← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 126: AML Series, Pt 12 - Treatment of patients with relapsed/refractory disease
Ronak Mistry, Vivek Patel, Dan Hausrath
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- [00:01]
A
This episode is sponsored by our global research partners. Want to contribute to the advancement of medicine? Make some easy money while sharing your thoughts with market research surveys. Learn more and sign up using the special TFOC link on our website and in the description box below. 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 Hemong Podcast. We're coming at you from Rouleau University Medical Center. I'm Roanoke.
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B
I'm Vivek.
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C
And I'm Dan.
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A
And in today's episode, we round out our AML series, focusing this time on relapse and refractory disease. Guys, we made it.
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B
I'm really excited to get done with this series. This took forever. No knock on AML and all the AML doctors out there, but, man, this is a lot of work to get this series done and. And I really hope that all of our listeners get a better understanding, particularly those who are in training or even if you're out in the community practicing. It's really important to understand how AML therapies have evolved and how we got to the place that we're at today.
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C
I just think it's incredible how fast it all changes. I feel like some of the stuff we're talking about in today's episode just happened. So up to the minute news here.
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A
Yeah, really, really impressive stuff. So without further ado, guys, let's roll that show. All right, everybody, so we're back after the holidays. You guys look super refreshed. It sounds like you guys had some great breaks. What was the biggest highlight for me.
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C
I think it was meeting my newest family member. My cousin's just had a baby. She's four months old. I think that makes her my second cousin. I'm not 100% sure what the name for that relation is, but it was super fun to meet her and play with her over the holiday season. I also made up a little scrapbook for Logan as a Christmas gift of our wedding from, like, the first time that we met all the way through our wedding and honeymoon. So it was fun kind of paging through that with him.
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B
Yeah, that's always the highlight of the break is getting to spend time with family. This year we went to North Carolina by the beach, hung out with Christine's family. It was really, really fun. Really enjoyed it. I think one of the best highlights for us was getting to eat another very nice turkey dinner. You can't get enough turkey dinners. I love that kind of stuff.
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C
You might be fairly unique in that perspective. I understand it's like one of the least popular holiday foods, but I'm right there with you. I want to defend turkey's honor.
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A
How interesting. But you got to get all your turkey meals in. I mean this is the season, right? Us two family certainly was first and foremost and this was extra special because this is the first time that Jen and I have owned a house and we were able to have both sides of our family for Christmas at our house for Christmas brunch and also for Christmas dinner. And we went out on all out on decorations and really made it a magical event. So it was just. This is probably going to be one of our most memorable Christmases ever. But I'm excited to be back with you guys. I'm excited to round out this AML series that we've been working on and looking forward to all the new things that are coming our way in the new year for sure. Vivek, in classic fashion, do you want to start us off with a case?
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B
Yeah, let's get it started. Here we have a 61 year old male who was admitted for symptomatic anemia and pancytopenia. He was ultimately found to have TP53 mutated AML cytogenetics, showed a monosomal karyotype with deletion 7 NGS, showed a tier 1 TP53 mutation with a variant allele frequency of 57% and a tier 1 IDH2 mutation with a variant allele frequency of 4%. He underwent intensive induction therapy at another facility with 7:3 his day 14 bone marrow biopsy showed persistent disease with a hypercellular marrow. He's now transferred to Rouleau for re induction therapy consideration. He otherwise was previously healthy and has an excellent performance status. His induction course was really only complicated by a transient neutropenic fever without bacteremia. So before we get into treatment options for relapse and or refractory aml, can we first define primary induction failure in aml? You know, it's always complicated and we get some of these patients we gave intensive induction to and they have persistent disease at day 14. So how do we define these things?
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C
Primary induction failure, also known as primary refractory aml, differs based on intensive induction with anthracycline based chemotherapy versus less intensive induction. So from the perspective of the European Leukemia Network, they provided a Little bit of guidance on these definitions back in 2022 for patients undergoing intensive induction. Primary induction failure is defined by persistent disease with greater than 5% blasts after two courses of intensive induction. Remember, that's the standard over in Europe. For patients undergoing less intensive induction, there's less of a consensus and it's sort of based on an arbitrary amount of time after starting therapy, anywhere from three to six months or 90 to 180 days. This is because some of those less intensive induction regimens can take to four cycles before you even get towards a cr. So you need to give a little bit more time to understand what direction the disease is going. Keep in mind that many of our patients who again are hospitalized for weeks will not achieve a CR after intensive induction therapy. And this differs based on that European leukemia network. That ELN risk group. There's a pivotal validation study for the ELN 2022 risk stratification published in 2023. Over 1100 patients from AML trials conducted in European countries between 1999 and 2012 who underwent intensive induction with cytarabine based chemotherapy were included in this analysis. There was a second validation cohort of over 1100 patients from the German Austrian AML study group trials to confirm the key findings. There were differing CR rates based on these risk groups. So the favorable had a nearly 75% CR rate, intermediate had about 66% CR rate and adverse had only 45% CR rate. In total, about 15% of patients were reclassified from the ELN 2017 risk stratification. That was sort of the standard prior to this. And one interesting finding in the study was that patients who had both TP53 mutated AML and complex karyotype had a five year overall survival of zero percent. I'll say that again. Patients who had both TP53 mutated AML AND complex karyotype had a 5 year overall survival of zero percent. And that really begs the question if these patients should be considered a category of their own, a very unfavorable risk disease. I mean it's a complete failure on our part as hematologists to treat these people adequately. So with all of that in mind, it's really important to understand that we now have some effective salvage options for patients who do have persistent disease after that first intensive induction or on that day 14 bone marrow biopsy with targeted therapies and venetoclax.
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B
So in this case our patient does not have induction failure or primary refractory disease. Technically, given that he only received one course of intensive induction Remember, it's after two courses of intensive induction where we call these patients primary refractory disease or induction failure. Regardless though, we can use this case to discuss salvage treatment options for patients with relapse or refractory aml, because at the end of the day we need to do something more here. So, Rona, can you give us a good framework for treatment options in these patients? How do you think about approaching a patient like this? Absolutely.
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A
And I will say, even during fellowship and after fellowship, this landscape has been changing pretty rapidly. So it's kind of exciting to see how far we've come. And listeners, as you'll see in this episode, we don't have robust randomized data in this setting. And overall the prognosis of these patients is unfortunately quite poor. The best thing that you can do is refer for consideration of a clinical trial. But as you may know from experience, this isn't always feasible for all of our patients. And so after that, intensive RE induction, regardless of targeted mutation status, is a reasonable option, particularly for those patients who need what we call debulking with one round of intensive induction before you go to something else. So regimens that you may hear about include things like FLAG or flag, IDA or CLAG or CLAGM or all these will make a lot more sense as we talk about this a little bit more. And we'll also include links to hemonc.org to break down some of these regimens as well. You can also consider something like HMA and Venetoclax, which we've previously talked about in lieu of intensive RE induction. Or you can consider the addition of Venetoclax to an intensive reinduction with flag, IDA and ven. For instance, if patients have primary refractory disease after two courses of of intensive induction or they have relapse after achieving a prior remission with or without an allo transplant, then an HMA plus Venetoclax therapy, or ideally a targeted therapy is going to be the way to go. Remember that the targeted mutations with Therapies include the IDH1 mutation, the IDH2 mutation and the FLT3 mutation. And now, hot off the press, we also have approval for a drug called a MEN, a menin inhibitor for the KMT2A rearrangement which involves translocations with 11q23 on the cytogenetics. So rapidly evolving landscape, but an exciting one nonetheless.
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C
Yeah, thanks for going over that framework. I think it's super important also that you highlighted thinking about clinical trials. The way we come to these discoveries like Foot 3 inhibitors and IDH inhibitors and this new menin inhibitor is by having patients be involved in clinical trials. So always keep that at the front of mind as well. All that said, what are the alternative intensive RE induction strategies for patients with aml?
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B
So it's really important to now take our interlude and go through a historical perspective to really understand how we got to these regimens. And one important thing that I want to highlight that Ronick said is that sometimes what we'll have is after a day 14 bone marrow biopsy, we'll have debulking of their original disease and you might have a reduction in the blast percentage. You might say, hey, more intensive chemotherapy makes sense here. So where do we get to this? So as we discussed in our prior consolidation episodes and remember, check out our website and check out that episode again if you want some more details on this. High dose cytarabine as a monotherapy was effective in achieving CR in the relapse and refractory setting at doses ranging from 1 gram per meter squared up to 7.5 grams per meter squared in a dose finding study that was published way back in 1983. So remember that we have what we call high doses of cytarabine, which conventionally we think of maybe 3 grams per meter squared, but we know that lower doses of one to one and a half grams per meter squared, as we discussed in that consolidation episode, can also be quite effective. And as a monotherapy we're seeing some of these CRs being achieved. So because of this, hydrocytarabine was a key component of the backbone for salvage intensive regimens for aml. So you'll see this A often in these regimens. So for FLAG and clag, the A stands for the cytarabine. There were also studies that showed efficacy of single agent or combinations of other chemotherapy agents like etoposide and alternative anthracyclines like mitoxantrone. And because etoposide and mitoxantrone were effective, there was a regimen called MEK that was developed and this stands for mitoxantrone, etoposide and higher doses of cytarabine at 1 gram per meter squared. That's the C for MEC. MEC CR rates with this regimen range from studies and he reported anywhere from 20 to 60%. But really we're looking at that about 40% cr rate when we're thinking about that regimen. So in addition to the use of etoposide and mitoxantrone with this MEK regimen, there was significant work done in the lab to understand how can we augment the effects of high dose cytarabine and aml. And remember, we discussed this before. What is cytarabine? It's cytosine, that DNA base pair with an arabinoside sugar attached to it. And this is an inactive prodrug. What has to happen is this drug has to enter the cell and through an enzyme needs to be converted to its active form where it's phosphorylated. So it's called ARA C is what we call it. And it has to be activated to something called ARA ctp, which happens inside the cell. So basically you have an inactive drug enters the cell and it needs to be activated. So the thought was, how can we increase activation of this drug in the body? And there's a pivotal study published in the JCO in 1993 that showed that the addition of the purine antimetabolite fludarabine prior to high dose cytarabine infusion increased the accumulation of this active ARA ctp, this activated form of cytarabine inside the leukemia cells, leading into greater cell death. So basically, fludarabine potentiates the effect of cytarabine. So the whole goal here is how can we potentiate cydarabine effect during this time period. There was also studies looking at another purine analog called cladribine, which again did the same thing. So we have the cladribine and fludarabine, which both will upregulate the activation of high doses of cytarabine that enter the cell. Another thing that was used was gcsf. So the thought was, well, if we push all of these cells into S phase, we'll upregulate this enzy and convert more active drug. The second thing is this active drug, this cytarabine activated really is going to do its efficacy when the cell is undergoing DNA replication and it ends up being incorporated into the actual DNA itself. So pushing quiescent AML cells into S phase will also be helpful. And so GCSF was added to the regimen. This led to the development of regimen called clag and flag, the CL and the FL for in the clag and the flag. The first two letters stand for cladribine or fludarabine. Flutarabine for flag, cladribine for clag. The A stands for the Aracea or the cytarabine and the G is for the gcsf. So really for clag and flag, you're just upregulating the effectiveness of the cytarabine with GCSF and with the antimetabolite fludarabine or cladribine. So that's the key to those regimens. There was also a push that said, hey, if CLAG and FLAG are working, let's add an anthracycline to it. Just something different than the Donna Rubicin used in seven plus three that we've talked about in our previous episodes. So this led to CLAGM and FLAG ida, the M for mitoxantrone and the IDA for idarubicin. We look at all of these regimens, the CR rates, when you really dig down to it, is somewhere between like 30 to 50%. When you look at all of the studies looking at this, and the big thing was there was never a randomized study evaluating differences in mek, clag, flag CLAGM or FLAG ida. So it makes sense how we got to these regimens. Right? Mitoxantrone was effective, etopizide was effective. So let's add it onto cytarabine because before all we had was high dose cytarabine relapse refractory setting for FLAG and clag. Let's potentiate the effects of high dose cytarabine by upregulating the enzyme that converts cytarabine into its active form. And no randomized trials. So what did we have? We had some retrospective studies. One showed that CLAGM was better than CLAG or mek and another study showed that FLAG is better than FLAG ida. So there's conflicting results all around. So at the end of the day, all of these are reasonable options. You'll see institutional differences, but it's really important for you to know why we use FLAG and clag. It's to upregulate the effects of cytarabine.
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C
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- [15:36]
B
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- [15:55]
A
To learn more and to sign up, use the special TFOC link on our website thefellowoncall.com and in the description box below. That makes so much sense and it's really interesting that FLAG and Clag regimens are purely designed to augment the effects of high dose cytarabine, like you were saying, which is really what's doing the heavy lifting as you've been pointing out. And we often see the addition of anthracyclines with flag, IDA or clagm. But it's also good to know that really we don't have good comparative studies. It's reasonable to admit the anthracycline and you will see different institutional practices as you're pointing out. So getting back to our patient, so he has AML that clearly did not respond to chemotherapy at all with a persistent hypercellular marrow and he had 80% blasts. We could consider more chemotherapy with FLAG or clag based regimens as potential options, but this may not be the best way to proceed without a novel agent. In a prior episode we discussed the excellent CR rates with HMA plus Venetoclax therapy for adults that are not fit for intensive induction. So I guess Dan, is there any role for Venetoclax in this salvage setting?
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C
Yeah, you know, Venetoclax has really been such a game changer in malignant hematology and it's broadened our treatment options in AML tremendously as you referenced. So venetoclax is a BH3 mimetic which inhibits the anti apoptotic protein BCl2. And remember that BCl2 is overexpressed in AML cells as a strategy that sort of protects them from apoptosis. So the addition of Venetoclax blocks that effect of BCl2 and helps potentiate or facilitate apoptosis. Remember that from our previous episode? Single agent Venetoclax has little activity in AML. The CR rates are around 10%, so it should always be combined with another drug, either chemotherapy or a hypomethylating agent. Given that we have this new standard of care in unfit patients with HMA plus Venetoclax, this regimen has also been tried in the relapse refractory setting and it can be a good strategy for patients with a concern for chemorefractory disease like in our case. There have been some conflicting reports on the efficacy of this combo in the relapse refractory setting and most of the trials have been retrospective in nature. One of the largest trials was a single center phase 2 study from MD Anderson that looked at dacitabine for 10 days with venetoclax added on. The study included both newly diagnosed and relapse refractory patients who are not eligible for intensive induction chemotherapy. Over 80 patients with relapse refractory AML were included and it's important to note that 70% of the relapse refractory patients had already received HMA monotherapy and about a third of these patients ended up having a TP53 mutation as well. The composite CR rate was roughly 40% in the relapse refractory patients despite prior HMA use, which is pretty impressive given that these patients were already exposed. There was another real world multicenter study from 11 centers in France presented at ASH 2023. This study included 146 patients with relapsed refractory AML and the composite CRA was 44%, which really confirms the findings that we saw in that phase two study in a real world setting. One other very important single center retrospective study from City of Hope that looked at HMA plus venetoclax for 32 patients who all had TB53 mutations showed a composite CR rate of 50%. And remember that is incredibly high risk group as far as including Venetoclax with more intensive regimens. The MD Anderson group also looked at adding venetoclax to flag IDA. There was a phase 1b phase 2 study with 59 patients who had relaxed refractory AML and used this flag IDA Venetoclax regimen and the composite CR rate was shockingly high at 66%. In summary, HMA and venetoclax and flag IDA venetoclax are both reasonable options in this relapse refractory setting. We haven't really seen an ironclad randomized trial run for these patients that's been reported on. So obviously still a lot of work to come to confirm that these regimens really are as good as they look like they might be. But promising early data for sure.
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B
Yeah, and with all of this there's really no correct answer, but it's great that we have more options now and when we really think about the use of a hypomethylating agent and venetoclax, the CR rates that Dan's are quoting around that 40 to 50% range is pretty good and you're sparing a lot of toxicity in patients. And what we hope to see in the future is a randomized study and some of these are being run right now that compares intensive salvage to something like an HMA and Venetoclax therapy for patients who already received an intensive induction with something like a seven in three. And I Think that would really help answer the question on what do we do next? And when it comes to this regimen, flag ita venetoclax. Remember that the flag IDA had been developed way back in the 90s even and adding venetoclax on had pretty impressive CR rates. So it's another good option. A lot of people say well you're burning your Venetoclax at that point, so what are you going to do after that? Now you can't do HMA ven. So really this is an evolving space for our patient. We decided to give him Azacytidine plus Venetoclax and he ultimately achieved a cr, underwent a myeloblade of allogeneic transplant and he's now remaining in CR for one year later. So you know, good conclusion to that case. And it also just shows, hey, we have a laundry list of options that we can use. Ronak, I want to switch gears now. Let's say that we have a different patient. Say we had a 68 year old female FLT3ITD mutated AML who achieved a CR with 7 plus 3 plus midastorin based on the Ratify trial and underwent an allotransplant. She's now here two years after transplant and is found to have relapse disease. Remember that anytime we have AML relapse we always repeat the same diagnostic studies that we've talked about in our prior episodes. And what we found was to summarize things and just to be short about this, she had a persistent FLT3ITD mutation found on NGS with a variant allele frequency of 30%. So Ronak, what are some of the salvage treatment options for patients with relapse? FLT3AML? Obviously we have on the table the FLAG and CLAG based regimens and the HMA VEN based regimens. But what about some targeted therapies for these patients?
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A
Absolutely. So the drug of choice, which our listeners may recall from earlier conversations, is going to be Gilteritinib which is the FLT3 inhibitor that was approved based on the Phase 3 randomized trial known as Admiral. So this was a study that included 371 patients who are randomized 2 to 1 to gilteritinib monotherapy versus salvage chemotherapy which was sort of dealer's choice of MEC or Flag IDA or Lodac or Azacytidine. It's really important to note that HMA plus Venetoclax was not an option as it was approved years after the study was published. So that is just something very important to keep in mind as you're sort of understanding the data behind this study. The composite CR rate was 34% versus 15% and there was improved median overall survival at 9 months versus 6 months. Notably at 2 year follow up, the survival rate was 20% in the giltiritinib arm with most patients undergoing allogeneic transplant. Another caveat is that only 13% of patients had received a FLT3 inhibitor in induction. And given that the ratified trial was published in 2017 and this trial, as in the Admiral trial, accrued from 2015 to 2018, we still don't know if HMA and Venetoclax or Gilternib monotherapy or potentially a triplet of HMA plus fen plus Gilternib is the ideal regimen in this setting. But once again it has presented us with another option for patients that may have that FLT3 mutation. So speaking of these targeted therapies, I just talked about FLT3. What about IDH1 and IDH2 that we had mentioned earlier in the show?
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C
For IDH1AML, the options are ivacitinib or eludacitinib. For me, the I in ivacitinib looks like A1, so that's how I remember that it's for IDH1 mutated AML. For IDH2AML, the option is nicitinib and it's kind of silly again just looking at the letters here, but nicidinib, like the letter N, that's like a two on its side. I realize that's very silly, it's just how I remember it. As we discussed in our treatment of unfit patients with AML episode, the IDH mutations are gain of function and leads to an excess of the compound 2Hg, which ultimately leads to hypermethylation block in differentiation and inhibition of apoptosis. So all the bad things that can facilitate cancer cell growth. When you inhibit the IDH mutation, normal differentiation is restored, so there's a risk of differentiation syndrome as the blast can rapidly differentiate into mature neutrophils. The median time to response for these therapies is around three to four cycles. So it's important to continue with the treatment for several months before saying patient is refractory given the hypermethylation. You will also see the addition of hypomethylating agents to these therapies, although there's really not a lot of great evidence behind this practice and this space will definitely be evolving with the addition of other agents. Just remember that it can take several months to achieve a response to these regimens. And we'll link the phase 12 studies for ivacitinib and eludacitinib. In our shownotes for IDH1 mutated AML, the overall response rate was at 46% and the composite CR rates are around 20%. Overall survival was median of 9 months. Roughly 1 third of patients will ultimately achieve transfusion independence as well, which is a super important quality of life marker. It's also important to know that these patients did not have prior venetoclax therapies given at the time of accrual. So we do have a phase three randomized trial for nicidinib versus conventional treatments. If we're thinking about IDH2 mutated disease in older adults, would one of you be able to go over that study?
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A
Absolutely. So this was called the Phase 3 Identify Study IDH Entify Super Clever. That was published in blood in 2022. This study enrolled 319 patients with relapse or refractory AML, with about 75% of these patients receiving prior intensive chemotherapy. This was an open label study that randomized patients one to one to either nicitinib monotherapy or conventional chemotherapy, including either azacytidine monotherapy intermediate do cytarabine, low dos cytarabine or best supportive care. There was no difference in overall survival with a median of six and a half months versus 6.2 months. Notably, 12% of patients in the control arm dropped out before receiving any therapy. And the composite CR was 30% in the nicitinib arm versus 6% in the control arm. Transfusion independence occurred in 30% compared to 10% in the control arm. And differentiation syndrome occurred in 14% of patients on the nicitinib arm. So an interesting study that does present potentially another option. But clearly there's more work that needs.
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B
To be done and to go along with that. One of the interesting things about an open label design, there were a ton of patients who were censored early. They just dropped out. They said, I want nicitinib. Why are you giving me this conventional stuff? And so that really makes it very difficult to interpret this data. One way to look at this is probably the patients who are the most fit and wise are the ones who dropped out, right? They're probably the richer patients with more resources. And when you look at the survival, there's no difference in either arm of this study. And what does that tell you? It tells you that, okay, well, these other therapies can be used, but what we do know is nicitinib provides a greater response and transfusion independence, as Dan said earlier, is an important marker of quality of life. So it's still. Yes, overall survival is still quite poor in these patients. This is a highly refractory population. That being said, this therapy can still be effective at achieving transfusion independence.
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C
Yeah, thanks for going over that, guys. And would one of you be able to finish out our discussion with talking about the recent approval of this menin inhibitor that we referenced earlier? It's spelled revuminib. Since I've never heard anyone actually say it, that's just how I'm going to assume it's said. And this is again for patients with KMT2 a rearranged AML. So another sort of targeted agent for a specific mutation in aml.
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B
Yeah, so I'm going to call it revuminib and I'm not sure if that's right, but that's what we're going to stick with in this episode. So remember that these are patients who have a translocation involving the chromosome 11q23, which is known as a KMT2A rearrangement. So any rearrangement involving 11q23 that you'll see on your cytogenetic or fish report, recall that this is also what you'll see with anthracycline related aml. The classic boards question, that patient who received anthracycline will have a rearrangement. 11Q23. So what does this rearrangement actually do in leukemia cells? It leads to an upregulation of something called the Hox gene. Hox gene which blocks cell differentiation and it promotes leukemia persistence. The KMT2A Hox gene interaction is mediated by a protein called Menin. And a similar mechanism to this is actually found in npm1 mutated AML, which is kind of interesting. So there's a push to develop an inhibitor of Menin because basically it's like, hey look, menin is critically important for the pathophysiology here in this leukemia cell. So what if we just block menin and there was a drug invented called Revuminib. In August of 2024, there was a phase two registrational study called AUGMENT101 which included pediatric and adult patients with relapsed and refractory KMT2 a rearranged or NPM1 mutated AML. And all of these patients were heavily pre treated and received revuminib monotherapy. Given every 12 hours as either a capsule or a liquid in 28 day cycles. Impressively, there was a composite CR rate of 23% with a median time to CR of about 1.9 months. Differentiation syndrome was common and occurred in about a quarter of patients. So it's really important to keep in mind. Remember, KMT 2, a HOX interaction blocks differentiation. When you give this drug, you're promoting differentiation like you can see in the IDH inhibitors. And in this case, 25% is a high number. So it's important to keep that in mind as this is a new drug that's going to be given to patients, whether in the community or in the academic setting, which is probably more where you're going to see it. But still, it's important to know this. And this was a big improvement as 75% of these patients had received prior Venetoclax treatment. And in general, the KMT2A rearrangement is often associated with chemotherapy refractory disease. So by achieving this 23% cr rate, that's huge. And it can open up the door for some patients to get to maybe an allogeneic transplant, maybe a second allotransplant, or in some cases a donor lymphocyte infusion where you're really just trying to, really trying to cure some of these patients. So it's a very good treatment that we're gonna see moved up in further lines of therapy. And we're excited to see this being moved up to things like the front line to see if we can really improve outcomes for these patients.
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A
My goodness, what a journey that has been. I think we've certainly covered a lot of ground in this episode and I think that the biggest takeaway for me for this discussion today is just there's no right answer with regards to what regimen we pick. I think what we've highlighted is that there's a lot of options that are out there and you have to use a little bit of the art of oncology to figure out what regimen may work best for you and your patient. Thinking about things like, like comorbid conditions and prior exposures. And of course, there's always going to be institutional differences between which regimens people pick. But it's good to know that there are options available and as we're saying, over an ever evolving landscape, for sure.
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B
Any final thoughts that you guys have? I thought that summed it up really well. Remember that evolving landscape, you'll hear about triplet therapies, which is hma, ven plus targeted agent. I don't know if that's going to be a better than the sequential treatments and that's what we should be asking. So keep an eye out. The question should be sequential versus all at once, not just all at once versus HMA monotherapy which is I fear what's going to happen but we'll see. And the last thing I want to say is remember clinical trials always refer to an academic center in this setting. This is how we've improved outcomes for these patients and is so critical.
- [32:12]
C
Yeah. And just like Vivek alluded to earlier, this is the space to look for the emerging treatments. Like look forward to seeing these treatments incorporated in earlier lines of therapy in the future.
- [32:23]
A
That's awesome, guys. All right. With that I think we can wrap up another fantastic episode and series of the fellow on call. Until next time. We'll see you all later.
- [32:33]
B
See you later.
- [32:34]
C
Peace.