider.

DR LOVE: I’ve been asking the breast cancer people about it and telling them about it. It doesn’t seem like it’s kind of gotten in there yet, but we’ll see. Always looking for something different.

DR WANG: No, I think that’s a great thought.

Case: A man in his early 40s with relapsed/refractory AML with an IDH2 mutation receives enasidenib

DR LOVE: Let’s hear a little bit about your 42-year-old man, because another issue, and again, I think this is really important for general medical oncologists to know about, is IDH inhibition.

DR WANG: Okay.

DR LOVE: And you have this 42-year-old man, so let’s hear about him.

DR WANG: This is a very unfortunate gentleman. He is really a good deeder. He’s a 42-year-old gentleman. He started his own business he inherited from his father. His major comorbidity prior to his diagnosis of his leukemia was really only having 1 kidney. And the reason he had only 1 kidney is he donated it to his father, actually.

He comes in, and he had presented with some groin swelling, and it had gotten bigger and bigger. He had gotten some antibiotics for it. It didn’t get better. It was in his left groin. He finally was referred by his primary care doctor to a surgeon to have a biopsy. And, incidentally, his primary care doctor also drew some lab work. The lab work came back showing about 10% or 20% peripheral blasts in his blood work. Around the same time, the surgeon had biopsied the inguinal mass and had found that it represented a myeloid sarcoma or extramedullary AML.

He was referred to our service. We repeated a bone marrow, evaluated the blasts. He had what we would call a favorable cytogenetic profile with translocation 8;21. But, unfortunately, his disease was characterized by additional cytogenetic abnormalities, as well as by a very aberrant molecular profile. He had not only the RUNX1, but he also had evidence of an IDH2 mutation.

We had tried to treat him. He was young. He was healthy. We went ahead and gave him conventional high-dose chemotherapy with 7 + 3. We added gemtuzumab, because his cells expressed CD33, and he did have a translocation 8;21. He went into remission, and he went on to get a couple cycles of consolidation.

There was some debate about, given various pros and cons, whether he should go to an allogeneic transplant. We were in the middle of considering that when he relapsed, and at the time of relapse we gave him the venetoclax/HMA therapy that we were just discussing as a salvage regimen. And that managed to decrease his disease that was in his bone marrow but unfortunately still had some evidence of leukemia remaining.

At this point his disease is characterized by the IDH2 mutation. We went back to our pharmacy, and we’ve started him on therapy with an IDH2 inhibitor to try to keep the disease in check while we pursue the logistics of potentially an allogeneic stem cell transplantation for him.

Similarities and differences between enasidenib and ivosidenib; recognition and management of treatment-associated differentiation syndrome

DR LOVE: What agent is he actually on? And how is he tolerating it?

DR WANG: He is on enasidenib, and he just started it, and he is tolerating it fine. His counts are relatively low. What we’re looking for, really, and what we look for for all patients that we put on IDH, and sometimes FLT3 inhibitors, is evidence of a clinical differentiation syndrome. Things like fever, infiltrates, shortness of breath, weight gain, things that we typically would see in the past when we gave retinoic acid to our APL patients. We’re now seeing similar biological phenomenon occurring with some of these other targeted therapies, particularly IDH1/IDH2 inhibitors and FLT3 inhibitors.

Enasidenib is the first drug to be approved for IDH2-mutant disease. There’s a sister compound, ivosidenib, which is approved for the IDH1-mutant disease. And both of these agents have very similar response rates, about 40% in the relapsed/refractory setting. Very well tolerated except for differentiation syndrome. But differentiation syndrome is definitely something to keep in mind, because some people do die from it.

It’s something that we would keep an eye on. It doesn’t happen right away. It happens after about 2 to 4 weeks. It could happen up to 2 months after it, so this is something that we need to be continuing to see our patients for, and when they develop shortness of breath, fever, infiltrates and weight gain not to just treat them with antibiotics but to think about this as a chemotherapy complication.

DR LOVE: I want to hear a little bit more about differentiation syndrome. But first, again, just listening to people talk about reading about it, is there any difference between IDH1 and 2 clinically and IDH1 inhibitors and IDH2 inhibitors? It kind of seems almost exactly the same.

DR WANG: Yes, I mean, I think that when you look at the data, they are different agents. They’re inhibiting different mutations and different isoforms of the IDH enzyme. However, the drugs are remarkably similar. They both have similar instances of differentiation syndrome and similar phenomenon. Is there a big difference between them? I think that clinically there’s not, necessarily. I think IDH2 is slightly more common, the mutation, than IDH1.

Interestingly enough, there’s some interesting preclinical data now saying when somebody fails an IDH2 inhibitor, so somebody’s on an inhibitor and they progress, there’s some data now that leukemia cells, again, they’re very wily, are able to switch their mutation. They can switch from being reliant on a mutant IDH2 to be reliant on a mutant IDH1 as a mechanism to avoid or to have recurrence. It’s very interesting. And then similarly to other kinases, you can develop mutations in these. But I did recently see that isoform switching is a way that these cells can avoid the inhibitory effects of one drug versus another drug.

DR LOVE: Wow, I’ve never heard that. Can you use the other drug in that situation?

DR WANG: I would think that you would, right? And, in fact, the company that developed these had initially a combination IDH1/IDH2 inhibitor that they didn’t move forward into trials for acute leukemias. But I think that the problem we have with IDH1/IDH2 is, it’s not very common. It’s generally thought of not has a driver mutation but as a founder mutation. We had talked about that.

There are mutations that occur potentially in hematopoietic stem cells. It could be age related or therapy related, these mutations. They’re called clonal hematopoietic mutations. And as one ages, just as your stem cells are aging, they can acquire some of these baseline mutations, which are what we call founder mutations. And then what happens again, over time or after exposure to certain things or just proliferation, you can develop a secondary mutation, and those mutations could be what we call driver mutations, like FLT3 and RAS. And those driver mutations are what takes those aberrant clonal hematopoietic-mutated cells into driving them into a leukemia.

There are certain founder mutations like p53 that over a 10-year period can be associated with almost a 100% incidence of acute leukemias. I think these mutations are a series of very active investigation to figure out whether there’s a possibility of targeting them early, late and how best to deal with these mutations.

DR LOVE: Hmm. Wow. That’s really interesting.

Integration of the FDA-approved IDH inhibitors enasidenib and ivosidenib into clinical practice

DR LOVE: Where are these agents approved clinically? And what do we know about their use in the up-front setting, either alone, for example, on an elderly patient, or combined with chemo?

DR WANG: They have established a very firm niche in the relapsed/refractory setting. What has been coming to the forefront since these drugs were approved is the routine testing of acute myeloid leukemia cells, at diagnosis and at relapse, for the possibility that these agents could be used in that select population of patients. Right now in the relapsed/refractory setting, overall response rate’s about 40% with both agents, clear CR/CRi rates in about 20%, but clearly very useful.

These agents have subsequently gone to the up-front setting as monotherapy. And early studies of Phase I, early Phase I data that’s been published has suggested very similar response rates in the up-front setting, but a little disappointing. We had thought maybe if we move it up front and they haven’t been pretreated we would get higher response rates than 30% or 40%, and we really haven’t. However, for patients who are elderly and unfit — and remember, Neil, the average age at presentation of acute myeloid leukemia is really 67 to 70 years old. We’re talking about a geriatric population. There are certainly patients that get diagnosed with acute leukemia that are not fit for therapy, and using a pill to treat an IDH1- or IDH2-mutant disease is very appealing for older individuals who don’t want to spend any time in hospital.

I think we’ve seen ivosidenib, which is the IDH1 inhibitor that got FDA approval for the up-front setting, as well as relapsed/refractory. Enasidenib, the IDH2 inhibitor, is only approved in the relapsed/refractory setting, but the data as monotherapy is very similar to ivosidenib. And then can we layer this on top of, as you mentioned, combination chemotherapy? A couple studies looking at adding IDH1/IDH2 to 7 + 3. Response rates are pretty good. It’s extremely well tolerated, and we’re waiting for follow-up data on whether it improves outcomes. CR rates, apparently, seem about equivalent to what we would see with 7 + 3 alone.

We’ve seen some very promising data with the addition of IDH1/IDH2 inhibitors to hypomethylating agents. In that particular setting we’re starting to see response rates of about 70%. It looks like IDH1/IDH2 monotherapy is effective in both newly diagnosed and refractory/relapsed patients with the same efficacy. Most promising combination really looks to be hypomethylating, where we’re starting to get 70% response rates.

Approach to therapy for older patients with AML with FLT3 or IDH1/2 mutations

DR LOVE: We actually recently conducted a survey of 25 AML investigators. You actually were nice enough to participate. But one of the things that we saw that was really interesting was older patients with either IDH or FLT3, where without those abnormalities we saw the investigators uniformly using venetoclax/HMA. But then the question comes up, what about those same patients when they have either FLT3 or IDH? Do you add it in? Do you not use it? How to you approach that?

DR WANG: It is difficult. We’re actually now having an abundance of choices. I think even a few years ago if you had a 75-year-old patient with comorbidities with AML, I tell you, Neil, we would have just said, “Oh, go home.” One option would have been hospice, right?

Then we started using some hypomethylating agents, and now we’re, like, confounded. We have pills. We have IDH mutations, FLT3 mutations, venetoclax, glasdegib. Where do we go? I think that my approach in that older individual is really to determine what they want in terms of a preference.

Now, my impression, again, I’m getting older in every minute that I’m sitting here, but my impression is, most people in their 60s, 70s or 80s have lived a full life, and they know what they want to do with the rest of their lives. They’ve seen family members come and go. They have relationships. If I have an elderly individual who has, for example, an IDH-mutant disease, I’m going to say to them, “Do you want to get venetoclax/HMA? In our center, that requires you to come into the hospital for a minimum 1 week and possibly 3 or 4 weeks, depending on the complications that you develop with the myelosuppression.”

Then you need to make the commitment to continue to get that HMA every week of every month going forward until it stops working, and/or to take the venetoclax pill and come in for transfusion support.

There’s some people that would say, “I don’t really want to be hospitalized for a week, 3 or 4 weeks. I don’t really want to get 1 week of hypomethylating therapy for the rest of my life, okay?” And best-case scenario, this works. That’s what we’re looking at, right? We don’t know how long to give the hypomethylating agent. We don’t know how long to give venetoclax. We do, with the up-front regimen, get about 50% of our patients alive at a year or 2 years afterwards. But that’s with a significant amount of time at our center, right?

Then there’re going to be some patients that say, “I don’t really want to do that.” And for those patients, despite the high response rates, 60%, 70%, 80%, 90% response rates with the venetoclax-based regimen, some of those patients are going to say, particularly the IDH1/IDH2, they are offered the option to take a pill and to go home, okay? The IDH1/IDH2 are not associated with very much transfusion dependence.

In fact, numerous of those patients, and part of the approval of those agents in the unfit population, was because they make a certain percentage of those patients transfusion independent. I would have to say that the overwhelming majority of my patients treated with venetoclax become transfusion dependent for some degree of time. I think that when we look at pure response rates for IDH-mutant disease, newly diagnosed, older, unfit, clearly the winner is venetoclax/HMA-based therapy, but for certain individuals who don’t want the side effects or the duration of treatment, IDH inhibitors are an option.

Similarly, I would — contrast in FLT3, I would also advocate using a FLT3 agent up front. I feel like, again, as we’ve talked about, that suppressing that clone is important to me. There is also emerging data that although FLT3-mutant AML patients respond pretty much probably similarly, maybe 50% or more, with venetoclax/HMA-based regimens, there is emerging data, and when you look at patients who recur after venetoclax/HMA, a high percentage of them are recurring with FLT3 mutations. And if you look at patients who don’t respond, a high percentage of those patients have FLT3 mutations.

FLT3 mutation could be a very relevant clinical little mechanism of resistance to ven/HMA, in which case I would rather do a FLT3 inhibitor up front. That’s just my bias.

Integration of venetoclax in combination with a hypomethylating agent into community practice

DR LOVE: Just getting back to your older patient, that 75-year-old patient says to you, “Look, I want everything that can keep me alive any extra day.” Would you give venetoclax/HMA plus IDH or FLT3?

DR WANG: I would love to do that. That’s currently what we would call off-label use. What we have done in some patients, like, for example, if we have somebody that was FLT3 mutant and we didn’t realize they were FLT3 mutant, maybe we didn’t get the result back, we have started them on ven/HMA therapy, and then if they’ve had recurrence or had disease that’s been stabilized, we might add a FLT3 inhibitor. If they still have disease, doing sequential therapy. Right now we’re looking at a lot of clinical trials looking at combinations. And that’s exactly what we’re looking at.

DR LOVE: That’s interesting. You use that term abundance of riches, and I think it’s been, like, 8 drugs approved in AML in the last couple years. But I saw — it was either a paper or a presentation you gave where you went into the background of the phrase abundance of riches. Am I remembering that correctly?

DR WANG: Yes, yes, yes. I mean, I do think it’s an abundance of riches. I think the definition is technically that there’s so many riches that you don’t know which one to pick. It’s like at Christmastime when you have all of these presents, and you can’t figure out which one to open first, which one’s going to be best. I think we’re in that period of time, where — in the old days, my job as a leukemia physician, and I’ve been a leukemia physician for 15 years now, is really simple. Like, you either got high-dose chemotherapy or you went to hospice. If you weren’t fit enough to get 7 + 3, then we didn’t have anything, right? And you remember those days.

I mean, when we talk to a lot of community physicians, that’s how they trained, okay? They’re training is, you’re either fit enough to get aggressive therapy or not. Recently we’ve been giving hypomethylating therapy, and so that was a change, to say now we have hypomethylating therapy, but that still requires a lot of effort.

Now we’re moving to totally oral-based therapy. Now, I think that we’re actually now starting to see, and you’ll see this in the community, now patients are saying, “I no longer have to go to the academic center and be hospitalized for 6 to 8 weeks. I no longer need to get my therapy only at major medical centers.” We’re moving some of our AML therapies to the community.

DR LOVE: You use the term abundance of riches. I use the term, maybe not a term, but the concept that nothing has ever happened like this in general medical oncology, where you go from a significant number of patients, of course I’m talking about the older patient, who, like you said, a lot of these people were going to hospice, to a situation where you can get a response — relatively nontoxic, at least from a quality-of-life point of view. And it’s amazing — I don’t know if you feel this way, but when we talk to people, when we’ve done programs, it seems like a lot of people in the community are using venetoclax/HMA. I mean, they’re on it. Is that your take?

DR WANG: Yes, I mean, what we typically do is, as this comes online and we have our colleagues in the community and they’re referring patients, what we typically are doing is seeing patients, offering the therapy. We sometimes will do the first cycle in house, to manage the complications and the risk of sepsis. And then after 1 or 2 cycles, we’re transitioning them back. There’re patients that live 3 or 5 hours away, and for those patients we’re helping the community doctors to learn about these things. But the community doctors need to be aware of these things, and they need to be comfortable with these drugs in order to offer those therapies to our patients.

We had a patient that was 88 years old. She came to see me with AML, because she said her local oncologist had never treated a patient that was 88 years old that had acute leukemia, and he was terrified. We brought her in. We gave her venetoclax/low-dose cytarabine. She had a history of MDS and prior HMA. She went into remission, and we transitioned her out.

And she comes back once a month now, and we are guiding her oncologist to provide local transfusions and to manage the venetoclax. And for her, she would have been dead if we hadn’t had this. And now her oncologist is gradually becoming much more comfortable with having this 88-year-old show up in his office to get venetoclax as an outpatient.

Use of gemtuzumab ozogamicin for patients with low- to intermediate-risk AML with no adverse cytogenetics

DR LOVE: As usual, when I try to do an interview on acute leukemias, like, we’re running out of time, and yet we have so many things to talk about. I think what I’m going to do is just throw out to you a bunch of these drugs that have come online, as I’m remembering the slide that you show where you show all the approvals, and just get your take, particularly, again, from the point of view of the general oncologist, in terms of what it means in practice. I think this patient, the IDH patient, actually got gemtuzumab, correct?

DR WANG: Yes. He did.

DR LOVE: Can you talk a little bit about gemtuzumab and where it fits in nowadays?

DR WANG: I think gemtuzumab is a perfect example of a resurgent drug. It has found its niche again. We are now using it in the up-front setting. There’s data suggesting it can vastly improve our outcomes for favorable-risk patients in addition to standard cytarabine and daunorubicin induction and high-dose cytarabine consolidation. Large studies, retrospective studies, meta-analyses show about a 20% improvement when added to standard 7 + 3 and consolidation, about a 5.7% improvement in overall survival when adding it to intermediate risk. No role for it in adverse-karyotype AML. We are also using it as a less preferred but still an option for elderly unfit patients that don’t want any oral agents, that don’t want any hypomethylating agents and just want to come in for some antibody therapy — 2 doses in the first month, 1 dose monthly.

There is also, obviously, a role in the relapsed/refractory setting. Less favored in that setting because of the risk of VOD that’s been associated with it. If we do give it to patients, we sometimes will give it for intermediate-risk patients in combination with induction, but we omit it from consolidation if those patients are going forward with an allogeneic transplant.

DR LOVE: Any other potential tolerabilities, other than VOD, veno-occlusive disease?

DR WANG: Liver toxicity is something that we have to watch out for. Patients with baseline liver dysfunction not due to their disease can have issues with the gemtuzumab, something that we’re keeping an eye on. And obviously anybody that is, for example, going immediately to stem cell transplantation right after induction chemotherapy, generally the practice has been to give at least a 2-month window between the use of gemtuzumab and a myeloablative regimen. Certainly the data suggests if you’re going to give a nonmyeloablative regimen, particularly in older patients, that it would be safe to go forward in that with gemtuzumab. And gemtuzumab is an agent that we’re very familiar with — fallen out of favor a little bit in the targeted therapy, but definitely something that we have back in our regimens now.

Activity and unique side-effect profile of the hedgehog inhibitor glasdegib for AML

DR LOVE: I usually don’t get a gigantic response to this one, but I have to put it out there: glasdegib.

DR WANG: Glasdegib, again, also has a role. I think that many people are not using it, and I think that’s because the baseline regimen that glasdegib has been layered upon has been low-dose cytarabine, and at least in this country, low-dose cytarabine has not been the standard. Glasdegib is an oral sonic hedgehog inhibitor, which we think blocks that leukemic stem cell, so it is a very unique mechanism. It improved overall survival when added to low-dose cytarabine in newly diagnosed unfit.

However, since the low-dose cytarabine has not been the standard for patients in this country, not in Europe or in Australia and other industries, it’s really been not favored. Also, I think people are looking at the outcomes, and they’re saying that overall the percentage of patients alive at 12 to 18 months is nowhere near the 50% that we get with the venetoclax-based regimen. The benefit of the glasdegib is, again, there are elderly unfit patients that don’t want or cannot tolerate the significant myelosuppression that we see with venetoclax. And the myelosuppression that we get is platelets down to single digits and patients requiring daily or every other-day transfusions. There’s a lot of elderly patients that can’t do that. For those patients, glasdegib plus a low-dose cytarabine regimen, which can be self-injected, represents a completely outpatient regimen that could be an option for some older unfit patients.

DR LOVE: I don’t know how many times you’ve actually used it, but you hear pretty nasty stories from the people who treat basal cell about hedgehog inhibitors in terms of tolerability — muscle spasms, lack of appetite and stuff. Do you see that here?

DR WANG: Definitely it’s an on-target toxicity that they did see in the trials. We haven’t seen a lot of it, mostly because most of their side effects that they’re getting are from their AML. It may be that we’re just not seeing it because the patients aren’t healthy enough to begin with to notice some of those issues. We haven’t noticed it to be a big problem. We have started a few patients on the combination but really unfit patients that just can’t tolerate the myelosuppression with the other agents.

Results of the Phase III QUAZAR AML-001 trial: Overall survival benefit with CC-486 as maintenance therapy for newly diagnosed AML in first remission

DR LOVE: I want to spend a few minutes talking about ALL also, but just one other question. You’ve been talking about oral therapies. We’re going to see some data on oral azacytidine. I’m curious where you think that’s heading.

DR WANG: Yes, oral azacitidine has been like a mirage. Ever since we started using hypomethylating agents for MDS and then for AML, every single one of my patients that comes in for these daily shots has been, “Dr Wang, this is ridiculous. Isn’t there an oral medication?” Moving forward, I think that the oral aza is finally moving into market.

The problem with azacitidine is that when we give the azacitidine, we give the shots, and the pharmacokinetics are that it wears off, certainly, afterwards. The epigenetic effects fade. But then we’re not able to go and give more shots, because it’s already torture for the patients to come in 7 days in a row once a month. Oral azacitidine not only has a convenience factor, but oral azacitidine, and soon I think oral decitabine coming down the pike, is going to offer us a way to give these hypomethylating agents, give it more continuously and to have more effective antileukemic effect, okay? Because obviously your cancer doesn’t take a 3-week break when you stop the hypomethylating component.

Oral azacitidine presented at the ASH meeting was used in the setting where it was said, “After you are in remission from your high-dose chemotherapy, there may be a period where we’re going to stop all chemotherapy after consolidation.” And then patients say, “Okay, I have this very aggressive cancer. I could have died. What are you doing now, doctor?” And I’m going to say, “I’m going to stop everything, and we’re going to wait to see if the disease comes back.” And in that setting, traditionally 50% of patients or more that go into remission are going to relapse.

This was attempting to address that and to randomize patients to getting oral azacitidine versus nothing, went into remission to decrease the risk of relapse, and the data show that adding something versus nothing is better than nothing, right? Epigenetic agents well tolerated, taken as a pill, low dose, can provide long-term epigenetic modification which can prevent, in a certain percent of patients, relapse from occurring and therefore translate into an overall survival benefit.

DR LOVE: It’s interesting the point you’re making about pharmacokinetics, because you might expect the possibility that just because of the convenience that you could actually maybe achieve a therapeutic advantage. I remember when I first heard about ixazomib, the oral proteasome inhibitor for myeloma. I was thinking maybe the pharmacokinetics of that’s going to change actually the efficacy. I don’t know that that really has happened yet, but do you think that — I mean, do you think, for example, oral hypomethylating agents plus venetoclax?

DR WANG: Right. I think that’s the new world. I think so, because I think it depends on the mechanism of the drug. Like, for example, if you had oral cytarabine, I don’t think that would work. Because that works by killing off rapidly proliferating cells. And you’re not going to have rapidly proliferating cells every single day that you have acute leukemia.

But the epigenetic agents work by removing methylation groups and allowing for derepression of processes at the gene level that are important for normal hematopoiesis, okay, and for antileukemic effects. Hypomethylating agents in and of themselves take 4 or 6 months to work. With that mechanism of action of these epigenetic long-term administration in order to get biological effects, they’re ideally suited for a long-term oral administration in a maintenance setting when you look biologically as opposed to, like, oral cytarabine. I think that yes, I think moving towards totally oral combinations, I think, would be where we’d like to go, right?

Mechanism of action and activity of the first-in-class small molecule APR-246 in combination with azacitidine for patients with AML or myelodysplastic syndromes with TP53 mutations

DR LOVE: Were there any data presented at ASH on up-and-coming novel agents that you found promising or interesting?

DR WANG: I do think that there are some interesting studies. There is a drug, APR-246, which is for a subset of acute leukemia, p53 mutant, and that is a small molecular reactivator of mutant p53, which has reportedly resulted in very high response rates in a notoriously horrible, dismal prognostic subset of acute myeloid leukemia and myelodysplastic syndrome. And I think that we’re looking forward to that, because I think that agent might be the next agent to potentially be approved if the results hold out in larger-scale studies.

DR LOVE: This p53 thing sounds really interesting. What kind of a substance is it?

DR WANG: It’s a small molecule, and it’s been in development. What it does is it binds, and it results in reactivation. p53 is a tumor suppressor gene, right? It’s found universally in most all cancers. And so the suppression of a tumor suppressor gene then leads to protumorigenic effects, right?

In about 5%, 10% of AMLs they’re characterized, particularly complex karyotype AMLs are characterized by p53 mutation, and those particular p53-mutant patients do horribly with standard chemotherapy. They relapse after transplant, and they have very short overall survival — I just had a patient, 31-year-old who just died after transplant and multiple rounds of therapy with this very resistant subtype.

This particular small molecule inhibitor goes in and results in reactivation of p53, so allows the normal function of p53 to be restored and also has some direct toxic effects on the leukemia cells. But that particular drug in early studies reportedly has, like, very high, 60%, 70%, even 80%, 90% response rates in that very poor subset that we would really expect only 10% or 20% response rates.

DR LOVE: As you said, p53 is a cancer-wide issue. Is this the only such agent that’s been used? Has it been used in other tumors?

DR WANG: I think they are looking at it in solid tumor, though I’m not familiar with the solid tumor data, but the data in liquid tumors, with really myeloid malignancies, AML and MDS, really looks very intriguing and very promising.

DR LOVE: That’s really interesting.

Mechanisms of action and activity of blinatumomab and the antibody-drug conjugate inotuzumab ozogamicin in patients with relapsed/refractory ALL

DR LOVE: I want to finish out with a couple questions on ALL, and I think that’s a cancer that a lot of general medical oncologists are kind of referring out, see from the point of view of secondarily being involved. But there are some things going on there that I think are really interesting and potentially relevant that docs are going to be following these people in practice. And one has to do with the evolution of blinatumomab, but the other agent is inotuzumab. Can you talk a little bit about those two agents, what they are and right now how they’re being currently integrated into the care of patients with ALL?

DR WANG: Okay. Blinatumomab is a bispecific antibody. It works by activating the immune system. Now, we know that in ALL the immune system is very important. The drug goes in, binds to CD19 as well as CD3 and activates the host immune system to identify and eradicate residual disease. Blinatumomab has been found to be highly effective not only in the relapsed/refractory setting but in minimal residual disease and is now approved for the use of patients who after standard cytotoxic chemotherapy have measurable residual disease by PCR or by flow cytometry. And the blinatumomab is used as a measurable residual disease eraser in that setting as well as in overt relapse.

Inotuzumab is different. Inotuzumab is a standard chemotherapy agent attached to a CD22 antibody, also expressed on B ALL cells. Inotuzumab has been used in the relapsed/refractory setting, has very high response rates, 80% in the first relapse setting, and is an agent that can continuously be given. But we think that because it’s attached to a DNA damaging agent, there are side effects. And because of the conjugation effects, it also is associated with VOD.

Blinatumomab and inotuzumab have changed the landscape for patients with relapsed/refractory disease, particularly adult patients that cannot be cured. Pediatric patients’ cure rates 80%, 90%, 95%. In older adults, where we’re seeing it more and more common, cure rates are down to 30%, 40%. And many elderly individuals, similarly to elderly individuals with acute myeloid leukemia, can’t tolerate cytotoxic.

Where we see those drugs, we are seeing increasing use of blinatumomab to eradicate disease in combination with cytotoxic therapy in the up-front setting. There are now trials moving inotuzumab into the up-front therapy in combination with induction chemotherapy and as a consolidation chemotherapy. Using it as another chemotherapy agent in our arsenal and reserving blinatumomab for measurable residual disease or blinatumomab and inotuzumab. Can we get rid of chemotherapy completely?

There’re some regimens that are taking out the cytotoxics for those older unfit patients and only giving them these two antibody-drug agents to see whether that, in combination with maybe low-dose chemotherapy or steroids, could control disease in patients biologically without the need for high-dose chemo.

Tolerability and safety of blinatumomab and inotuzumab ozogamicin

DR LOVE: You seem to have a great eye for not only clinical toxicities but how it affects people’s lives. What do people go through, both in terms of toxicities as well as inconvenience when receiving both of these agents or either of them?

DR WANG: The challenge with blinatumomab is, because it is a bispecific antibody, it has to be continuously infused for 28 days. Also, because it activates the immune system similarly to checkpoint inhibitors or CAR T cells, there is a risk of cytokine release and neurological phenomenon.

There is currently the recommendation for patients with active relapsed and refractory disease that they be in the hospital for cycle 1 of blinatumomab for 10 days. And obviously a 28-day infusion is something that logistically has to be managed outpatient and with independent patients’ lives. Twenty-eight-day continuous infusion is clearly not optimal, can be something that is limiting.

Inotuzumab is easier to give. It’s a cytotoxic, so we give it in clinic, usually 1 time a week for many weeks in a row. But I have a patient now that I think has developed a secondary myelodysplastic syndrome from the continuous administration of cytotoxics, including inotuzumab. The challenges with inotuzumab, really the myelosuppression, the risk of VOD in certain patients. Blinatumomab, the 28-day infusion.

DR LOVE: Inotuzumab’s been associated with VOD?

DR WANG: Yes. Up to 11% to 14% of patients given the initial doses of inotuzumab at the higher doses developed VOD, some of them in conjunction with subsequent allogeneic stem cell transplantation. The veno-occlusive disorder has been most associated with gemtuzumab. The recent redosing or re-emergence of gemtuzumab was premised based on new toxicity data that when you dropped the dose of gemtuzumab from 9 mg per meter squared to 3 mg per meter squared, the risk of veno-occlusive disorder went down to about 4% in the up-front setting.

Similarly, with inotuzumab we’re getting the same lessons that we’re learning. Reducing the dose of inotuzumab to lower doses in a chronic setting seems to be associated with a reduce rate of the veno-occlusive disorder. And something that we’re really looking closely at, patients with relapsed ALL going to transplant should really have only 2 cycles of inotuzumab and again, in interval if possible.