Sex disparity in acute myeloid leukaemia with <i>FLT3</i> internal tandem duplication mutations: implications for prognosis

Hellesøy, Monica; Engen, Caroline; Grob, Tim; Löwenberg, Bob; Valk, Peter J.M.; Gjertsen, Bjørn Tore

doi:10.1002/1878-0261.13035

Cited by 14 publications

(12 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, male and elderly patients show a molecular profile with a higher frequency of adverse risk genetic abnormalities and limited targeted therapy opportunities [34][35][36]. Indeed, some studies suggest that these features should be considered as an essential variable in clinical trials to deepen understanding of the disease and to identify new treatment opportunities [37,38].…”

Section: Discussionmentioning

confidence: 99%

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry

Sargas¹,

Ayala²,

Larráyoz³

et al. 2023

Cancers

View full text Add to dashboard Cite

Next–Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross–validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS–AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co–occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia–related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry

Sargas¹,

Ayala²,

Larráyoz³

et al. 2023

Cancers

View full text Add to dashboard Cite

show abstract

“…This finding could explain our results in elderly patients with more than 60% of patients allocated in the adverse risk category following 2022 ELN criteria. In contrast, younger patients were more likely to belong to favorable and intermediate risk groups due to higher incidence of NPM1 and FLT3 mutations, which also had a significant impact in terms of eligibility for targeted therapy treatment [ 17 ]. It should be noted that our study validates 2022 ELN risk groups in a real-world setting, contrarily to the BEAT-AML clinical trial analyses [ 14 ], thus supporting broad applicability of these classifications in routine practice.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group

Sargas¹,

Ayala²,

Larráyoz³

et al. 2023

Blood Cancer J.

View full text Add to dashboard Cite

Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines. We validated and compared the 2022 ELN risk classification in a real-life cohort of 546 intensively and 379 non-intensively treated patients. Among fit patients, those aged ≥65 years old showed worse OS than younger regardless risk classification. Compared with the 2017 classification, 14.5% of fit patients changed the risk with the 2022 classification, increasing the high-risk group from 44.3% to 51.8%. 3.7% and 0.9% FLT3-ITD mutated patients were removed from the favorable and adverse 2017 categories respectively to 2022 intermediate risk group. We suggest that midostaurin therapy could be a predictor for 3 years OS (85.2% with vs. 54.8% without midostaurin, P = 0.04). Forty-seven (8.6%) patients from the 2017 intermediate group were assigned to the 2022 adverse-risk group as they harbored myelodysplasia (MDS)-related mutations. Patients with one MDS-related mutation did not reach median OS, while patients with ≥2 mutations had 13.6 months median OS (P = 0.002). Patients with TP53 ± complex karyotype or inv(3) had a dismal prognosis (7.1 months median OS). We validate the prognostic utility of the 2022 ELN classification in a real-life setting providing supportive evidences to improve risk stratification guidelines.

show abstract

“…Considering the sex and age, the female and younger population had poor OS, while there was not any significant difference in OS between the young and old male patients. 81 …”

Section: Prognostic and Clinical Impact Of Flt3 Mutationsmentioning

confidence: 99%

“…Considering the sex and age, the female and younger population had poor OS, while there was not any significant difference in OS between the young and old male patients. 81 In a recently published study, 2017 ELN risk classification has been revisited based on the current understanding of the roles of molecular targets in AML. The updated version included AML with FLT3-ITD in the intermediate risk group, irrespective of the AR or co-presence of NPM1 mutation.…”

Section: Prognostic and Clinical Impact Of Flt3 Mutationsmentioning

confidence: 99%

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

View full text Add to dashboard Cite

FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

show abstract

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis

Cited by 14 publications

References 52 publications

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry

Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Contact Info

Product

Resources

About