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

Loschi, Michaël; Sammut, Rinzine; Chiche, Edmond; Cluzeau, Thomas

doi:10.3390/ijms22115873

Cited by 12 publications

(7 citation statements)

References 54 publications

(55 reference statements)

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“…Both FLT3 and C-kit mutations provide the potential for exploration of targeted RTK immunotherapy in AML cases in the future. [17][18][19][20] 6. Conflict of Interest None.…”

Section: Discussionmentioning

confidence: 99%

C-Kit and Flt3 mutation status in acute myeloid leukaemia with cytogenetic correlation and prognosis: A series of 75 cases

Parikh,

Dhandapani,

Shankaralingappa

et al. 2023

JDPO

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Recent WHO classification (5 edition) has included Acute Myeloid Leukaemia (AML) with mutations in NPM1, CEBPA as separate entities along with AML with cytogenetic abnormalities in AML with recurrent genetic abnormalities. Even though C-kit and FLT3 mutations in AML have no diagnostic importance, prognostic significance in different subtypes of AML for the presence of these mutations are not the same.To assess the correlation between French American British (FAB) AML classification, specific cytogenetic abnormalities with C-kit, and FLT3 mutation in AML and to evaluate the prognosis and survival of AML patients with respect to cytogenetic abnormalities and C-kit and FLT3 mutation status. Retrospectively all AML cases in which C-kit and FLT3 mutation status was assessed were retrieved; C-kit D816V mutation status had been assessed by Real time PCR; For FLT3 mutation, both Internal tandem duplication (ITD) and D835V mutation status had been assessed using PCR and gel electrophoresis; The data regarding morphological with immunophenotypic diagnosis, conventional karyotyping, FISH for translocation 8;21 (t (8;21)) and inversion16 / translocation16;16 (t (16;16) were also retrieved in all these cases along with follow-up from hospital records. Total 75 cases were included; Male/ Female ratio was 1.21:1 (41/34); Median age was 31 (Range: 2 - 64); 18 cases had translocation 8;21 (t (8;21)); 3 cases showed inversion16 / translocation16;16 (t (16;16); Out of the 18 cases which showed t (8;21), 10 cases had associated loss of sex chromosome. Eight cases had C-kit D816V mutation; three of which had t (8;21) while two had inversion 16. 12 cases had FLT3 mutations among which nine were ITD while three had D835V mutation. On karyotyping, one of these cases showed hyperdiploidy while the majority had normal karyotype. A single case had both C-kit D816V mutation and FLT3 D835V mutation with inversion 16 on karyotyping; Most common type of AML in both cases with FLT3 mutation and C-kit mutation was AML-M2 (FAB); Commonest karyotyping abnormality for cases with C-kit mutation was t(8;21); while for FLT3 mutation, the majority had normal karyotype; The single case which had both C-kit D816V mutation and FLT3 D835V mutation was alive event-free at three-year follow-up. Both FLT3 ITD and TKD mutations had a worse prognosis in our study. However, AML cases with C-kit mutation had a similar prognosis comparable to C kit negative cases. A large-scale study is required to elucidate the significance of this.

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“…Both FLT3 and C-kit mutations provide the potential for exploration of targeted RTK immunotherapy in AML cases in the future. [17][18][19][20] 6. Conflict of Interest None.…”

Section: Discussionmentioning

confidence: 99%

C-Kit and Flt3 mutation status in acute myeloid leukaemia with cytogenetic correlation and prognosis: A series of 75 cases

Parikh,

Dhandapani,

Shankaralingappa

et al. 2023

JDPO

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“…Recent advances in the development of MTTs targeting driver mutations prolonged the survival of AML patients. For example, FLT3 mutations such as point mutations in the tyrosine kinase domain (TKD) and internal tandem duplication (ITD) in the jaxtamembrane (JM) domain are observed in about 30% of AML patients and the patients harboring these FLT3 mutations show poor prognosis [ 19 ]. Tyrosine kinase inhibitors for mutant type FLT3 such as gilteritinib, quizartinib and midostaurin efficiently suppress the growth of FLT3 mutation positive AML cells in preclinical studies and prolong survival of AML patients in clinical trials [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model

et al. 2022

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Antibody drug conjugates (ADC) are one of the attractive modalities for the treatment of acute myeloid leukemia (AML). Previously, we have developed ASP1235, a novel ADC targeting Fms-like tyrosine kinase 3 (FLT3) which is widely expressed on the leukemic blasts of AML patients. In this study, we sought to evaluate the therapeutic effect of ASP1235 in combination with venetoclax plus azacitidine, a novel standard-of-care treatment for elderly AML patients, in ASP1235 poor sensitive AML cells. To identify the suitable preclinical model, we first evaluated the growth inhibitory effect of ASP1235 on several leukemia cell lines expressing FLT3 and found that THP-1 cells were partially sensitive to ASP1235 in vitro . Furthermore, ASP1235 showed marginal anti-tumor activity in a THP-1 xenograft model. Compared to the leukemic blasts in most of the relapsed or refractory (R/R) AML patients tested, THP-1 cells expressed equivalent protein levels of Bcl-2, suggesting that ASP1235 in combination with venetoclax plus azacitidine is a rational treatment in the THP-1 model. In vitro , ASP1235 showed a cytotoxic effect on THP-1 cells in combination with venetoclax, and the combination effect was greater than the additive effect. Furthermore, ASP1235 also showed a combination effect with venetoclax plus azacitidine treatment. Similarly, the combination of ASP1235, venetoclax and azacitidine showed a superior anti-tumor effect in a THP-1 xenograft model without obvious body weight loss. These findings provide supportive evidence that the triple combination of ASP1235, venetoclax and azacitidine would improve the clinical outcome of ASP1235 monotherapy and venetoclax plus azacitidine regimen in AML patients.

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“…However, the introduction of FLT3 tyrosine kinase inhibitors has significantly improved outcomes for patients with this subtype of AML. This shift in prognosis, secondary to the introduction to a targeted therapy, highlights the potential of the latter, including venetoclax, in leukemia patients [7][8][9].…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome

et al. 2023

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Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are two closely related blood cancers that are more frequent in older adults. AML is the most common type of adult acute leukemia, and MDS is characterized by ineffective blood cell production and abnormalities in the bone marrow and blood. Both can be resistant to treatment, often due to dysfunction in the process of apoptosis, the body’s natural mechanism for cell death. Venetoclax, an orally-administered medication that selectively targets the BCL-2 protein, has shown promise in enhancing treatment sensitivity in some hematological malignancies by reducing the apoptotic threshold. This review aims to evaluate the effectiveness of venetoclax in treating AML and MDS, as well as potential mechanisms of resistance to the medication. Methods A literature search was conducted utilizing PUBMED to capture all relevant research articles on the use of venetoclax as a therapy for both diseases. The MeSH terms “acute myeloid leukemia”, “myelodysplastic syndrome” and “venetoclax” were searched. Furthermore, Clinicaltrials.gov was accessed to ensure the inclusion of all ongoing clinical trials. Results Although Venetoclax showed modest results as a single-agent therapy in AML, venetoclax-based combination therapies? mainly with hypomethylating agents or low-dose cytarabine? yielded significantly positive results. Preliminary results oN the use of venetoclax-based combination therapy with HMA, mainly azacitidine, in unfit high-risk MDS also yielded optimistic results. Identification of mutations for which various drugs have been approved has spurred active investigation of venetoclax in combination trials. Conclusion Venetoclax-based combination therapies have been shown to induce rapid responses and increase overall survival in AML patients unfit for intensive chemotherapy. These therapies are also yielding positive preliminary results in high-risk MDS patients in phase I trials. Resistance to venetoclax and drug-related toxicity are two main obstacles that need to be overcome to reap the full benefits of this therapy.

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

Cited by 12 publications

References 54 publications

C-Kit and Flt3 mutation status in acute myeloid leukaemia with cytogenetic correlation and prognosis: A series of 75 cases

C-Kit and Flt3 mutation status in acute myeloid leukaemia with cytogenetic correlation and prognosis: A series of 75 cases

Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model

Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome

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