Treatment Options for a Young, Fit Patient Newly Diagnosed with AML
The panel discuss the need for personalized treatment approaches for young, fit patients with newly diagnosed acute myeloid leukemia, as well as when transplant should be considered.
Transcript:
Naval Daver, MD: I’ll turn it here to Dr Wang. Eunice, your thoughts for a young patient suitable—we’re going to use that word suitable or appropriate—for intensive chemotherapy, what are you thinking about? What are the treatment options?
Eunice S. Wang, MD: …I agree with my colleagues that it’s not just medical fitness or performance status, it’s actually biological fitness for certain therapies. We need to look at not just what we can give, because we can give intensive chemotherapy to [many] people, but what we should [give] to our patients. And in the era where we’re offering or have the ability to give targeted therapy that biologically may even work better than conventional chemotherapy, we really shouldn’t be giving conventional [treatment]. For example, the ADMIRAL trial [NCT02421939] clearly showed that in the relapsed setting, giving a targeted monotherapy with a pill is better than giving high-intensive salvage chemotherapy to patients who have FLT3-mutant disease. So, for this young patient, I think my question would be, “What does this patient need to get to that end point?”
They’re young, they’re fit. However, if this individual has on their diagnostic workup, which I will be waiting for, a complex karyotype and a TP53 mutation with a high-variant allele frequency, I’m going to say that, based on decades of information, we know this patient is going to potentially have maybe a 30% to 40% response rate to conventional 7+3 [therapy]. And the only curative strategy for that patient would be an allogeneic stem cell transplantation. So given those numbers, even though they’re fit enough to get high-dose-intensity chemotherapy like IDA [idarubicin] [or] venetoclax as the MD Anderson group [does with] very high response rates in patients with poor adverse risk, that intensive regimen doesn’t work well in people with TP53-mutant disease. I would be looking to see whether this patient has maybe 70% to 80% cure rate with chemo[therapy] alone if they have a core binding factor, and then I would go with 7+3, gemtuzumab [ozogamicin (GO)]. Gemtuzumab is part of 3- to 4-cycle high-dose cytarabine-based consolidation, and then looking for cure.
For patients who are adverse-risk, I would be looking for the way to get them to an allogeneic stem cell transplantation without significant risk of inducing potentially fatal neutropenic sepsis or debilitating cardiomyopathy that might render them ineligible for a myeloablative transplant down the line. And then for patients with intermediate risk, I think that that’s the group [for which] we have the greatest potential. Those are [patients with] normal karyotype, intermediate risk—making up 50% of our patients that we see—particularly younger patients. Many of those [patients] will have FLT3-mutant disease, and we’ve seen the results of the QUANTUM-First trial [NCT02668653] led by Dr Erba and others, demonstrating the superiority of quizartinib, a second-generation FLT3 inhibitor for FLT3-ITD disease over a standard 7+3. We have the results of the RATIFY trial [NCT00651261]. And I think an increasing proportion of intermediate-risk patients are those with NPM1-mutant disease. Now 50% of those will have FLT3-mutant disease, but I think the patients who have NPM1-mutant without FLT3 there is a group that we are saying that those [patients] will typically do well with induction chemotherapy. But there’s debate about whether those patients even long-term. Only about 40% will have long-term survival.
So, do we transplant those people? Do we not transplant those people when they relapse? We know that they’re going to have poor survival. So for that younger, fit patient, I think [we have to look] at the biology because we’ve had complaints from recent meetings that community providers are saying, “This is really complicated. How did this become so complicated? I can’t keep up with this.” And it’s because we now have so many strategies and we have to learn how to integrate those strategies on top of that backbone therapy. I would advocate [that] although [a patient is] medically fit for therapy, we need to determine the biological fitness and the expected response rates and try to personalize or individualize therapy for that young individual [with] the major [question] being transplant [or] no transplant. And if transplant, then how do we get that person to that transplant? Which is going to be the curative [treatment]? [If] no transplant, how do we optimize chemotherapy to induce a long-term survival?
Naval Daver, MD: I totally agree. I think Dan mentioned this as well. …If your goal is to get these patients with the intermediate adverse risk to transplant, then their borderline fitness, time and again we’re seeing this. Nick Short[, MD] from our group published a very nice retrospective [study]. It’s from MD Anderson. The analysis basically looked at outcomes post-transplant in patients [aged] 60 to 75 years, depending on the 3 paths they [took] to transplant. One was giving them intensive chemotherapy, FLAG [fludarabine, cytarabine, and filgrastim], FLAG-IDA [idarubicin], FLAG-IDA-VEN [venetoclax], whatever was available that time, one was HMA [azacitidine or decitabine]-VEN, and the third was low-intensity therapy clad[ribine] and low-dose cytarabine and VEN. And the question was, is there something special about chemotherapy or magic about the intensive chemo that after getting the transplant, it still continues to give you benefit?
What we saw was very interesting. In fact, the patients after transplant who had the best survival were those who got lower intensive therapy…compared [with] those with intensive chemo[therapy]. So not only are you more likely to get to transplant with lower intensive therapy; we also saw that [for patients aged] 60 to 75 [years] who started lower intensity [therapy], transplanters were more likely to take them to transplant because they don’t have mucositis, they don’t have fungal infection. They [are] in the hospital for 40 days…in the ICU [intensive care unit], [then transplanter sees them, he’s happy. [The] fit patient moves forward. But in addition to even getting to transplant, post-transplant outcomes are better probably because those patients went in with better protoplasm, better conditions… So I think more and more the data are coming. Randomized studies, of course, will be needed to make that final switch, but I do think getting to transplant, I don’t necessarily feel that I have to push towards intensive chemotherapy. I think it’s an interesting approach. Here I’ll turn it over to you, Harry. What about NPM1 [mutations] and KMT2A [rearrangements] in a newly diagnosed patient suitable for intensive chemo[therapy]? Do you have anything different? What are the trials you’re looking at? What else should we be thinking about?
Harry P. Erba, MD, PhD: I don’t have anything different for initial therapy [for patients] who are fit for intensive chemotherapy. It is interesting. I agree with the points made about NPM1. You’re going to be trying to cure those patients. But the patient with intensive chemo[therapy], on the other hand, if they’re marginal, I don’t feel that badly about giving them an HMA + VEN regimen given the very high response rate in the NPM1 subset. And now some case reports or case series [show] that some of these patients may enjoy treatment-free remissions. Now that’s not ready for primetime, and I’ll let Dan talk more about getting rid of those stem cells with this regimen, but in a way, I think that’s a possibility if they’re marginal. For [a patient with] KMT2A [rearrangements], if they are fit for intensive chemotherapy, it’s still 7 + 3.
Nothing has been shown to be better than that. It still has a very high response rate, but you need to get them to transplant. With transplant or without transplant, the relapse rates are very high and we need to be thinking about alternatives for those patients, but right now we don’t have an alternative. You may remember for NPM1, the SYK inhibitor [entospletinib] was being evaluated in this population. And the sponsor had to close the trial because of poor accrual. It’s so difficult for the world to find these patients. That’s part of the reason, as Dan said, that we need to think about these larger platform studies that will allow us to screen for subsets that may benefit from one therapy or another. I’ll let Eunice begin the conversation about the menin inhibitors in those 2 subtypes. But basically, if [a patient is] fit for intensive chemotherapy, I will give them intensive chemotherapy for both NPM1 with the expectation of cure and KMT2A rearrangements with pretty good expectation of remission [and] sometimes cure if they have a 9:11 translocation, but most often relapse and needing other alternatives for them.
Transcript is AI-generated and edited for readability.
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