Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

Yılmaz, Musa; Alfayez, Mansour; DiNardo, Courtney D.; Borthakur, Gautam; Kadia, Tapan M.; Konopleva, Marina; Loghavi, Sanam; Kanagal‐Shamanna, Rashmi; Patel, Keyur P.; Jabbour, Elias; Pemmaraju, Naveen; Pierce, Sherry; Issa, Ghayas C.; Montalban‐Bravo, Guillermo; Takahashi, Koichi; Assi, Rita; Alotaibi, Ahmad S.; Ohanian, Maro; Andreeff, Michael; Cortes, Jorge; Kantarjian, Hagop M.; Ravandi, Farhad

doi:10.1186/s13045-020-00964-5

Cited by 18 publications

(18 citation statements)

References 17 publications

(43 reference statements)

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“…In the frontline setting, there was a sequential decrease in CRc rates (77%→31%→25%) and OS (16.7→6.0→1.4 months). A comparable decrease in CRc rates (45%→21%→10%) and OS (7.9→4.0→4.1 months) was observed with sequential FLT3i-based therapies in the R/R AML setting 73 . Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib.…”

Section: Future Directionsupporting

confidence: 53%

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021

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Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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Section: Future Directionsupporting

confidence: 53%

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021

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“…It should also be noted that there was greater availability in our cohort of salvage therapies incorporating new and investigational FLT3i based combinations, which may have also contributed to improved outcomes among those patients who did not receive FLT3i in the frontline and may be improving survival in those not undergoing SCT. 29 The incorporation of FLT3i into the frontline regimens may be playing an important role in improving outcomes with respect to the historically adverse prognostic significance.…”

Section: Discussionmentioning

confidence: 99%

Improved outcomes among newly diagnosed patients with FMS‐like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification

et al. 2022

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Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance.The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT. | INTRODUCTIONMutations in the fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML), identified in approximately 30% of cases. 1-3 FLT3 mutations occur commonly in two regions: the juxta membrane domain leading to internal tandem duplication (FLT3-ITD), representing the most common type of FLT3 mutation, seen in approximately 25% of all cases; and the tyrosine kinase domain (FLT3-TKD), which occurs in approximately 7%-10% of cases. 1,2 FLT3-ITD mutations have been found to be adverse in

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“…Regarding the duration of FLT3 TKI efficacy after several courses of the drugs, a recent retrospective study reported the outcome of FLT3-mutated AML patients who received sequential courses of FLT3 TKI because of AML relapse [ 62 ]. In this trial, 239 patients receiving FLT3 TKI for the first time, either as front-line treatment (56 patients) or as a salvage treatment for an R/R AML (183), were enrolled.…”

Section: Perspectivesmentioning

confidence: 99%

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review

Loschi

Sammut

Chiche

et al. 2021

IJMS

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FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.

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Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

Cited by 18 publications

References 17 publications

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Improved outcomes among newly diagnosed patients with FMS‐like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review

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