Targeting FLT3 in AML | Medhub

FLT3 is a receptor tyrosine kinase that is normally expressed on progenitor cells in bone marrow and plays a role in hematopoiesis. FLT3 is expressed on 70% to 100% of leukemic blasts in all patients with AML.1 Mutations in the FLT3 gene are found in the blasts of approximately 30% of patients with newly diagnosed AML1 These patients have a poorer prognosis, including an increased risk of relapse and shorter DFS and OS.1,2 FLT3 inhibitors are being developed to address the unmet need in this high-risk patient population.3

 

FLT3 Mutations in AML

There are 2 forms of FLT3 mutations that are commonly found in patients with AML that result in constitutive activation of the receptor.5-6 The first type, internal tandem duplications (ITDs), is found in approximately 25% of all patients with AML.2 The prevalence of FLT3-ITD is highly age-dependent, ranging from 5% to 16,5 % in pediatric patients with AML and 20% to 32% in adult patients with AML.6-7    
 

FLT3-ITD
A number of large cohort studies have documented that FLT3-ITD mutations are associated with a poor prognosis. These studies have clearly shown that patients with AML with FLT3-ITD-positive mutation (FLT3-ITD+)  have significantly shorter DFS, EFS, and OS 2 and an increased risk of relapse.2,6
 

FLT3-TKD
FLT3-TKD mutations are small mutations in the activation loop of FLT3, mostly representing point mutations in codon D835 or deletions of codon I836.10  The prognostic value of FLT3-TKDs is less well established than that of FLT3-ITDs and remains controversial.6,10 The low prevalence of FLT3-TKD mutations (approx 6-7,5%)  may make determining their prognostic impact more difficult.10  A meta-analysis of adult AML cases demonstrated an impact of FLT3-TKD mutation on DFS but not on OS.  
 

FLT3 is a Prognostic and Predictive Marker

Prognostic markers provide information about long-term outcomes, whereas predictive markers are associated with the efficacy of a particular drug and can be incorporated into treatment decisions.11 FLT3-ITD mutations in patients with normal cytogenetics have been linked to worse long-term outcomes for many years.3,9

Recent  RATIFY -study has  shown that patients with FLT3-mutated AML – including FLT3-ITD and FLT3-TKD – benefit from midostaurin therapy,12 rendering FLT3 as both a prognostic factor and a predictive marker (Table 7).3,9,12 

With the shift from prognostic to predictive, FLT3 testing (for both FLT3-ITD and FLT3-TKD) is now recommended for all patients, in parallel with initial diagnostic tests.9  Because the outcome of the test is required to determine whether a patient is eligible for FLT3 inhibitors, the turnaround time should be nowadays 48-72 hrs according to European Leukemia Net guidelines.
 

Testing for FLT3 Mutations

FLT3 testing is recommended by several international guidelines.3,27  Patients who have FLT3-mutated AML are eligible to receive midostaurin, a FLT3 inhibitor, in addition to chemotherapy.3,9,12, 

Midostaurin is approved for patients with AML with FLT3 mutations (ITD and TKD), who are eligible to receive intensive chemotherapy. Midostaurin is the only FLT3 inhibitor approved in Sweden today. The treatment should start during day 8 of high-dose induction chemotherapy.13 Therefore, it is important that FLT3 status is determined within 8 days of a diagnosis of AML. Current guidelines support testing early in the diagnostic process, in parallel with morphological and immunophenotyping evaluations.3,9

 

 

References

1. Gilliand DG, Griffin JD. Blood. 2002;100(5):1532-1542.
2. Kottaridis PD, Gale RE, Frew ME, et al. Blood. 2001;98(6):1752-1759.
3. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. V1.2018.
4. Litzow MR. Blood. 2005;106(10):3331-3332.    .
5. Kayser S, Schlenk RF, Londono MC, et al. Blood. 2009;114(12):2386-2392.
6. Thiede C, Steudel C, Mohr B, et al. Blood. 2002;99(12):4326-4335.
7. Frohling S, Schlenk RF, Breitruck J, et al. Blood. 2002;100(13):4372-4380. 
8. Yanada M, Matsuo K, Suzuki T, et al. Leukemia. 2005;19(8):1345-1349.  .
9. Dohner H, Estey E, Grimwade D, et al. Blood. 2017; 129(4):424-447.
10. Bacher et al. BLOOD.  2008; 111 (5):2527-2537
11. Nalejska et al. Mol Diagn Ther (2014) 18:273–284
12. Stone et al N Engl J Med 2017;377:454-64 (RATIFY study)
13. Rydapt (midostaurin) Summary of Product Characteristics

 

 

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