Dr. Uma Borate:
Hello, everyone. Welcome to the ASCO Post Roundtable Series on Navigating the Complexities of Relapsed Refractory Acute Myeloid Leukemia: Identifying Mutations and Optimizing Targeted Therapy. I'm Dr. Borate. I work at the Ohio State University and I'm the clinical section head for the acute leukemia section in the division of hematology. Joining me today are two of my colleagues and friends. I'll start with Dr. Naval Daver, who is a professor of medicine in the one and only MD Anderson Cancer Center in the leukemia department. And Dr. Joshua Zeidner, who leads the leukemia program at UNC Chapel Hill and is a leader of their clinical research division as well.
Together, we'll be discussing the treatment and management of relapsed refractory AML with three patient case studies. Our first installment will focus on the management of relapsed KMT2A-rearranged AML. So, maybe I'll start with you, Dr. Daver, and talk about case one, and Dr. Zeidner, I'm going to come to you in a minute as we continue this discussion. But this is a case that I think we're all sadly familiar with.
NS is a 35-year-old female. She was diagnosed 3 years ago with breast cancer treated with systemic chemotherapy and radiation therapy. Now she has new-onset pancytopenia. Her white blood cell count is 1,200, her hemoglobin 7.1 and her platelets are low at 51,000. The bone marrow biopsy shows a hypercellular marrow with 68% blasts, with the normal myeloid phenotype of CD33, CD13, (CD)11b, (CD)117, (CD)123, doesn't have CD34 expression. And her cytogenetics, I think this is key, shows translocation (9;11) with the FISH confirming a KMT2A rearrangement. You have comprehensive NGS mutational panel showing no actionable mutations. And her workup actually shows an adequate cardiac function. Her 2D ECHO results with an EF of greater than 60%. Her performance status is zero. So, in this case, what would be your choice of therapy for this patient in terms of front-line therapy for AML?
Dr. Naval Daver:
Yeah, thank you, Dr. Borate. So, pleasure to be with both of you here. This is unfortunately a relatively common presentation in patients who've had prior chemoradiation for other tumors as this patient did for breast cancer. And 3 to 4 years later, we may see this patient presenting with the KMT2A rearrangement. So, today for these patients who are young, and young is below 70, maybe between 65 and 70 we can consider as well. But we would be going with intensive chemotherapy in the front-line setting, anthracycline-cytarabine based.
And in general, I think there are two approaches. So, one is the standard 7+3 that's used across many centers in the U.S., as well as Europe. And there are also more enhanced regimens that we at MD Anderson, the UK, and other groups have tried such as FLAG-IDA based with or without venetoclax. So, at MD Anderson, if I was seeing this patient, I would do a FLAG-IDA-venetoclax. We have shown that that is a very powerful regimen and can be well tolerated in patients below 60 or otherwise fit with a high remission rate. And actually one of the subsets that included a good response rate was KMT2A. So, I think this would be one option.
Now, there is also recent data that the UK has presented just at the ASH meeting 5 months ago where they showed that the addition of gemtuzumab, GO, to the anthracycline-cytarabine also really improved the response rate, as well as the 3-year survival. In fact, this was the first time, to my recollection, they had a 3-year survival with KMT2A beyond 60%. So, I think that this is quite interesting and maybe potentially adding GO is another option.
And then thirdly, before I turn it back to you and Dr. Zeidner, of course, if I had the option of a trial, the number one thing I would be looking for would be a menin inhibitor added to intensive chemo. And so, these trials are now open with various menin inhibitors including revumenib, and enzomenib and bleximenib for the KMT2A. Those would be the ones I would prefer. And if I had a front-line trial, whether it's with the anthracycline-cytarabine, 7+3 and/or FLAG-IDA with menin, that would be my first choice. And I think in the future that will become the most efficacious approach. But we don't know yet. We have to get more data.
Dr. Uma Borate:
Thank you for that great summary. So, what I'm hearing from you is you would prefer something that's obviously intensive, potentially FLAG-IDA-venetoclax. That's something your center has pioneered, maybe the addition of GO. But really very excited about the addition of menin inhibitors to induction therapy. And as you mentioned, a lot of these trials are ongoing. So, I'll turn it over to Dr. Zeidner and maybe twist this around a little bit. You've led some of these trials yourself. Obviously this can be a discussion in terms of if this patient were not 35 and not a candidate for intensive induction, or maybe even if she were, would there be an option of something different that could be less intensive for an older patient or even a younger patient that maybe you're not excited to do induction with. So, maybe you can give us an idea of what's going in that space, the trial you're leading, and any other discussion points that you might want to add.
Dr. Joshua Zeidner:
Yeah, well, thank you, Dr. Borate, for the invitation and being here with you. First off, I agree with everything that Dr. Daver went through with intensive chemotherapy. I think the standard for a fit 35-year-old, even with the KMT2A rearrangement right now is some form of intensive chemotherapy. But what I would recommend for a patient right now is to look for a menin inhibitor trial. So, we know we're fortunate to have front-line menin inhibitor trials both incorporated into intensive chemotherapy with let's say a 7+3 backbone. And we also have menin inhibitor trials in the front-line setting in combination with azacitidine and venetoclax in a lower intensive approach, which I'll get to in a bit, more for an older, unfit patient population.
In this patient, I would look everywhere for a menin inhibitor trial because I truly believe, A, KMT2A rearrangements are very high-risk genetic abnormalities that don't respond well and don't have favorable outcomes with conventional chemotherapy without the addition of the investigational menin inhibitors that really look to be a game changer for KMT2A rearrangements. So, there are a number of front-line studies both in the randomized and non-randomized setting now, adding investigational menin inhibitors to front-line intensive chemotherapy.
And I agree that I do think that's going to be a practice-changing eventual standard of care currently. Obviously not available as a standard regimen, but certainly ongoing trials asking that question. Now, we've seen incredibly high response rates adding a specific menin inhibitor, revumenib, to a backbone of azacitidine and venetoclax for older, unfit AML patients over the age of 60, where we've presented data in the past year at the European Hematology Association Congress, we’ll have updated data soon, that our response rates are incredibly high. Close to 100%.
And so, I think the question is, which we don't have data for currently, but the question is if you can get remarkably high response rates that are, let's say as close to 100% as you can get, do you need intensive chemotherapy even in a younger fit patient population? Because that's the current paradigm. We have an age cutoff; our patients younger, fit, for intensive chemotherapy. And if so, that's the standard. And if they're not, we have a backbone of azacitidine and venetoclax. But if you can get equal or higher response rates with a lower intensity regimen, is there any reason to pursue a more intensive toxic approach with 7+3 or intensive chemotherapy?
That's an unanswered question that I don't think... We certainly don't have those answers, but I think that is where I'd be excited about moving forward in this field. Currently, I would not offer this 35-year-old a low-intensity treatment right now, but I don't think that it's unreasonable to ask that question in the future. We need data to guide us there. So, I think I would recommend an intensive chemo plus a menin inhibitor if we can find one from a trial perspective for this patient.
Dr. Uma Borate:
That's great. So, just maybe going back to this case. Unfortunately, this case happened before the advent of menin inhibitors. So, this patient received a CPX-351 induction. Unfortunately, she achieved a CR without MRD as seen by flow or cytogenetics. And I think my next question, which I think, Dr. Zeidner, you already alluded to, is would you choose this therapy if she was more than 60 years old with a worse performance status, maybe a performance status up to 2?
And I think you very elegantly summarized this debate in the field where potentially the trial that you're leading that you're presented at EHA, and we'll update, as you said, showed these amazing response rates for the combination of azacitidine plus venetoclax plus revumenib. And so, obviously to me that would be a great choice for a patient like this if it were an older patient with a performance status that wasn't as robust. So, maybe I can ask Dr. Daver to comment on this scenario with this older patient, poor performance status. What would you do? Obviously we're now in the era of menin inhibitors, so tell us a little about what you would do.
Dr. Naval Daver:
Absolutely. And I think very similar to what Dr. Zeidner mentioned, we're very, very excited about this idea that having targeted therapies added to HMA then with optimization of dosing, and of course using appropriate strategies to reduce myelosuppression growth factors, early bone marrow assessment. But this could be actually a highly effective approach and not to be pigeonholed only in the older unfit. In fact, it may actually be even better in slightly younger populations.
So, today for many of our so-called triplet regimens, we will consider strongly, patients 65 to 75, even 60 to 75 if they may have some comorbidity, some issue borderline where I'm worried intensive chemo is going to create a problem and may actually then make transplant even more difficult because they started with a little bit of issues. Now you have more issues with intensive chemo and transplant comes off the table. So, I think there is then a revumenib, as Josh mentioned, is I think a very good strategy front-line for these patients, 60 to 75. Maybe in the future, even younger, we need more data, I agree, before we go there and then plan for allotransplant in CR1 after three, four cycles followed by post-transplant maintenance. I think this could be as good if not potentially better in the future as compared to intensive chemotherapy.
So, I think this would be a strategy and there are many of these menin inhibitors looking at that same approach. Bleximenib, enzomenib are also having those triplets. So, then we will have to decide in 2 years which one is suited for a patient. Maybe it's based on their underlying comorbidities. If you have cardiac issues, revumenib may not ideal, then you could use enzomenib, bleximenib. If you have higher white count, maybe bleximenib has more differentiation, then you can use some of the others. So, this will be a good problem to have if we get all of them approved. But I do think the triplet here may start marching slowly down the age as we get more data and confidence.
Dr. Uma Borate:
So, what I'm hearing you're saying is you're all excited about these triplets in combination with azacitidine/venetoclax, potentially even with a younger age group once we have data. And that there's different menin inhibitors that can be combined with azacitidine/venetoclax that have slightly different properties, whether it be cardiac side effects, differentiation, QTc prolongation. And some of what we will end up doing is probably optimizing the therapy and the toxicities for the patient that's in front of us in clinic.
So, moving on to a little bit of this patient journey, as we mentioned, this was before the era of menin inhibitors. Luckily she has achieved a remission with induction. She then receives two cycles of consolidation and is being planned for an allogeneic stem cell transplant. Unfortunately, as happens with these patients that are high risk, the bone marrow biopsy that was done just prior to her transplant showed relapsed AML. She's been in CR now for about 2.5, 3 months. Now she has 10% blast and has a persistent KMT2A rearrangement. So, maybe I can ask Dr. Zeidner, and maybe it's a little bit of a multi-choice question, back to our days of test taking. What would be the next step in your opinion in the management of this patient? And the choices you have are single-agent revumenib, a clinical trial with a menin inhibitor, maybe multi-agent salvage chemotherapy, azacitidine and venetoclax, which this patient has not seen, and lastly, a hypomethylating agent alone.
Dr. Joshua Zeidner:
Yeah. So, before I answer that question, I just wanted to reinforce one of the things that I think Naval mentioned in brief with these patients with KMT2A rearrangements is really the goal for this patient is to get to an allogeneic stem cell transplant. So, we need to find something to lead to a response long enough and deep enough to allow that patient to be cured with an allogeneic stem cell transplant with or without maintenance thereafter. And I think unfortunately in this case, the intensive chemotherapy clearly did not lead to a long enough remission, which is why we need better therapies for these patients.
I think this patient did not get a menin inhibitor upfront. And now let's say we're in the new era where we actually have menin inhibitors. Revumenib is now FDA approved for relapse refractory KMT2A rearranged acute leukemia. So, that is actually on label and approved, I think would be a very reasonable standard, in fact, option for this patient. Overall response rates are in the 60% range. Complete remission rates when you kind of add the composite remission rates are close to 40%, 45% with revumenib. So, it would be a very reasonable option. A lot of us have clinical trials with other investigational menin inhibitors, Naval mentioned a few of them with bleximenib, enzomenib, ziftomenib. Some are with combination therapy, some are single agents. So, I think it really depends on what flavor of options an individual institution has. I think a clinical trial with the promising advanced menin inhibitor would be quite reasonable. But revumenib, I would argue is probably the standard here. And certainly getting a menin inhibitor is absolutely the next approach for me for this patient.
Dr. Uma Borate:
Now, that makes a lot of sense. And since we're at the end and have to wrap up this case, maybe I could turn it to Dr. Daver and ask, let's say you chose revumenib for this patient. Like Dr. Zeidner said, it's FDA approved, it's on label. What side effects would you monitor for once you start this patient on revumenib?
Dr. Naval Daver:
Yeah, I mean I think in general I agree with Josh. But I actually think I would not be averse to doing a clinical trial with the menin inhibitor here. Even though I agree revumenib is approved, but we are seeing data with some of the other menin inhibitors that may be equal or better. And then one could say, "I can still use revumenib later in another combination." So, I think it's fine if you have a trial and one is excited to do that, to consider that and then still have revumenib remaining. But either way, I think with all the menin inhibitors, it's very, very important as these come into the community and even in the trial setting for all of us to be aware of two or three key side effects.
So, one is differentiation syndrome, which is not really even an adverse event. It's an on-target enhancement of what you expect to happen. So, you start seeing rapid leukocytosis in some patients, even without the leukocytosis, you see shortness of breath, fatigue. And it can have very different manifestations. We've seen bone pain, we've seen lymph node swelling, we've seen creatinine increase, LFT changes, skin rashes. Bottom line, if something is happening in that first 4 to 6 weeks after starting a menin inhibitor, which is new, very different and no other clear etiology has emerged, I think you have to think about a possible differentiation syndrome. Do a workup, give steroids as a stress test if needed for 2, 3 days, you will see a change. And then of course, in parallel, continue antibiotics and other things. So, that is probably the number one thing. A high awareness, a low threshold, and if not sure, early intervention for a potential differentiation syndrome.
Even if the white count is not high, many people think the white count must be high. This is not true. We are seeing it with white count 3 to 4. And so, one cannot afford to wait for the white count to come up. The second is QTc. This is kind of more unique for revumenib, but it is quite important because there is a grade 3 QTc, 13% to 14%. Now in the trials, it was OK because we were very careful to avoid concomitant medications. The trials had good criteria for this. But in the community, again, I think one has to be careful to avoid QT prolonging meds. And then third, which I think, and I won't go too long into this, but I think myelosuppression is a very important thing. And we are touching the tip of this. We don't know for sure. But more and more as data is coming out, especially in the maintenance, I think it's a clear on-target effect. And so, as we move into combos, which we're all very excited about, this is going to be something where we may have to dose adjust, give interruptions, and even in maintenance, consider holding or giving growth factors if needed. So, yeah.
Dr. Uma Borate:
Great. So, I'm going to maybe summarize some of the key takeaways that both of you have so wonderfully sort of outlined for this very high risk group of AML. And those to me are KMT2A mutated AML is very high risk. We see this more commonly in younger AML patients and is commonly associated with prior cancer therapy. Menin inhibitors are a new class of small molecule inhibitors that can target patients with KMT2A gene rearrangements and NPM1 mutations. Revumenib is FDA approved for relapse refractory KMT2A mutated AML. And side effects, as Dr. Daver really nicely mentioned can include GI toxicities, QT prolongation, and differentiation syndrome, which requires prompt recognition and management with cytoreduction and steroids.
