Upfront Treatment of FLT3-Mutated AML: A Look Back at the RATIFY Trial and Beyond

Keiffer, Gina; Aderhold, Kimberly; Palmisiano, Neil

doi:10.3389/fonc.2020.562219

Cited by 6 publications

(4 citation statements)

References 23 publications

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“…Midostaurin was the first approved TKI for use in combination with standard intensive chemotherapy for adult patients without age restriction with newly diagnosed FLT3 -mutated AML in the USA and Europe. 37 , 38 The approval of midostaurin was based on the positive results of the large, international randomized phase III CALGB RATIFY trial. 39 The addition of midostaurin to intensive chemotherapy significantly improved OS in younger adults with FLT3 -mutated AML with a median OS of 74.7 months for the midostaurin arm (range, 31.5 months - not reached) as compared to 25.6 months for the placebo arm (range, 18.6-42.9 months).…”

Section: Flt3 Mutationsmentioning

confidence: 99%

The clinical impact of the molecular landscape of acute myeloid leukemia

Käyser

Levis

2023

haematol

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Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk-stratification schemes and have been proven to be clinically relevant, targetable lesions. The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. We here discuss the utility of molecular markers in AML in prognostication and treatment decision-making. New therapies based on targetable markers include IDH inhibitors (ivosidenib, enasidenib), venetoclax-based therapy, FLT3 inhibitors (midostaurin, gilteritinib, and quizartinib), gemtuzumab ozogamicin, magrolimab and menin inhibitors.

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Section: Flt3 Mutationsmentioning

confidence: 99%

The clinical impact of the molecular landscape of acute myeloid leukemia

Käyser

Levis

2023

haematol

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“…However, several concerns were identified with this trial, which warrant further consideration. 58 For instance, the median age of patients with FLT3 mutations in this trial was much younger compared with published data and the study population was unusually enriched for FLT3-TKD mutations (22% compared with 5–6% in general). Patients with FLT3-TKD mutations, which do not result in worse prognosis compared with wild type FLT3, also experienced significant clinical benefit from midostaurin.…”

Section: First-generation Inhibitorsmentioning

confidence: 64%

FLT3 and IDH1/2 Inhibitors for Acute Myeloid Leukemia: Focused Clinical Narrative Review of Forthcoming Drugs from an Indian Context

Singh,

Jain,

Singh

et al. 2024

Indian J Med Paediatr Oncol

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Therapeutic approaches for acute myeloid leukemia (AML) have witnessed minimal evolution in recent decades, primarily relying on advancements in supportive care and transplantation to drive improvements in overall survival rates. However, treatment with intensive chemotherapy may not be feasible for patients with advanced age or reduced fitness, and outcomes for patients with relapsed/refractory disease continue to be suboptimal. Several agents with a novel mechanism of action have been developed in the past decade and have shown efficacy in patients with both newly diagnosed and relapsed AML. Out of these, several FLT3 (FMS like tyrosine kinase 3) and IDH1/2 (isocitrate dehydrogenase 1/2) inhibitors have received regulatory approval in specific clinical settings and are available for clinical use. This is an actively expanding field with several ongoing clinical trials in advanced phases. We provide a focused narrative review of drugs from these two categories with available clinical data.

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“…Internal tandem duplications in FLT3 - ITD can be managed with FLT3 inhibitors. Two of the FLT3 - ITD inhibitors—midostaurin and gilteritinib—were approved by the FDA in relapsed/recurrent FLT-3 mutated AML in April 2017 and November 2018, respectively [ 92 , 93 ]. The approval of midostaurin followed the promising results of phase 3 RATIFY trial [ 94 ], conducted in 18–59 year old patients with de novo AML, harboring mutations in FLT-3.…”

Section: Treatment Options In Secondary Amlmentioning

confidence: 99%

In Pursuit of Genetic Prognostic Factors and Treatment Approaches in Secondary Acute Myeloid Leukemia—A Narrative Review of Current Knowledge

Stefaniuk

Szymczyk

Podhorecka

2022

JCM

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Secondary acute myeloid leukemia can be divided into two categories: AML evolving from the antecedent hematological condition (AHD-AML) and therapy related AML (t-AML). AHD-AML can evolve from hematological conditions such as myelodysplastic syndromes, myeloproliferative neoplasms, MDS/MPN overlap syndromes, Fanconi anemia, and aplastic anemia. Leukemic transformation occurs as a consequence of the clonal evolution—a process of the acquisition of mutations in clones, while previous mutations are also passed on, leading to somatic mutations accumulation. Compared de novo AML, secondary AML is generally associated with poorer response to chemotherapy and poorer prognosis. The therapeutic options for patients with s-AML have been confirmed to be limited, as s-AML has often been analyzed either both with de novo AML or completely excluded from clinical trials. The treatment of s-AML was not in any way different than de novo AML, until, that is, the introduction of CPX-351—liposomal daunorubicin and cytarabine. CPX-351 significantly improved the overall survival and progression free survival in elderly patients with s-AML. The only definitive treatment in s-AML at this time is allogeneic hematopoietic cell transplantation. A better understanding of the genetics and epigenetics of s-AML would allow us to determine precise biologic drivers leading to leukogenesis and thus help to apply a targeted treatment, improving prognosis.

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Upfront Treatment of FLT3-Mutated AML: A Look Back at the RATIFY Trial and Beyond

Cited by 6 publications

References 23 publications

The clinical impact of the molecular landscape of acute myeloid leukemia

The clinical impact of the molecular landscape of acute myeloid leukemia

FLT3 and IDH1/2 Inhibitors for Acute Myeloid Leukemia: Focused Clinical Narrative Review of Forthcoming Drugs from an Indian Context

In Pursuit of Genetic Prognostic Factors and Treatment Approaches in Secondary Acute Myeloid Leukemia—A Narrative Review of Current Knowledge

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