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Updated: Oct 8, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with
Yazan Numan1, Zaid Abdel Rahman2,3,4, Justin Grenet5
1Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Abstract:
Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.
Insights
Gilteritinib shows efficacy in relapsed/refractory FLT3-mutated AML, achieving a 48.7% composite remission rate. Survival is improved with a complete remission, especially a MRD-negative response.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Gilteritinib is approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3-mutations (FLT3mut+).
- The ADMIRAL trial predates current standards of care, including midostaurin use and post-transplant FLT3 inhibitor maintenance.
- Real-world data on gilteritinib in this evolving treatment landscape is crucial.
Purpose of the Study:
- To evaluate the efficacy of gilteritinib in a real-world R/R FLT3mut+ AML patient cohort.
- To assess the impact of prior therapies and specific mutations on gilteritinib treatment outcomes.
- To analyze overall survival and remission rates in patients receiving gilteritinib.
Main Methods:
- Retrospective analysis of 113 R/R FLT3mut+ AML patients treated with gilteritinib at 11 US centers.
- Data collection included patient demographics, prior treatments, mutations, and treatment outcomes.
- Composite complete remission (CRc) and overall survival were primary endpoints.
Main Results:
- The overall CRc rate was 48.7% (n=55).
- Patients treated with prior 7+3 induction and midostaurin achieved a 58% CRc rate with a median survival of 7.8 months.
- Complete remission, particularly with MRD negativity, correlated with significantly longer survival.
- Patients with RAS/MAPK pathway activating mutations (NRAS, KRAS, PTPN11) had lower CRc (35% vs. 60.5%) and shorter median overall survival (4.9 vs. 7.8 months).
Conclusions:
- Gilteritinib demonstrates significant efficacy in R/R FLT3mut+ AML in a real-world setting.
- Prior treatment with midostaurin may be associated with improved outcomes.
- Identifying resistance mutations like NRAS, KRAS, and PTPN11 is critical for predicting treatment response and guiding therapy.
