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Induction Therapy for an Older Patient With IDH1-Mutant AML

In this video, Drs. Richard Stone, Courtney DiNardo, and Eunice Wang discuss the management of newly diagnosed older patients with acute myeloid leukemia (AML). The case is a 75-year-old woman with no past medical history who presents with fever and bone pain. She is diagnosed with AML, and next-generation sequencing reveals a mutation in IDH1, among others. The faculty discuss the potential choices for induction therapy in older patients such as this, debating the merits of intensive chemotherapy vs lower-intensity options such as azacitidine/venetoclax and azacitidine/ivosidenib.


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Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Dr. Stone: Welcome to The ASCO Post Roundtable Series on Updates in Acute Myeloid Leukemia. I'm Dr. Richard Stone, chief of staff and director of translational research in the Leukemia Division here at Dana-Farber Cancer Institute in Boston, Massachusetts. Joining me today are two of my colleagues. First, Dr. DiNardo? Dr. DiNardo: Hi, Courtney DiNardo in the Leukemia Department here at MD Anderson in Houston, Texas. Dr. Stone: And Dr. Wang? Dr. Wang: Eunice Wang. I'm on the Leukemia Service here at Roswell Park Comprehensive Cancer Center in Buffalo, New York. Dr. Stone: Thank you. Today we'll be discussing new updates in AML, including recent data presented at the 2021 American Society of Hematology Annual Meeting, and we'll be integrating these new developments into four patient case studies. Our second installment will focus on an older patient presenting with bone pain. So this is a 75-year-old female with bone pain, really quite robust and healthy. But for the past three months, she's had low-grade fevers and two weeks of severe back and neck pain. On presentation, her white count is 11,000 with 32% blasts, hematocrit 23%, and platelet count 90,000. Peripheral blood flow shows that these blasts are myelomonocytic in lineage, and there's also a background of trilineage dysplasia. Cytogenetics show an extra copy of chromosome 8, and NGS panel testing reveals mutations in DNMT3A, ZRSR2, KRAS, EZH2, and IDH1, with the latter having a variant allele frequency of 22%. So we have a lady who was well and is now not well and needs some therapy. Choice one, or A, is 3+7 using daunorubicin 60 mg per day and cytarabine for 7 days. Choice B is CPX-351. Choice C is azacitidine with venetoclax. Choice D is azacitidine with ivosidenib, and choice E is CPX-351 with venetoclax. So we have many options here, and we have to make a decision. So I'll start with Dr. Wang. What would you do in this case? Dr. Wang: So in this situation, I understand that this is a very healthy 75 year old. She is presumably has good performance status prior to her development of her symptoms related to her acute leukemia. But when push comes to shove, she is 75 years old, and per the Ferrara criteria and other criteria, 75 years old is considered, in general, an age cutoff for whom we would not necessarily think about giving intensive chemotherapy. We now also know that her disease expresses an IDH1, as well as other secondary mutations, which provides a potential targetable therapy for her cancer. So in this situation, though one could argue that she should be eligible for intensive chemotherapy, specifically with CPX-351 for what looks like in AML MRC, I would really favor one of the lower-intensity regimens. And the options would really be between venetoclax/azacitidine, which we're all familiar with as the new standard of care, or azacitidine and ivosidenib, which has recently been presented to have a significant survival advantage over azacitidine alone. So in my mind, after discussion with the patient, I would really favor one of the lower intensity options. I would be curious, however, in the absence of a randomized trial, what everyone else would be thinking. I think if the patient was potentially 60, 65, or younger and eligible for an allogeneic stem cell transplantation, I do think at that point CPX-351 would be a valid option. At our center, we do not perform allo transplants routinely in individuals greater than 75. Dr. Stone: Excellent. So I think the age of allo transplants varies from center to center. She is 75, which depends, I guess, when her birthday is as to whether she'll be in remission by the time she could have a transplant, that's obviously so much facetious. So Dr. DiNardo, Dr. Wang said that she likes azacitidine and ivosidenib here. You have really great data with azacitidine and venetoclax that you published in The New England Journal of Medicine in the context of the VIALE-A trial, and those people that had an IDH mutation did quite well with that combination. So would you consider that as your primary therapy with this patient? Dr. DiNardo: I would certainly consider it. And I will say that I think for the majority of patients who are in their 70s, despite how fit or unfit they are, I really am more and more leaning towards HMA/ven, azacitidine and venetoclax, over intensive chemotherapy. And the things that make me a little bit just thinking out loud as I'm thinking through this case, the things that make me a little bit nervous about aza/ven are the myelomonocytic nature of this case and the KRAS mutation that was identified. So, depending on the study you look at, some say monocytic diseases are more resistant. Others, like the one we did here at MD Anderson, it was really the RAS pathway mutations that correlate with monocytic disease that are associated with resistance, secondary resistance, primarily. So that's in the back of my mind, although I don't think that's why you should or should not choose an aza/ven regimen. As you mentioned, I think the most important part of this case is the IDH1 mutation. And you're right that we see two-thirds of patients with IDH1 mutations responding to aza/ven. The median survival is 18 to 20 months or so. I want to raise a point though, I think there is a difference for whatever reason between IDH1- and IDH2-mutated patients. So when you really dig into the data of the VIALE-A and the combination that they've done with the earlier phase I/II HMA/ven studies, the IDH2-mutated patients do particularly well. You're seeing remissions above 80% and you're seeing survival above 2 years, and the IDH1s fall a little bit below that. And then in the meantime, we have this new AGILE data, which is aza/ivo, where you're seeing kind of remission rates and survival, which are along the lines of what you see with the VIALE-A, without that degree of cytopenias and cytopenia-related neutropenic infections. And so I do think the aza/ivo combination is definitely a consideration here, and one that I would potentially choose in a patient like this who had an IDH1 mutation over aza/ven. Although the majority of the time, I'm choosing aza/ven. Dr. Stone: Sure, if you want to compare median overall survivals, the AGILE data is 24 months... Dr. DiNardo: 24 months. Dr. Stone: And I think it's a little bit less with VIALE-A and the IDH1, but not that much. Dr. DiNardo: Yeah. But the numbers are small and it's so hard to cross-compare studies. So in my mind, they're about equivalent. And so the question then is the tolerability. Dr. Stone: Yeah. When clearly I think aza/ivo is, as you pointed out, more tolerable than aza/ven. But I just want to go back to CPX-351 for a second, because she does have myelomonocytic disease, which might be less amenable at least to aza/ven. And if she's going to get something very myelosuppressive, because she's robust, she has that KRAS mutation, which is a tough one and might be at least initially chemo responsive. So what do you think of the CPX-351 versus 3+7 trial that was published a number of years ago and updated recently by Dr. Lancet where the outcome for that regimen was pretty good. And it seemed like if you were going to get a transplant in first remission, and maybe this patient would because she's just at the upper limit of age that one would consider it, why not use a regimen with a proven track record? Eunice? Dr. Wang: So I think if you were to give this patient the best option for cure, the only option for cure, you would pursue an allogenic stem cell transplantation. And the data supports with the 5-year overall survival that you can get 20%, 30% of these patients long-term survival with the combination of CPX-351 followed by allogenic stem cell transplantation. And that data was really, although the numbers are small, really transformative because this is a patient population with therapy or your secondary related AML that in the past, we would've given them like a 0% chance. In fact, if you look at the control arm 7+3, like there's hardly anybody alive at that same time point. So to get that percentage, and I think it was two-thirds of patients going through that process did get long-term survival is really an accomplishment that can't be minimized, you know, 5-year survival or more. The question is which to use. There were some retrospective studies presented in fact, three different abstracts presented at ASH 2021 where investigators both in the academic and community settings tried to evaluate who should get CPX and who should get ven/aza and who would do better. Now, all three retrospective abstracts were flawed by sort of investigators or physician bias. And that all the patients that were older and had de novo disease received overwhelmingly received venetoclax/HMA, and those that were you younger with known secondary disease received CPX. However, all of the studies really showed the same thing that for patients 60 and above, CPX and ven/aza resulted in almost identical – it was actually pretty remarkable how overlapping the survival curves were despite the different patient populations. What did seem to pan out was the ability to perform allogeneic stem cell transplantation really made the difference in terms of long-term survival. And that brings up the question, which is now being investigated, so if this patient needs allogeneic stem cell transplantation, can't they get venetoclax/HMA, or even maybe ivosidenib/azacitidine and achieve a good enough response and successfully undergo allo transplant in that setting. And so that is data that we don't have, but there is a very limited single-center publication that was recently put out there dominating very high successful allogeneic stem cell transplantation rates after ven/azacitidine based regimen. So I don't know that we know which is the best route to go. I would argue that whatever route gets the patient successfully to an allo transplant would be worth pursuing. Dr. Stone: Right. So I think you both made some great points. I would just say that even though HMA/ven in the original trials, you weren't supposed to be a candidate for standard chemotherapy, let alone an allogenic stem cell transplant, we know that things change over time and when people are in remission, they become a candidate for allogeneic stem cell transplant. So I think that's a definitely a moving target. And I think most of us would agree that it doesn't really matter how you get to stem cell transplant. If you get to a minimal residual disease state with either HMA/ven or more standard chemotherapy or late CPX, it doesn't really matter. So to finish this case, I'd say the key clinical takeaways are that HMA/ven is the standard therapy for older adults with AML. We don't know if HMA/ven or CPX-351 or equivalent in patients who are candidates for either. Dr. Wang just pointed out the retrospective studies that obviously didn't answer the question, not that we expected them to. And in the beginning of our discussion, we both noted that HMA/ven and aza/ivo were both more effective than HMA alone, and there are separate trials that compared that IDH inhibition plus azacitidine may be more tolerable than azacitidine plus venetoclax, but they have not been directly compared. So that concludes case 2. Again, please view the other segments for further discussion about the latest data in AML or visit ascopost.com. Thank you.
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