Treatment strategies…Intermediate-risk cytogenetics and FLT3-mutated (ITD or TKD)...Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2 x 3 days and oral midostaurin 50 mg every 12 hours, days 8-21 (FLT3-mutated AML) Category 2A recommendations

AML:…after standard-dose cytarabine induction...standard-dose cytarabine with daunorubicin and oral midostaurin...(FLT3 mutated [ITD or TKD]

For the remaining patients, 7 þ 3 þ midostaurin is recommended if they are FLT3-ITD or FLT3-TKD positive.

Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase...Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction...Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen.

...phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR)...

Most pts had a FLT3-ITD mutation (82.7%), with 17.6% having a FLT3-TKD mutation...242 pts achieved CR/CRi (80.7%)....Midostaurin plus CT resulted in high response rates regardless of pt age, sex, induction drug, or alternative CT regimen.

...AML diagnosis, documented FLT3 mutation (ITD and/or TKD). Patients aged ≥18 years received midostaurin with 1-2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of high-dose cytarabine consolidation chemotherapy or as single-agent maintenance therapy.

The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.

...Patients must have a documented FLT3 mutation (ITD or TKD).)...

...Documented FLT3 mutation (ITD or point mutation), determined by analysis in a protocol- designated FLT3 screening laboratory...

In our experience Midos plus IC as first line in FLT3-ITD AML patients is highly effective CR 83.4% and 2 years OS 65%.

Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible….In comparison to a historical control cohort, the addition of midostaurin to intensive therapy led to a significant improvement in EFS and OS in both younger and older adult patients with AML and FLT3-ITD.

Pts' total ITD VAF significantly decreased after Cy2 and EOT (median reduction: 4.3 and 4.7 log10; p<.001, each), and MRD negativity (MRD-) was achieved in 68% and 85% of pts. In pts MRD positive (MRD+) after Cy2 (n=13) and EOT (n=6), 33 ITDs were identified (median VAF: 0.048%; range, 0.006-2.004). Of MRD+ pts after Cy2 and EOT, 7/13 (54%) and 4/6 (67%) exhibited ITDs in the beta1-sheet....In this first cohort of FLT3-ITD+ AML pts all treated with midostaurin in the prospective AMLSG16-10 trial we could demonstrate that MRD monitoring using our NGS assay is feasible and represents a promising tool to evaluate therapy response and identification of pts at high risk of relapse.

Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients....Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML.

Both compounds potently inhibited FLT3-ITD–expressing cells with a half maximal inhibitory concentration (IC50) of 13 nM for PKC412 and 2.5 nM for AC220, respectively. FLT3 N676K-expressing cells were also sensitive to FLT3 inhibitors with an IC50 of 7.5 nM for PKC412 and 3 nM for AC220. FLT3-ITD-N676K double mutants showed a strong resistance to both inhibitors (IC50 greater than 80 nM for PKC412 and greater than 16 nM for AC220).