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Symposium | Implications for clinical practice: Managing AML with FLT3-ITD and -TKD mutations
Featured:
Gail J. RobozDo you know... What is the impact of MRD on post-transplant outcomes in patients with FLT3-mutated AML?
The AML Hub held a virtual symposium on November 19, 2025, titled Understanding the differences between FLT3-ITD and -TKD mutations in AML: Implications for clinical practice. Here, we share a presentation from the symposium by Gail J. Roboz, Weill Cornell Medicine, New York, US, in which she discussed the management of patients with acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD) and FLT3-tyrosine kinase domain (TKD) mutations in clinical practice.
Symposium | Implications for clinical practice: Managing AML with FLT3-ITD and -TKD mutations
Symposium | Implications for clinical practice: Managing AML with FLT3-ITD and -TKD mutations
Roboz reflected on whether 7+3 regimens are the most appropriate approach for older patients with FLT3-mutated AML, and reviewed considerations for using targeted FLT3 inhibitor therapies in combination with standard intensive chemotherapy. She then highlighted the importance of measurable residual disease (MRD) assessment in guiding treatment decisions before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and the potential of triplet therapies for the treatment of patients with FLT3m AML.
Key points
- In clinical practice, standard of care treatment for patients with FLT3m AML is a FLT3 inhibitor in combination with a standard 7+3 backbone; however, clinical trials investigating these regimens have primarily mainly included younger patient populations.
- For instance, the RATIFY trial investigated midostaurin with 7+3 in patients aged 18–60 years with newly diagnosed (ND) FLT3m AML,1 and the QuANTUM-First trial investigated quizartinib with 7+3 in patients aged 18–75 years with ND FLT3-ITD AML.2
- Ten-year follow-up data from the RATIFY trial indicate that improvements in survival were primarily driven by allo-HSCT; the median overall survival (OS) in patients who underwent transplant in first complete remission was not evaluable vs 24.6 months in those who did not (p < 0.0001).3
- Therefore, there is still an unmet need to identify the most appropriate approach for patients not eligible for transplant, such as older patient populations.
- As understanding of AML develops, treatment algorithms are becoming increasingly complex. Given that MRD is a key prognostic factor in AML,4–7 algorithms are now tailored according to MRD status as well as mutation type and risk classification.8
- An important consideration for MRD assessment is the choice of assay; conventional polymerase chain reaction (PCR) assays used for FLT3m AML diagnosis are not as helpful for FLT3-ITD MRD detection due to their limit of sensitivity (~1%).5
- The PCR next-generation sequencing (PCR-NGS) assay was developed specifically for the QuANTUM-First trial and utilizes ultra-deep sequencing to identify FLT3-ITD MRD with high sensitivity and specificity (Figure 1).5,7
Figure 1. High-sensitivity MRD assessment for FLT3-ITD AML4–7,9
- The impact of MRD has been demonstrated in the post-transplant maintenance setting in the phase III MORPHO trial (NCT02997202) of gilteritinib in patients with FLT3-ITD AML following HSCT, where any detectable level of MRD was associated with poorer outcomes compared with MRD negativity.10
- In the placebo arm, patients with MRD-positive AML were found to relapse quickly following HSCT. Of patients with MRD positivity, 42.2% relapsed vs 13.4% of patients with MRD negativity.10
- Gilteritinib maintenance reduced the risk of post-HSCT relapse in patients with FLT3m MRD positivity either before or after HSCT.11
- For older patients with FLT3m AML who are not eligible for transplant, non-intensive regimens of venetoclax plus a hypomethylating agent (HMA) have been investigated.8
- Data have demonstrated that survival benefit with venetoclax + azacitidine is primarily driven by outcomes in the subgroup of patients with FLT3-TKD AML (median OS, 19.2 months vs 9.9 months in patients with FLT3-ITD AML).12
- An alternative proposed strategy for these patients is to add a FLT3 inhibitor to the non-intensive backbone.13
- A retrospective analysis of outcomes with quizartinib or gilteritinib + venetoclax and an HMA indicated that these triplet regimens may improve relapse-free survival and OS in patients with FLT3-ITD or -TKD AML.13
- Trials are ongoing investigating FLT3 inhibitor combinations with standard chemotherapy, as well as with less intensive regimens for those patients who are unable to tolerate standard chemotherapy.14–24
- For the majority of patients, maintenance therapy following remission should be considered, and tailored depending on whether they will undergo allo-HSCT, their risk classification, and mutation status (Figure 2).25
Figure 2. Maintenance therapy should be considered for the majority of patients with AML25
This educational resource is independently supported by Daiichi Sankyo. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.
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(5):454-464. DOI: 10.1056/NEJMoa1614359
Erba HP, Montesinos P, Kim H-J, 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;1571-1583. DOI: 10.1016/S0140-6736(23)00464-6
Stone RM. 10-year follow up of C10603/RATIFY: midostaurin vs placebo plus intensive chemotherapy for newly diagnosed FLT3-mutant acute myeloid leukemia (AML) patients 18-59 years old. Oral Abstract #218. 66th American Society of Hematology Annual Meeting and Exposition; Dec 7–10, 2024; San Diego, US.
Jongen‑Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378(13):1189-1199. DOI: 10.1056/NEJMoa1716863
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. DOI: 10.1182/bloodadvances.2018015925
Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. DOI: 10.1182/blood.2022016867
Levis MJ, Shi W, Chang K, et al. FLT3 inhibitors added to induction therapy induce deeper remissions. Blood. 2020;135(1):75-78. DOI: 10.1182/blood.2019002180
Shimony S, Stahl M, Stone RM. Acute myeloid leukemia: 2025 update on diagnosis, risk-stratification, and management. Am J Hematol. 2025;100(5):860-891. DOI: 10.1002/ajh.27625
Rohrbach JEC. Quantum-First: Deep-dive analysis of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) detection methods utilized for enrollment and longitudinal MRD detection in newly diagnosed (nd) patients (pts) with FLT3-ITD-positive (FLT3-ITD+) acute myeloid leukemia (AML). Poster #4278. 66th American Society of Hematology Annual Meeting and Exposition; Dec 7–10, 2024; San Diego, US.
Levis MJ, Hamadani M, Logan BR, et al. Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML. Blood. 2025;145(19):2138-2148. DOI: 10.1182/blood.2024025154
Levis MJ, Hamadani M, Logan BR, et al. Gilteritinib as post-transplant maintenance for AML with internal tandem duplication mutation of FLT3. J Clin Oncol. 2024;42(15):1766-1775. DOI: 10.1200/JCO.23.02474
Konopleva M, Thirman MJ, Pratz KW, et al. Impact of FLT3 mutation on outcomes after venetoclax and azacitidine for patients with treatment-naïve acute myeloid leukemia. Clin Cancer Res. 2022;28(13):2744-2752. DOI: 10.1158/1078-0432.CCR-21-3405
Short NJ, Loghavi S, Yilmaz M, et al. Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor. Haematologica. 2025. Online ahead of print. DOI: 10.3324/haematol.2025.288553
ClinicalTrials.gov. A safety and tolerability study of crenolanib in combination with chemotherapy in newly diagnosed acute myeloid leukemia patients with FLT3 mutations. https://clinicaltrials.gov/study/NCT02283177. Updated Feb 2, 2024. Accessed Oct 24, 2025.
ClinicalTrials.gov. Quizartinib with standard of care chemotherapy and as continuation therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First). https://clinicaltrials.gov/study/NCT02668653. Updated Aug 6, 2024. Accessed Oct 24, 2025.
ClinicalTrials.gov. Daunorubicin, cytarabine, and midostaurin in treating patients with newly diagnosed acute myeloid leukemia. https://clinicaltrials.gov/study/NCT00651261. Updated Aug 18, 2021. Accessed Oct 24, 2025.
ClinicalTrials.gov. A study of ASP2215 (gilteritinib) by itself, ASP2215 combined with azacitidine or azacitidine by itself to treat adult patients who have recently been diagnosed with acute myeloid leukemia with a FLT3 gene mutation and who cannot receive standard chemotherapy. https://clinicaltrials.gov/study/NCT02752035. Updated Sep 12, 2025. Accessed Oct 24, 2025.
ClinicalTrials.gov. Study investigating the efficacy of crenolanib with chemotherapy vs chemotherapy alone in R/R FLT3 mutated AML. https://clinicaltrials.gov/study/NCT03250338. Updated Apr 30, 2021. Accessed Oct 24, 2025.
ClinicalTrials.gov. (QuANTUM-R): An open-label study of quizartinib monotherapy vs. salvage chemotherapy in acute myeloid leukemia (AML) subjects who are FLT3-ITD positive. https://clinicaltrials.gov/study/NCT02039726. Updated Feb 24, 2021. Accessed Oct 24, 2025.
ClinicalTrials.gov. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) with FMS-like tyrosine kinase (FLT3) mutation. https://clinicaltrials.gov/study/NCT02421939. Updated Sep 12, 2025. Accessed Oct 24, 2025.
ClinicalTrials.gov. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) With FMS-like tyrosine kinase 3 (FLT3) mutation. https://clinicaltrials.gov/study/NCT03182244. Updated Aug 1, 2025. Accessed Oct 24, 2025.
Federal Institute for Drugs and Medical Devices. A double-blind, placebo-controlled, randomized, multi-center phase II trial to assess the efficacy of Sorafenib-maintenance therapy in FLT3-ITD positive AML in complete hematological remission after allogenic stem cell transplantation. https://drks.de/search/en/trial/DRKS00000591/details. Updated Dec 6, 2024. Accessed Oct 24, 2025.
ClinicalTrials.gov. sorafenib for prophylaxis of leukemia relapse in allo-HSCT recipients with FLT3-ITD positive AML. https://clinicaltrials.gov/study/NCT02474290. Updated Aug 26, 2019. Accessed Oct 24, 2025.
ClinicalTrials.gov. A trial of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients with FLT3/internal tandem duplication (ITD) acute myeloid leukemia (AML). https://clinicaltrials.gov/study/NCT02997202. Updated Jan 17, 2025. Accessed Oct 24, 2025.
Roboz GJ, Canaani J. How I use maintenance therapy in acute myeloid leukemia. Blood. 2025;145(12):1273-1281. DOI: 10.1182/blood.2024024010
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Symposium series | Understanding the differences between FLT3-ITD and -TKD mutations in AML: Implications for clinical practice
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