The use and array of FLT3 inhibitors continues to mature and proliferate as 2023 brought another landmark phase III clinical trial of an upfront FLT3 inhibitor and another in the post-transplant setting. With two prospective trials of two different FLT3 inhibitors — midostaurin and quzartinib — in combination with induction chemotherapy showing significant improvements in survival, there is no longer a question of whether to incorporate FLT3 inhibitors into upfront induction chemotherapy, but rather, which one to use and in what setting. Questions that remain include which FLT3 inhibitor is best in the upfront chemotherapy setting; how can post-transplant maintenance therapy be optimized and in whom; and what is the ideal approach for patients with FLT3-positive newly diagnosed acute myeloid leukemia (AML) who aren’t eligible for a transplant.
ASH Clinical News reached out to Elizabeth Griffiths, MD, a hematologist on the leukemia service at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and Alex Ambinder, MD, MPH, a hematologist in the Division of Hematology Malignancies at the Sidney Kimmel Comprehensive Cancer at Johns Hopkins University in Baltimore, to discuss what we do and don’t yet know about FLT3 inhibitors in the treatment of AML.
Elizabeth Griffiths, MD Alex Ambinder, MD, MPH
Let’s just get this out of the way: Is anthracycline and cytarabine plus a FLT3 inhibitor the standard of care for chemotherapy-eligible patients with FLT3-positive AML?
Dr. Griffiths: There’s not going to be much disagreement here. This treatment combination offers the highest chance of a deep remission. Midostaurin is not a great FLT3 inhibitor. It’s a pretty broad kinase inhibitor in general and has a lot of side effects, including gastrointestinal toxicity, and it smells terrible. Many patients are very unhappy about the drug, but it’s certainly been the mainstay of our approach.
Dr. Ambinder: Right.
What evidence supports the use of midostaurin in AML?
Dr. Ambinder: Midostaurin was the first FLT3 inhibitor to be approved by the U.S. Food and Drug Administration (FDA) based on the RATIFY trial in 2017.1 This was an international phase III randomized, double-blinded study of 7+3 plus midostaurin versus 7+3 plus placebo in patients between the ages of 18 to 59 with an activating FLT3 mutation. There are two major types of FLT3 mutations — tyrosine kinase domain (TKD) point mutations and internal tandem duplications (ITDs) — and midostaurin is a type 1 FLT3 inhibitor that is active against both. In the RATIFY trial, the addition of midostaurin is approved for use in both cases, and it showed a clear overall survival (OS) benefit compared to 7+3 alone.
Dr. Griffiths: For many years, we have been using midostaurin in combination with chemotherapy. The issue is that we didn’t have data about post-transplant maintenance, and there was no real measurable residual disease (MRD) assessment associated with that study. The study took a long time to accrue, partly because when they were originally doing the study design, a lot of people were not doing transplants for FLT3-mutant disease. What became very clear in that study was that adding allogeneic transplant to induction made a substantial positive impact on the likelihood of relapse for patients with FLT3-mutant AML, even in the absence of a FLT3 inhibitor. The expected survival for patients with FLT3-mutant disease was markedly better in the control arm than it was expected to be. I think they expected that to read out at least three or four years earlier, if not before, because before the advent of really intensive therapeutics for people with FLT3-mutant disease, this population did very poorly.
Partly because we didn’t appreciate the importance of early allogeneic transplant, we didn’t appreciate the importance of aggressive therapy and on-time delivery of chemotherapy in a scheduled fashion, and we didn’t have FLT3 inhibitors that were effective. Another issue is that midostaurin and other FLT3 inhibitors are extensively protein bound, so it was very hard to assess whether the drugs were getting into patients and hitting the target.
One of the steps forward made by Mark Levis, MD, PhD, was the development of the plasma inhibitory activity assay to determine whether FLT3 was being inhibited effectively by serum concentrations of the drug that you were able to get.2
What evidence supports the use of gilteritinib in AML?
Dr. Griffiths: Gilteritinib is currently only FDA approved in the context of relapsed or refractory (R/R) disease; it’s not approved upfront yet. Gilteritinib has been tested in combination with 7+3 chemotherapy in a phase IB study that was just published by Keith Pratz, MD, and colleagues, and showed a substantial response rate, had a pretty good outcome, and identified a phase II dose.3
Dr. Ambinder: Gilteritinib was approved based on the ADMIRAL trial.4 Patients were randomized to either gilteritinib or a physician’s choice of chemotherapy regimens, and gilteritinib clearly improved OS in that setting. However, patients still have very poor outcomes, even with gilteritinib. Midostaurin and gilteritinib are approved in totally different contexts, and we don’t know yet how gilteritinib compares to midostaurin when combined with intensive chemotherapy in the upfront setting.
What is the risk of relapse with each treatment?
Dr. Ambinder: The risk of relapse really can’t be compared between the newly diagnosed and R/R settings. Most patients treated with gilteritinib alone in the R/R setting, even those who have a good response, will eventually relapse. Very few long-term survivors are relapse-free. Midostaurin looked quite a bit better in the RATIFY trial, and there have been a few subsequent trials that studied the combination of 7+3 plus midostaurin with transplant.
Dr. Griffiths: The question is in the context of patients with newly diagnosed FLT3-mutant AML: Is there currently one standard of care, 7+3 plus chemotherapy approach, that is superior to another? Unfortunately, we don’t have upfront randomized controlled trials that compare the FLT3 inhibitors we have available to us, which are midostaurin, quizartinib, and gilteritinib. So we have midostaurin, which has, I would argue, the best and longest-term data. We’ve been using it for the longest time, it covers both FLT3-ITD and FLT3-TKD mutations, and it has been the standard of care for any patient younger than 60 with newly diagnosed FLT3-mutant AML either with a TKD or an ITD mutation. The majority of us would give 7+3 chemotherapy with midostaurin for 14 days and then consolidation with high-dose cytarabine followed by an allogeneic transplant for patients who have high-risk disease features, particularly those with FLT3-ITD mutations.
OK, so the main question here: In a chemotherapy-eligible patient with newly diagnosed FLT3-mutated AML, what should the standard-of-care FLT3 inhibitor be and why?
Dr. Griffiths: We have these more potent FLT3 inhibitors that have slightly different side effect profiles and slightly different activity. Quizartinib, which was recently approved in combination with 7+3 chemotherapy, was studied in the randomized phase III QuANTUM trial, which was distinct from the RATIFY study in that it enrolled patients up to age 75.5 Unfortunately, it compared against placebo, which many of us would argue is probably not the correct comparator arm. So it’s very concerning, but it was done in places where midostaurin is not universally available, and that allowed some equipoise for the investigators. That study demonstrated a substantial rate of response, but it also demonstrated, for the first time, the value of assessment of MRD in patients with FLT3-mutant disease.
Dr. Ambinder: You’re asking which is the best FLT3 inhibitor in combination with chemotherapy, and we really don’t know yet. You can’t compare the outcomes between the two trials for lots of reasons, but especially because the selection criteria were quite different. As Dr. Griffiths has mentioned, age is one big difference. In the RATIFY trial, the age cutoff was 59, and in QuANTUM-First it was 75. The median age of enrollment was 10 years different. The RATIFY trial also included patients with AML with FLT3-TKD mutations. FLT3-ITD mutations are associated with a particularly poor prognosis in the absence of FLT3 inhibitors, whereas the prognostic significance of TKDs is less clear. They are certainly not as adverse of a prognostic factor as ITDs. And in RATIFY, 22% of the patients enrolled had FLT3-TKD-mutated disease, so when you’re comparing results, you’re really comparing two very different patient populations.
How do MRD and allogenic transplant fit into the discussion?
Dr. Griffiths: There are data from the phase I and phase IB studies using 7+3 plus gilteritinib in combination.6,3 These studies also demonstrated high response rates for gilteritinib, but we can’t really use that in the context of upfront therapy outside of a clinical trial. Owing to the fact that these drugs do inhibit recovery of the stem cell population because of the effect on FLT3, which is a stem cell growth factor, you get delayed time to count recovery in these cases as an on-target effect of the drug. So, both gilteritinib and quizartinib can cause some delay in times of count recovery and increase the risk of infections, arguably, driving deeper, complete remission rates and clearance of the FLT3-mutant clone. If your disease is truly driven by FLT3, driving that clonal burden as low as possible and then taking that patient to allogeneic transplant with no evidence of clonal burden at the time as MRD negative to low states seems to result in dramatic improvements in survival and obviate the need for post-transplant maintenance, which was previously suggested to be an important component of prevention of relapse in patients with newly diagnosed FLT3-mutant disease.
Dr. Ambinder: There have been a few subsequent trials that studied the combination of 7+3 plus midostaurin with transplant. A recent study looked at this combination within transplant and then for a year post-transplant maintenance, and these patients did reasonably well, especially by historic standards.7 I think the study that has now provided the most insight into the importance of transplant and the role of MRD testing is the MORPHO trial.8 In MORPHO, patients who had undergone intensive induction chemotherapy, most of whom actually did not receive a FLT3 inhibitor, and who underwent transplant were randomized to gilteritinib or to placebo in the post-transplant setting. Post-transplant gilteritinib did not meet the threshold for significance for improving relapse-free survival (RFS); it just barely missed its cutoff. One of the important things they did in that study, though, was measure pre- and post-transplant MRD. When they did a subanalysis only looking at patients who had MRD detectable immediately pre- or post-transplant, there was suddenly a big difference in RFS between those who were randomized to gilteritinib versus placebo.
I think this has major ramifications for the field, beyond simply answering the question of whether we should be giving post-transplant FLT3 inhibitors. You could argue that measuring MRD in a targeted fashion also moves the ball forward in terms of developing FLT3 MRD as a surrogate for clinical outcomes such as RFS or OS, which we’ve not previously had. I also think FLT3 MRD testing may help us compare the efficacy of these FLT3 inhibitors, especially in the absence of randomized, head-to-head data.
Does FLT3 inhibition have a role in post-transplant maintenance?
Dr. Griffiths: For patients who had undetectable FLT3 variant allele frequency using this MRD test, the benefit of post-transplant maintenance in patients going on to transplant was less clear and that’s partly because there’s some suggestion that these FLT3 inhibitors can increase the risk for graft-versus-host disease, so you can have more non-relapse mortality. It’s important to recognize that in the MORPHO study, you have to be negative for both the pretransplant and the post-transplant time points. Positivity in either of those time points confers benefit of the gilteritinib maintenance, so it is important to identify those patients who failed to achieve an MRD-negative state in either the pre- or post-transplant setting and offer them gilteritinib or some form of maintenance chemotherapy.
For those people who are truly negative at both of those time points using a validated assay, perhaps the post-transplant maintenance is not without side effects, not without risk. In that context, withholding therapy may be more important.
Dr. Ambinder: There have been studies looking at post-transplant maintenance with different FLT3 inhibitors, and maybe what will come out of this is that what’s even more important than which FLT3 inhibitor you use — gilteritinib versus quizartinib, for example — is whether a patient has MRD before deploying one of them.
What questions remain in relation to these two treatments, and are they being investigated currently?
Dr. Griffiths: One of the things we continue to learn about AML therapeutics is that the first bite at the apple is probably your best bite. You should take as deep a bite as possible and drive the disease into as deep of a remission as you possibly can. Where we know the stem cell clone is likely to be predominant, it’s likely to be resistant to any form of chemotherapy, so allogeneic transplant is likely to offer substantial benefit. Then, depending on what’s left of the disease, assessing what that disease burden looks like from a clonal perspective in a very rigorous way will help us make sure we don’t leave any potentially resistant players behind.
Dr. Ambinder: The other issue we’ll come across is that midostaurin is a relatively weak FLT3 inhibitor, but it hits lots of other tyrosine kinase receptors, and there’s speculation that perhaps some of the benefits of midostaurin are off-target, such as its inhibition of other signaling pathways involved in leukemia cell survival and proliferation. Quizartinib and gilteritinib are both far more potent FLT3 inhibitors that are quite a bit more selective for FLT3, so there’s some thought that each has its advantage. Midostaurin is dirtier but may inhibit other off-target tyrosine kinase receptors; maybe that’s not just a weakness, but an advantage. On the other hand, quizartinib and gilteritinib may be a little bit more surgical. There are also studies now that show the promise of quizartinib in FLT3 wild-type AML, such as the QUIWI study, which suggests some benefit for the addition of quizartinib to chemotherapy in FLT3 wild-type AML.9 It’s exciting that there may be a whole other population of patients with FLT3 wild-type AML who may benefit from very potent FLT3 inhibitors such as quizartinib.
References
- Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454-464.
- Levis MJ, Perl AE, Altman JK, et al. A next-generation sequencing-based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations. Blood Adv. 2018;2(8):825-831.
- Pratz KW, Cherry M, Altman JK, et al. Gilteritinib in combination with induction and consolidation chemotherapy and as maintenance therapy: a phase IB study in patients with newly diagnosed AML. J Clin Oncol. 2023;41(26):4236-4246.
- Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728-1740.
- Erba HP, Montesinos P, Kim HJ, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10388):1571-1583.
- Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061-1075.
- Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840-851.
- Astellas and BMT CTN announce topline results from phase 3 MORPHO trial of gilteritinib. PR Newswire. March 9, 2023. Accessed January 4, 2024. https://www.prnewswire.com/news-releases/astellas-and-bmt-ctn-announce-topline-results-from-phase-3-morpho-trial-of-gilteritinib-301767481.html.
- Montesinos P, Rodríguez-Veiga R, Bergua Burgues JM, et al. S130: preliminary results of QUIWI: a double blinded, randomized clinical trial comparing standard chemotherapy plus quizartinib versus placebo in adult patients with newly diagnosed FLT3-ITD wild-type AML. Hemasphere. 2023;7(Suppl):e734771d.
Disclaimer: The statements made by the participants do not necessarily reflect the opinions or stance of the American Society of Hematology.
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