Expert perspectives on the emergence of FLT3-targeted therapies and their role in the first-line setting of acute myeloid leukemia management.
Jorge E. Cortes, MD: The other category you highlighted was patients with FLT3 mutations. That’s a common mutation—about 25% to 30% of patients may have FLT3 mutations, particularly ITDs. You mentioned that we have midostaurin and the potential for quizartinib. Hetty, I’d like to ask about your approach for FLT3-mutated patients. Are you regularly using midostaurin in combination? Do you use it with consolidation? Do you use it for maintenance? How do you incorporate it, and how do you see quizartinib if it’s approved? It’s still an if, but let’s say—because it was a positive study—that it’s approved. How do you think you’d incorporate that and decide between that and midostaurin?
Hetty E. Carraway, MD: We’re using 7+3 and midostaurin for all our patients who are FLT3 positive. We can get that information back. Regarding FLT3 status, this is for FLT3-ITD and FLT3-TKD patients. Sometimes our next-generation sequencing testing comes back after day 8 for some of the TKD mutations, but we’re typically able to start midostaurin on day 8. In the United States, we’re challenged by getting these oral medications approved by insurance companies. We’re using idarubicin, so I’ve had patients denied by insurance companies for midostaurin, because the NCCN [National Comprehensive Cancer Network] Guidelines specify that doxorubicin needs to be used rather than idarubicin. Shockingly, that has happened. Nonetheless, in the up-front setting for our patients, we’re using midostaurin during induction and consolidation and even as maintenance in the post-transplant setting, should patients be able to do that.
The quizartinib data were presented by Dr [Harry] Erba at EHA [European Hematology Association Congress] in June 2022, showing that it’s well tolerated and that patients can proceed with receiving. In that study, they received 7+3 plus quizartinib versus 7+3 plus placebo, and there was improvement in overall survival in those patients that received quizartinib. That study very much mimicked the RATIFY study, led by Rich Stone, in which patients received quizartinib day 8 through day 21, also in conjunction if they got into CR [complete response] or CRi [incomplete hematologic recovery] with their consolidation therapy with high-dose araC [cytarabine]. In that study, I believe, they had 3 years of maintenance therapy with quizartinib. What’s nice about that agent is that it’s a once-a-day dosing, and there are some advantages to that. There were some things to be mindful of with regard to grade 3 toxicities—namely, more toxicities in patients who received quizartinib vs placebo—but those were all things that are manageable. Just like in our patients receiving midostaurin, more patients came off the therapy with combination quizartinib than with placebo.
This is what we’re challenged by as we think about combination therapies in any of our patients with AML [acute myeloid leukemia], whether it’s quizartinib plus 7+3 or the other combinations we’ll talk about, including FLT3 inhibitors in combination with azacytidine-venetoclax. It’s likely that these are going to be similar. We’re eager to see some head-to-head studies regarding which 1 is better. Some of it will be tolerability, drug-drug interactions, and frequency of delivery in terms of the oral drug and what the insurance dictates vis-à-vis the United States.
I want to mention that quizartinib hits only the ITD. It doesn’t hit both ITD and TKD. That’s an important detail that we can’t forget. That’s important for us to be mindful of, especially as we roll out these targeted therapies. Finally, we also have the crenolanib study. Eunice Wang shared some of the outcomes in June 2022 at ASCO [American Society of Clinical Oncology Annual Meeting]. This study had 44 patients who went on therapy with crenolanib, a 3-times-a-day drug given with 7+3 for patients who achieve remission along with consolidation. They were allowed to receive therapy for 1 year for maintenance therapy. Many of these patients— upward of 75% to 86% of patients—were able to achieve CR/CRI. The median follow-up for those patients was 45 months, and the median overall survival had not been reached.
Interestingly, the data on the smaller subset of patients who were older showed that they were able to tolerate the therapy—older being defined as ages 61 to 75. About 80% of patients achieved CR/CRI. That’s tolerable and good control of leukemia. There’s more to come with crenolanib, but we’ll be challenged by that with the 3-times-a-day dosing. My hope is that they’ll be able to formulate that so that it doesn’t have to be 3 times a day.
Jorge E. Cortes, MD: It will be interesting to see what happens with that drug. There’s also a randomized trial going against midostaurin. [It will be interesting] to see what happens with that. You mentioned an important differentiator that I want to highlight: quizartinib is a type 2 inhibitor. It not only doesn’t hit the D835 but also becomes a mechanism of resistance to these type 2 inhibitors. The only 1 we would have would be quizartinib. Sorafenib is another, but that’s vanishing, although we used it a lot in the past. Now we have drugs approved with this indication. That’s important.
Hetty E. Carraway, MD: The other thing with crenolanib is that it’s a SIK inhibitor and has some other attributes. When you think about resistance, that’s something to keep an eye on.
Jorge E. Cortes, MD: Absolutely. Before I move to the next category and subset of patients, I want to ask Brian about the quizartinib and the midostaurin studies. Both are positive and statistically significant. There’s a clear advantage in survival, but the benefit is modest. Are you disappointed? Is that what you expected? How do we move from here?
Brian Andrew Jonas, MD, PhD: As you pointed out earlier, outcomes for patients with AML have improved steadily over time. Perhaps I’ll take any benefit and be happy with it. Could the benefits be greater? Absolutely. That’s always been a criticism of midostaurin. With the more potent drugs, which are still being evaluated in randomized fashion, like gilteritinib and crenolanib, perhaps there will be more signal there than with the quizartinib and midostaurin. I like the way those studies are set up, as randomized trials with midostaurin being the control arm. I’m moving slightly away from your question, but I want to get the point in that we still aren’t sure whether a broad kinase inhibitor—with multiple targets up front—might be a rational way to treat AML. As we all know, it’s a malignant clonal. In many cases, or the more potent, more selective inhibitor might be better up front in terms of having general effect and able to prevent relapse. Going back to the original answer, I’m happy to see any benefit whatsoever when I take care of patients with AML. I’m hopeful that some of the more advanced TKI[tyrosine kinase inhibitor] will prove more exciting once those phase 3 studies read out.
Jorge E. Cortes, MD: I’m with you. We’re not going to see an interferon ... dramatic change. This is AML; it’s a lot more complex. I’ll take this benefit. Would I like more? Sure, but this is AML.
Transcript edited for clarity.