← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 125: AML Series, Pt 11 - Treatment of patients unfit for intensive therapy
Ronak Mistry, Vivek Patel, Dan Hausrath
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Transcript33 lines
- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the hemonk Podcast. We're coming at you from Rouleau University Medical Center. I'm Ronuk.
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B
I'm Vivek.
- [00:24]
C
And I'm Dan.
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A
In today's episode, we are continuing on our AML journey, this time talking all about the elderly and and patients that are not quite fit for intensive chemotherapy.
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C
It's exciting to get into this. We did not have a lot of options for this even, you know, as recently as when I was starting fellowship. So definitely some fun science success stories here.
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B
Excited to get into this one and really excited to kind of get close to finally wrapping up this series. AML is super complicated as we always plan the series to be a couple of episodes and that turns into these 10 part series.
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A
No, but this is such an important episode because as we had discussed in an earlier episode, the age at which many people get AML tends to be later in life. And so understanding what the options are for treatment as patients get older and aren't as fit for intensive chemotherapy, certainly really important. So lots of high yield pearls coming your way, guys. Let's roll that show. All right, y'. All. So how are we doing today?
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C
Not bad and feeling good. Recently doing a little bit more aerobic training. This sort of like zone. Are you guys familiar with this Zone two heart rate training?
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A
I see people doing stuff like that from Instagram, but I'm not really sure I know exactly what that means. What is that, Dan?
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C
It's kind of the best. It's like basically one of the lower heart rate zones. The idea is you're trying to build your ability to work out in the aerobic range, so burning fat as your source of fuel. Sort of. Rule of thumb is if you're working out easily enough that you can just breathe through your nose or carry on a conversation and kind of keep that pace indefinitely, then you're probably in zone two. And I gotta say, I'd feel awesome when I do it. Like if I work out in the morning and do a Zone two run before that. Before I go to work? Yeah, the whole day I just feel fantastic. So I don't know, I'm buying in. All right.
- [02:14]
B
While Dan does the Zone two running, I think our listeners probably already skipped fast forward. So let's get on to our scheduled programming here. This time I'm going to maybe toss it to Roanok. Ronick, do you want to start us off with a case today?
- [02:24]
A
Yeah, absolutely. So we have a case of a 78 year old male with an ECOG performance status of 2 who had presented to the emergency department with really severe fatigue. His CBC had shown a white blood cell count of 10.4 with 60% circulating blasts. He had normal neutrophils. He was also noted to be anemic with a hemoglobin of 5.8 and he was thrombocytopenic at a platelet count of 74. So the ED had given him two units of packed red blood cells and admitted him for workup and treatment. And they were concerned for acute leukemia, so they paged hematology and the astute fellow that was on call recommended sending a flow cytometry that showed an abnormal myeloblast population that was CD34 negative, CD117 positive, HLA Dr. Negative, CD13 positive, and CD33 positive. So because of these findings, he underwent a bone marrow biopsy which showed increased abnormal myeloblast that were at 55% by manual differential. A rapid molecular testing identified the presence of IDH1 mutation and the absence of an NPM1 mutation, IDH2 or the FLT3ITD mutation. Cytogenetics were also performed with FISH for common MDSAML chromosomal changes and that was unremarkable. His conventional karyotype revealed a normal karyotype, reducing the likelihood of a TP53 mutation in the absence of complex karyotype. The patient had no history of prior chemotherapy, no prior radiation, or any sort of myeloid neoplasm, which ruled out secondary aml. And they did send off NGS testing, but that's currently pending. So we have been on this journey through the treatment of aml and we've really focused on curative intent therapy. And so in this episode, you know, we have this older patient who is 78 years old, coming in with a new diagnosis of AML, and from what we're told, right, his ECOG performance status is 2. So not as healthy as maybe we would hope that he would be. So I guess the first question I have for you guys is how do we define patients who are not fit for intensive induction therapy?
- [04:35]
C
Yeah, we've referenced this fitness for intensive therapy or fitness for transplant in the past. And it's important to keep in mind that there's really no one size fits all it's purely clinical judgment and sort of a holistic assessment of somebody's status. We have several geriatric assessment tools in development, a few that have been validated, but the reality is we don't have good prospective evidence incorporating these into clinical practice. There's a lot that are out there and that are used, but whether or not these are truly predictive, it's hard to say. Metrics like the EcoCHG performance status that you referenced, those are good. And Karnovsky performance and data is another one. They're helpful, but they can be a little misleading. Remember that ECOCHG performance status goes from 0 to 5. 0 is perfectly normal, functional, fully capable of work, and 5 is literally deceased. So it's not a very fine grained scale. And they really don't incorporate all the patient's comorbid conditions, things like that. It's also important to keep in mind things that specifically interact with the therapies that we would offer. So heart failure with reduced ejection fraction, for example, is a contraindication to anthracycline chemotherapy. And so those patients would be not fit for intensive induction because again, that intensive induction therapy is going to involve some anthracycline exposure for the most part. Thinking about patients above the age of 75 are not going to be candidates for allogeneic stem cell transplant and they should be offered less intensive induction. Again, always going to be some exceptions to these rules, but broad strokes, the other key point is that some patients may not even be candidates for these less intensive induction regimens if they have several comorbid medical conditions and a very poor performance status. You know, spending most of their day in bed, completely bed bound, that sort of thing. These are the patients that might be better fit for supportive care, you know, trying to keep their counts down with hydroxyurea and managing their symptoms of cytopenias with transfusions as indicated, sort of more comfort oriented measures. This is an important area of research in terms of figuring out how to deal with the most frail patients. So hopefully some of you that are listening will come up with therapies that anybody could get that could help improve quality of life and also figuring out who really would be fit for assessment, figuring out really who could be fit these sort of geriatric assessments to identify people who are fit for treatment and who are not fit for treatment. It's a really fertile area of research.
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B
All right, so we have our patient here and you know, going from what Dan said, it's really important to kind of gauge whether this patient should honestly go to best supportive care route. Fortunately, our patient said, hey, look, I've been ambulating, I've been doing well, and it really just seems like the symptomatic anemia has. Has declined his performance status. So before I throw it to Ronick to talk a little bit about risk stratification, I just want to recap the diagnostic testing a little bit and contrast this to what we do for patients who are fit for intensive induction chemo. Really, the answer is we do the exact same thing. So everything we've talked about before, we're still going to do for these patients. We're going to initially stabilize them and evaluate for TLS and dic. We're going to give hydroxyurea early for cytoreduction because we don't want those blasts to start coming off. And when we think about Venetoclax, we don't want tumor lysis syndrome. So it's really important to start that. And we'll talk about Venetoclax in this episode. We still want to rule out apl. Don't forget that, that just because the patient's older, they can still have apl, and you want to start that ATRA promptly. If there's a concern by morphology, when we think about the rapid molecular testing, the cytogenetic testing and the ngs, this is all done, but the risk stratification is different. So, Rona, can you talk a little bit about how risk stratification is different in patients who are less fit for intensive induction based on studies looking at.
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A
Our modern treatment paradigm with HMA and Venetoclax? For these patients, the European Leukemia Network put out a consensus statement for risk stratifications for patients receiving less intensive therapies, actually as recently as this year, in 2024. So this is solely based on molecular data and it will be evolving. So be on the lookout for more literature to come. But adverse risk is TP53 mutations with a median overall survival around 5 to 8 months. Intermediate risk is a FLT3 ITD mutation and or a RAS mutation pathway. So that's like NRAs or KRAs, and these patients have a median overall survival around 12 months. Favorable risk is everything else, with a median overall survival of over two years. So the study that led to this system was published essentially at the same time as this recording in November of 2020. And it was a pooled analysis of the phase 1b trial and a phase 3 randomized control trial that led to the approval of Azacitine and Venetoclax as standard of care. This new risk stratification System outperformed the ELN 2022 system and interestingly, patients with MDS related gene mutations without FLT3ITD, a RAS pathway or a TP53 mutation still did well.
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C
That's awesome. Thank you for going through that. I always struggle a little bit with wrist stratification, so it's nice to have a good review. As for our patient, we started him on hydria 1 gram q 12 hours as a cytoreductive measure as well as some allopurinol 300mg bid with IV fluids for TLS prophylaxis. He has IDH1 mutated AML which would be a favorable risk for less intensive induction. Pending his NGS results, we now have our standard treatment options. Hypomethylating agent either with either with azacytidine or acetabine plus venetoclax which is a BCL2 inhibitor, as a first line option and for IDH1 mutations, azacytidine plus ivacitinib which is an IDH1 inhibitor. Before we get into the mechanism and data behind those medications and how they were approved, can we go through our sort of classic historical perspective on the treatment of AML with less intensive approaches? How do we get to where we are today and how much better is any of this stuff?
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B
Now it's time for everybody to click fast forward, but this will all be on our website. It's really interesting to see the history and how this all developed. So remember from our prior induction episode, check it out if you haven't, that we had this 7:3 regimen with seven days of continuous cytarabine infusion at 100 milligrams per meter squared. I'm mentioning the dose because it'll become important in a second. With three days of anthracycline and that was published from the Roswell park group back in 1973 and that was really the standard of care treatment for AML for decades and decades to come. The problem was for patients above the age of 65 there were really high rates of treatment related mortality, particularly in the eras back in the 70s and 80s. So there was a push to say, well this cytarabine medicine works really, really well. What if we did lower doses instead of doing this 100 milligrams per meter squared, what if we did 10 to 20 milligrams per meter squared twice a day for maybe let's say 10 days, something like that, which is our Modern treatment regiment. So the first study to do this was published in 1981. It's very fascinating. And they did 10 milligrams per meter squared of cytarabine. So much, much lower, a tenth of the dose of these continuous infusions for seven days. And they found that three patients were treated with it and all three patients went into cr. So it was incredibly promising. After that there was a randomized phase three trial that compared low dose cytarabine. Sometimes we call that Lodac, if you ever hear that low do Cytarabine at 20 milligrams per meter squared every 12 hours versus intensive induction chemotherapy in patients older than the age of 65. This was run in the 80s and ultimately published in the JCO in 1990. There was no difference in overall survival. And that's the key because these patients, right, they can't tolerate all this intensive therapy and these allotransplant, they have high non relapse mortality. So Even though the CR rate was less with low dose cytarabine in the 30% range compared to the 50% range with intensive induction therapy, there was no difference in overall survival. And after that time, low dose cytarabine was considered a standard of care for these less fit patients for intensive chemotherapy. Based on this publication way back in 1990 and subsequent studies were done looking at low dose cytarabine, that whole 30% CRA was very likely overblown. We're really looking at these single digit percentage range, maybe that 12% range of CR rates with low dose cytarabine. And for many patients above the age of 75, best supportive care with transfusions that Dan had talked about was really a reasonable option for many of these patients. And it wasn't until the 2000s when we had a new medicine, we had these things called hypomethylating agents which Roanoke had really talked about in our previous maintenance episodes. And remember that patients with AML often have epigenetic mutations. And what does this mean? It means that these mutations upstream will silence or methylate genes that are further downstream that are important for cells functioning and regulating apoptosis and those things. So hypomethylating agents basically say, hey, let's take off the silencing of those genes, let's fix that problem. It's like if you had a bunch of light switches and methylations turning off the switch. Hypomethylation says just turn on all the genes and hope that we restore normal functioning. And it was originally tested in mds there were two drugs, one's called dacitabine and another one's called azacytidine. And after the efficacy in mds, these were tested in AML in randomized trials against Lodac. Low DO cytarabine or best supportive care. It was really standard of care. It was a hypomethylating agent versus standard of care, which could be low dose cytarabine or it could even be best supportive care. And there's improved overall survival with dacitabine, which is a five day regimen that was at about eight months median overall survival compared to about five and a half months with the other standard Lodac regimen. Azacytidine had a similar outcome again with improved overall survival here at 10 months compared to 6 months. So again we now have hypomethylating agents that beat Lodac, which was the standard treatment since like 1981. And it wasn't until about 2007, 2009 when these dacitabine and azacytidine hypomethylating agents or HMAS is what we call them as single agents, became the standard of care for patients who are less fit for intensive induction. The so that kind of leads us to our current landscape of things.
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C
It's kind of hard to believe that we had low dose cytarabine and best supportive care as standard treatment options. Until we came to the mid 2000s and got hypomethylating agents, survival was still really poor for these patients and low CR rates were seen kind of across the board. Before we get into the pivotal trial that led to the approval of azacytidine and Venetoclax, how exactly does this drug work? We mentioned it's a BCL2 inhibitor, but what does that mean?
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B
Before Rona gets into the mechanism of action of Venetoclax, I wanted to point out the comment you made about CR8. I didn't mention those. In those studies that were done, we're talking CR8s maybe 15 to 20% with HMAs. So still not great. So I really wanted to highlight that what Dan mentioned. So that leads us we are now until this Venetoclax. So Ronak, how does this Venetoclax thing work?
- [15:33]
A
I feel like Venetoclax is this magic drug that came onto market and it's really been playing a critical role in the management of a lot of different types of diseases. So super important to know how the mechanism of Venetoclax works. So essentially IT is a BH3 mimetic that acts as a BCL2 inhibitor to induce apoptosis so that is the fundamental mechanism. Several studies have shown that AML cells actually have an overexpression of BCl2 and BCl2, remember promotes cell survival by inhibiting apoptosis. So essentially BCl2 will inhibit and sequester apoptotic proteins that activate BAX and BAC. Venetoclax will bind to BCL2 which frees the pro apoptotic proteins to activate BAX and bac, leading to mitochondrial permeability and this leads to the release of cytochrome C and caspase activation resulting in apoptosis. So again, long story short, BCL2 allows for inhibition of apoptosis and the mechanism of action of Venetoclax is that it inhibits BCL2. So remember that cytochrome C piece as this is important. The one piece I do want to highlight is just remember cytochrome C, because this is going to be important in just a second. So another thing to know is that patients with an IDH mutated AML are exquisitely sensitive to Venetoclax. To understand this, it is important to understand what IDH actually is. IDH1 and IDH2 are key enzymes that convert alpha ketoglutarate in the Krebs cycle that ultimately allows for the generation of ATP in the electron transport chain. So throwback to biochem in aml, the IDH mutations are gain of function mutations and rapidly convert alpha glutarate into another compound called 2Hg. And this 2Hg molecule prevents further function of several alpha ketoglutarate enzymes that are important for DNA repair and prevention of DNA hypermethylation. As a result, there is less DNA repair and a significant amount of gene silencing due to methylation. 2 Hg increases histone methylation in the hemopoietic stem cells leading to blocking and differentiation which leads to proliferation of immature myoblasts. And the last thing is that two HG messes with the electron transport chain in the mitochondria and inhibits that cytochrome C oxidase protein we just mentioned. So there is much lower threshold to release cytochrome C and induce apoptosis. And so because of this low threshold to Release cytochrome C, IDH mutated cells are dependent on BCl2 overexpression for survival, which makes them a prime target for venetoclax. So again, just to recap, remember guys, in patients with an IDH mutation, these patients are exquisitely sensitive to venetoclax because of the underlying mechanism that IDH plays in the cell cycle, in the cell energy production process.
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B
It's really important to understand how these things work in that last piece that IDH mutated patients are sensitive, Venetoclax. This will come into play as we talk about some of these trials. Another thing that I really wanted to mention that Ronak highlighted there is that IDH mutated patients have a block and differentiation, this byproduct called 2Hg. So it's that Krebs cycle, who cares? But basically what this. It's a gain of function mutation that creates too much of this thing called 2Hg, causes hypermethylation. So that means a hypomethylating agent seems like a good target for IDH mutated patients. Right. And the second thing is that it blocks differentiation for these stem cells. So what if you, if you inhibit idh, maybe you could restore differentiation in. And this is why we can see something called differentiation syndrome when we give things like IDH inhibitors. And we'll get to that in just a bit. So I want to kind of go back to the case we have for our patient. So we're eventually going to plan on giving this guy a hypomethylating agent with azacytidine plus venetoclax. So, Dan, how did we get to the doublet with Venetoclax as the first line? Why are we even trying this? The first line? Was it ever used as a single agent in the relapse refractory setting?
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C
So the first time that we really saw success with Venetoclax was actually in a different disease state. It was in cll. And we discussed that in a prior series. It was then tested as a single agent with escalating doses up to about 800 milligrams daily in a phase 2 study of patients with AML. And there were relapse refractory setting, as he suggested, the overall response rate was pretty poor. It was 19%. So sort of comparable to what we were seeing with HMA monotherapy. And we'll have a link to that study in our show notes. But there was a subsequent phase 1b study that looked at hypomethylating agents combined with venetoclax using either dacitabine or azacytidine. And this study included untreated patients with AML who are not fit for intensive therapy. This is also one of the studies that was used to develop the risk stratification for less intensive induction. So kind of a good data set to be using the composite CR rate was an astounding 61% with a median overall survival of 17.5 months. Remember previously we're like in the 15, 20% ballpark. That is a massive increase in CR based on toxicity with mild suppression and infections. The recommended dose for the phase 2 study was 400 milligrams daily. We'll have a link to that phase 1b study data in our show notes as well. The key takeaway is that this Venetoclex doublet was so much better than HMA monotherapy and some patients were even able to achieve a durable remission. And we also know from what we talked about that monotherapy with Venetoclax not really a great option. So it's really this doublet that seems to have magic greater than the sum of its parts.
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B
So this gets us to the current standard of care for most patients with AML who are not fit for intensive induction. So Rona, can you go through the pivotal phase 3 viali a study?
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A
This is such an important trial to be aware of and this trial really challenged the treatment landscape for AML and and has also been used for patients who relapse or are refractory after intensive induction. So in this study, patients were included if they were 75 years or older, so definitely older than a lot of the other trials. They were randomized to azacytidine for seven days with venetoclax at that 400 milligram daily dose for 28 days versus azacytidine monotherapy. There were over 400 patients who were enrolled in this study and the composite CR rate was 66% in the AZA and VEN group and and 28% in the AZA monotherapy group. In patients with that IDH mutation, the CR rate was 75%, which fits the pathophysiology that we had previously discussed. And the median Overall survival was 14.7 months compared to 9.6 months. And the median duration of azacytidine plus venetoclax was 7 cycles. So there was significant myelosuppression in the azacytidine Venetoclax army with about 75% of patients requiring a dose interruption or a dose reduction and 25% requiring discontinuation. Furthermore, tumor lysis syndrome was reported in 1% of patients in this study even with some of these toxicities. And I say that, though not trying to minimize toxicities, because that is an important component, especially in this demographic that we're now talking about, but we are seeing significant, significant changes both statistically and clinically with this combination therapy. And so this Viali trial is just something to store away in the back of your mind as an important one to remember in the treatment paradigm landscape of aml.
- [23:11]
B
It's pretty amazing that we can extend patient survival who are older with aml, two years plus if they're in that favorable group that we had talked about at the beginning of this show. And remember that these are different risk stratifications. No TP53 mutation, no RAS pathway mutation, no FLT3 mutation. All of those patients have very, very favorable overall survivals with good response of Venetoclax. One thing I want to point out that Ronick had mentioned is that there's a lot of myelosuppression. So practically, how is this done? Our patient, we had actually planned on starting him on azacytidine for seven days and venetoclax for 21 days. There's a really good how I treat azacytidine and Venetoclax article from blood that we're going to link to our show notes. It's really important. We're going to put a really table that shows how to dose reduce in our shownotes as well. But the bottom line is this for these patients, even though it said do 28 days in the trial, in practice because of myelosuppression, we're doing 21 days of therapy, doing a bone marrow biopsy at day 21. If it's empty, less than 5% blast, it's reasonable to give GCSF. So you can give that next cycle on a more reasonable schedule. So that's really, really important. It's also important to know that it's okay to dose reduce these patients, typically reducing the frequency of venetoclax down to 7 days, sometimes even 3 days, and also reducing the HMA agent. Please read that article. And we're going to put some important dose reduction guidelines in our show notes and we're not going to belabor the points here. It's just important that everybody reads that if you're treating some of these patients. Another thing that we mentioned, so our patient here, he's a guy who's got IDH1 mutated AML. We had talked about why they're sensitive to Netoclax and the VALEA study, Roanoke pointed out the subgroup there, 75% CRA. It's really, really good. Dan, though, you know, we have this other option of azacytidine plus Ivacitinib. So can you talk about the Data behind that?
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C
Absolutely. There was a Phase 3 randomized control trial called Agile that ultimately led to approval of this combination. And it was patients with IDH1 mutated AML. They were randomized to either azacytidine plus ivacitinib versus azacytidine monotherapy. One major issue is that azacytidine and venetoclax as a combination was approved shortly after this trial opened. Unfortunately, right after they started recruiting, we're looking at their comparator ARM not really being standard of care anymore. As a result, the trial was amended to have a primary endpoint of event free survival defined by the failure to achieve a complete remission at six months, relapse after remission or death. This is kind of a weird primary endpoint, but it was not powered for overall survival. And there was poor recruitment in the United States given the widespread approval of Venetoclax. So it's kind of what we were stuck with. A total of 146 patients were enrolled, so again, much smaller than the vialih study and randomized one to one between the arms. The estimated event free survival was 37% in the doublet arm versus 12% in the monotherapy arm with a statistically significant hazard ratio of 0.33. The CR rate was 47% in the azacytidine plus ivacitinib arm, which was notably lower than than what was seen in the Viali A population with this molecular subgroup. The median Overall survival was 29 months in the azacytidine plus ivacitinib arm compared to 7.9 months in the monotherapy arm. And we'll have a link to that in our show notes. Ultimately, the good news is that we really have two great regimens for patients with IDH1 mutated AML. And the problem is we don't really know which to choose between these two. I mean, both of these are obviously a drastic improvement over HMA monotherapy. But how do you think about sort of comparing these two pivotal trials in the space?
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B
I think this is really important because it's easy to say the median overall survival in agile is 29 months. So everybody should be getting that. With IDH1 mutated disease there's a lot of problems. So we did some cross trial comparisons there. We should never do that. And I think the number one important thing is when you look at the ELN risk stratifications and again we'll link this to our show notes. When you look at the pooled analysis looking at AZA Ven data in IDH mutated patients. What's their median overall survival? About the same. It's really good. These IDH mutated patients tend to do well. So that's one thing to say. Well, we can't just say that everybody should be getting AZA Ivacitinib. The second problem is, well, another thing people say was myelosuppression is a huge problem with AZA Van, let's just give Azov Ivacitinib. There's that differentiation syndrome that we had talked about, about 14, 15% in that group. The problem is, while that sounds nice with more optimization of giving aza Vin nowadays, it's really something that's very reasonable to get through. And many of these IDH mutated patients end up having very few transfusion requirements because they do achieve CRS at pretty early time points and sustain those CRs because they're exquisitely sensitive to the regimen. The other problem is the cost. When you think about it, one day of ivacitinib is $1,000, so it's $30,000 a month. And when it comes to Venetoclax, Venetoclax is much cheaper. We're talking that over a month Spanish, we're talking about a fraction of that cost. So we think about cost effectiveness. It doesn't make any sense to give AZA plus ivacitinib from a cost perspective. It is really just not worth it when you really think about it. Those are some pretty significant issues. And the last issue I want to point out with when people will say, well, there's data for Venetoclax after AZA plus ivacitinib, but not the other way around. Some people will make some arguments like this. I'll say, well, single agent Venetoclax activity is terrible. Dan just went through the data, right? Response rates were only 19%. It's not even CR rates, that's just response rates. So single agent ven doesn't work. So why are you going to burn that option when we know single agent ivacitinib works quite well and we can have durable remissions with single agent ivacitinib. So which is better? I wish we had the randomized study and that would be a smart thing to do for this patient subgroup and we should do it. We shouldn't just assume that one is better than the other.
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C
That's awesome. I'm really glad you went over that. It's so important to think deeply and critically about this and also remember the hazards of comparing these two trials because it's not how we look at data. Right? We have to take each of these individually and do the best we can to come up with a good plan. But I really like we talked about. So that's fine for IDH1 mutated patients, but previously we talked about patients with the FLT3ITD mutation, for example, and we have some specific inhibitors for that. Is there any role for HMA and FLT3 inhibitors in our less fit patients?
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A
So unlike the Agile study where it was unclear if patients got ivacitinib on relapse, there was a phase 3 study called Lacewing that randomized patients to the FLT3 inhibitor gilteritinib and combined that with azacytidine and they compared this to azacytidine monotherapy. And in this study, 50% of patients got the FLT3 inhibitor at relapse in the control arm, which is what should happen as this is the standard of care and these targeted inhibitors have efficacy as single agent, unlike Venetoclax. And this is in line with what Vivek just mentioned about the IDH1 inhibitor as well. And so this data was published in blood 2022 and they showed no difference in median overall survival after about 120 patients were enrolled. So the study was actually terminated early. There is speculation on why this doublet didn't improve our overall survival, but both higher risk disease and adequate post protocol therapy at relapse in the control arm is what likely led to these findings. So guys, let's finish out this episode with the future landscape and with Ash around the corner at the time of this recording. And of course we've got years and years and years of AML research waiting to be done. Are there novel regimens that have shown promising efficacy?
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B
I think now my concern is that we're going to head towards triplets, which is going to be hypomethylating agent, Venetoclax plus ivacitinib plus nicitinib plus gilteritinib plus some of these targeted inhibitors. And we'll go through all of these names in our relapse refractory episode listeners, so don't worry about memorizing them. Bottom line is that those three are the triplet. What I worry about is these are going to be single arm studies. We're going to say, oh man, they have great response rates, but you have to compare the sequences. When we know we have good single agent activity for FLT3 inhibitors and IDH inhibitors, you have to ask should we give everything now or should we give some now and sequence it with others later? And what is the most cost effective approach? So hopefully that'll come in the future, but I do worry about that. Another promising regimen coming from MD Anderson as a single center study is a combination therapy of Cladribine, Lodac, lodocytarabine and Venetoclax alternating with azacytidine and Venetoclax. And it seems pretty great actually. The CR rates are like 90%, plus the MRD negative rates are like 84%. It seems pretty incredible. My hope is that we're actually going to test this in a randomized phase 3 trial immediately. This should be tested against HMA Venn as soon as possible. We've already shown that we can do this. The Phase 1B portion was published in 2019 and shortly during that time period we had the Phase 3v Alea trial published very shortly after that. So we can definitely do this and we should. So what I really hope is that right now that study is going to be run, but that's something to look forward to in the future. We do not recommend doing any regimens that are not tested in phase three randomized trials here at the Fellow on call, and I hope that that happens. Ash will be really interesting to see. What are the new things coming down the pipeline?
- [32:32]
A
Cladribine. A blast from the past. An oldie, but a goodie that just always seems to make its way back into treatment modalities. But I'm excited to see how this plays out and of course I'm excited for another big meeting right around the corner. All right, guys, I think that wraps up another fantastic episode of the Fellow on call. So until next time, we'll see you all later.
- [32:51]
B
See you later.
- [32:51]
C
Peace.