Meet the Expert: Prof. Alessandro Isidori
Meet the Expert
Prof. Alessandro Isidori (San Salvatore Hospital, Italy)
Prof. Isidori on comprehensive management of FLT3-ITD–positive AML
“Many more patients can now achieve MRD negativity and live longer. Acute myeloid leukaemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) mutation is generally associated with a poor prognosis. Comprehensive management can significantly prolong overall survival (OS). Prof. Alessandro Isidori (San Salvatore Hospital, Italy) explains the rationale and implementation of this treatment approach, including the use of a FLT3 inhibitor from induction through maintenance, in combination with chemotherapy, potentially followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), and guided by minimal residual disease (MRD) monitoring.
Advances in AML treatment enable more tailored therapeutic approaches [1–3]. Approximately one-third of newly diagnosed patients carry a FLT3 mutation. The 2 main types are FLT3-ITD and FLT3 tyrosine kinase domain (FLT3-TKD) mutations, with FLT3-ITD accounting for about 80% of all FLT3 mutations [4]. These mutations are associated with an increased risk of relapse and reduced OS [2]. For treatment-eligible patients with newly diagnosed FLT3-ITD–positive AML, quizartinib is currently the only approved FLT3 inhibitor that can be used across induction through maintenance therapy. As Prof. Isidori notes, it offers “a full package strategy applied from the very start through to maintenance and potentially cure.”
Key prognostic factors
Patients with FLT3-positive AML face a high risk of relapse, according to Prof. Isidori [5]. Prognostic factors include FLT3 mutation type (ITD vs TKD), ITD insertion site, allelic burden, and co-mutation(s) like DNMT3A and NPM1, which are commonly co-mutated with FLT3. Prof. Isidori explains: “Patients with an NPM1 mutation generally have a more favourable prognosis and do not necessarily need an allo-HSCT. In contrast, patients without NPM1 mutations, especially those with additional adverse mutations such as DNMT3A, tend to have worse outcomes and higher relapse risk.”
However, MRD status is considered the most important prognosis determinant, Prof. Isidori adds, particularly before and after allo-HSCT [5]. “We now have highly sensitive methods to monitor MRD. Before transplant, MRD assessment can help select eligible patients for allo-HSCT; after transplant, continued MRD monitoring is also recommended [5]. MRD negativity is consistently associated with improved outcomes, whereas MRD positivity indicates a higher likelihood of relapse. Importantly, MRD status is dynamic and can change during treatment, making continuous monitoring essential. Achieving deep MRD negativity—at very low detection thresholds—may be associated with long-term remission or even cure.”
These findings are supported by further analyses of the QuANTUM-First trial, showing that quizartinib induces deeper remissions and increases MRD negativity rates compared with placebo [7].
Treatment from induction to maintenance
Possible treatments for FLT3-ITD–positive AML include intensive induction chemotherapy combined with a FLT3 inhibitor (e.g. midostaurin or quizartinib), followed by consolidation and maintenance therapy, with or without preceding allo-HSCT [5].
Quizartinib is the first FLT3 inhibitor to demonstrate an improvement in OS compared with chemotherapy in patients with relapsed or refractory AML with FLT3-ITD mutations. It can be administered during induction, consolidation, and as maintenance therapy. Prof. Isidori notes: “No specific drug was approved as maintenance therapy after allo-HSCT before quizartinib. Our FLT3-positive patients, therefore, experienced high rates of relapse. That has changed after the QuANTUM-First study of quizartinib.”
In the phase 3 QuANTUM-First trial (NCT02668653), quizartinib, in combination with chemotherapy, followed by continuation therapy, significantly improved OS compared with placebo in patients with newly diagnosed FLT3-ITD–positive AML. Median OS was 31.9 months with quizartinib versus 15.1 months with placebo (HR 0.78, 95% CI 0.62–0.98, P=0.032) [7]. Toxicity was manageable. “The bottom line is that a higher proportion of patients achieved MRD negativity with quizartinib and could undergo allo-HSCT,” Prof. Isidori states [7]. “If, for whatever reason, a transplant is not an option, you can still administer maintenance therapy and achieve complete remission.”
Allo-HSCT and maintenance therapy
Eligibility for allo-HSCT remains a subject of debate, according to Prof. Isidori. “Patients must, of course, be fit enough. Beyond that, the decision to perform allo-HSCT should mainly be based on MRD status and NPM1 co-mutation. About 70% of patients carry an NPM1 co-mutation and should be considered for allo-HSCT, as it remains the only curative. For the remaining 30% of patients who are NPM1-negative, current guidelines do not recommend allo-HSCT if the patient is MRD negative after induction and consolidation, but instead advise continued MRD monitoring.” He adds: “In my opinion, NPM1-negative patients should also be considered for allo-HSCT.”
Prof. Isidori thinks there is no discussion about the importance of maintenance therapy for MRD-positive patients, before or after transplant. “It may reduce relapse risk and contribute to the graft-versus-leukaemia effect.” This is less clear in MRD-negative patients, he says. “I would suggest giving them maintenance therapy too, especially if they are not NPM1 positive. In the QuANTUM-First trial, the number of patients on maintenance therapy was not high enough to demonstrate a statistically significant effect, but there was a numerical superiority” [6].
In MRD-positive patients following transplant, maintenance therapy should be initiated early. “Preferably between 30 and 60 days post-transplant. If you postpone maintenance in MRD-negative patients, and they become MRD positive after, for example, 6 months, you cannot start maintenance, which is a shame. You must then give another tyrosine kinase inhibitor instead,” Prof. Isidori cautions.
The optimal duration of maintenance therapy also remains a matter of debate. “In the QuANTUM-First trial, the duration was 3 years. This is what the label says and what we try with quizartinib. After a transplant, this is not always easy for the patient. I think 1 year is definitely too short, but depending on the MRD status, 2 years may suffice for some patients.”
“Driving a Ferrari”
Prof. Isidori is enthusiastic about quizartinib as an option for FLT3-ITD–positive AML patients, but it should be used with caution. “Like driving a Ferrari, you do not master it right away. Clinicians must consider important factors like mutation status, patient selection, available dosages, transplant-related risks, MRD monitoring, and concomitant use of a strong CYP3A inducer increasing exposure of quizartinib.” He concludes: “The full package strategy that we can apply with quizartinib is a big opportunity for our patients with FLT3-ITD–positive AML. It opens up a path to longer survival and even a cure for more patients than ever before.”
Quizartinib is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation chemotherapy, followed by quizartinib single-agent maintenance therapy for adult patients with newly diagnosed FLT3-ITD-positive AML [8].
References
1 Daver, N, et al. Blood Cancer J. 2020;10:107.
2 Kennedy VE, et al. Front. Oncol. 2020;10:612880.
3 Bhansali RS et al. J Hematol Oncol. 2023;16(1):29.
4 Patel PJ, et al. N Engl J Med. 2012;366(12):1079–1089.
5 Döhner H, et al. Blood. 2022;140(12):1345–1377.
7 Levis MJ, et al. Blood Adv. 2026;10(3):917–928.
6 Erba HP, et al. Lancet. 2023;401(10388):1571–1583.
8 Vanflyta (quizartinib) EMA product information (SmPC), current EMA version.
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Written by Dr Michiel Tent