FLT 3 mutation and inhibitors in AML

Type 1 inhibitors good against TKD and ITD FLT3 ( ITD is the one associated with shorter DOR and higher relapse rates)

Type 2 ( quizartinib and sorafenib) are only useful against FLT 3 ITD.

Reference

The efficacy of quizartinib appears comparable to midostaurin, which resulted in the same HR of 0.78 when evaluated in the RATIFY trial compared to placebo, although the analyzed population in RATIFY also included patients with FLT3-TKD (tyrosine kinase domain) mutations and restricted inclusion to patients aged 18 to 59 years.

Secondary factors may therefore influence the decision to use midostaurin or quizartinib. For example:

• Quizartinib is the only FLT3i approved for maintenance treatment after alloHCT.

• The pretreatment QT interval using Fridericia's correction (QTcF) must be less than 450  ms for quizartinib and equal to or less than 500  ms for midostaurin (midostaurin dose must be reduced for QTcF of 471-500  ms).

• Quizartinib is inactive against FLT3-TKD (D835) and Y842 mutations and must not be used in these patients.

• Quizartinib works even if FLT 3 mutations are associated with DNMT3 A or NPM1 mutations.

• Quizartinib leads to worse outcomes if FLT 3 mutations are combined with ASXL1 mutations. So do not use Quizartinib if you see both these mutations together.

• The AMLSG 16-10 trial reported a high efficacy of midostaurin in younger and older patients (61-70 years old), while the effect of quizartinib was most pronounced in patients aged less than 60 years.

• It is not understood why subgroup analyses showed a better efficacy of quizartinib in female and midostaurin in male patients. 

• FLT3i maintenance treatment after alloHCT is recommended in all FLT3-mutated patients.

• The prognostic effect of FLT3-ITD MRD is established for the time point after 2 cycles of chemotherapy and before alloHCT using either bone marrow or peripheral blood. The proportion of MRD-positive patients after 2 cycles of chemotherapy ranges from 29% to 56%.

• The most discriminatory threshold for MRD is a VAF of 0.01%, although MRD detection below this threshold is also associated with a higher relapse rate

• Sorafenib improves OS when given in the maintenance setting irrespective of MRD status before or after allo HCT.

• Quizartinib and gliteritinib showed improved OS if FLT 3 MRD positive by NGS before or after allo-HCT. Duration of maintenance 2-3 yr.