Miduoline combined with first-line chemotherapy can reduce the cumulative recurrence rate of AML patients with FLT3 mutation

25%-30% of adult patients with acute myeloid leukemia (AML) have FLT3 gene mutations, of which three-quarters are FLT3 internal tandem duplication (ITD) mutations, which are related to the high recurrence rate of patients and lead to poor clinical prognosis; about 8% of newly diagnosed AML patients have tyrosine kinase domain (TKD) point mutations.
The impact of FLT3-TKD mutation on the prognosis is still uncertain
.

Miduoline is a multi-target kinase inhibitor that can inhibit FLT3 signal transduction
.

The results of pre-clinical trials have shown that during the course of chemotherapy after induction and induction of remission, midostatin can be administered in combination with standard daunorubicin and cytarabine (DA) chemotherapy, and the side effects are tolerable
.

The results of a prospective, international multicenter, randomized, double-blind, placebo-controlled clinical trial (CALGB10603/RATIFY) showed that in AML patients with FLT3 mutations, standard first-line chemotherapy can be improved by adding midostaurin The overall survival (OS) of the patient
.

Recently, investigators further analyzed the effect of midotoline on the cumulative recurrence rate (CIR) of AML patients in the CALGB10603/RATIFY trial, and to maintain the outcome of patients receiving midotoline
.

Research methods The study included 18-59-year-old newly diagnosed AML patients with FLT3-ITD or FLT3-TKD mutations.
Most patients were subjected to cytogenetic analysis and NPM1 mutation analysis
.

Allows subgroup classification of patients based on available cytogenetic results and newly acquired mutation data (NPM1, FLT3-ITD, FLT3-TKD, RUNX1, ASXL1, TP53) and according to the 2017 European Leukemia Network (ELN) standards
.

The research was conducted in 225 research centers in 17 countries
.

Patients enrolled in the study received two treatments at random with the same probability, and were stratified according to FLT3 mutation subgroups: TKD mutation, ITD allele ratio <0.
7 (low mutation) and ITD mutation allele ratio ≥ 0.
7 (high Mutation)
.

Research results 1 Short-term efficacy and research flow chart 403 patients (56%) achieved complete remission (CR) (CR60) within 60 days after treatment, and there was no significant difference between the groups (P=0.
15)
.

Before initiation of program consolidation therapy (CRind), a total of 441 patients (65% in the midostauline group and 58% in the placebo group) achieved CR after 1 or 2 cycles of induction chemotherapy (Table 1)
.

The above-mentioned 441 patients constituted a separate analysis group for the evaluation of CIR
.

Table 1: CR rate and recurrence rate of each treatment group 504 patients (70%) reached CR at any time during the study period, and the other 3 patients reached CR with incomplete recovery of peripheral blood counts (CRi)
.

Among them, 172 patients received allogeneic hematopoietic stem cell transplantation (Allo-HSCT) at the first CR (CR1), and 130 patients withdrew from the study before starting maintenance
.

After consolidation therapy, patients on maintenance therapy will remain in the initially assigned double-blind treatment group and will not be re-randomized
.

Therefore, a total of 205 patients who achieved CR/CRi at any time and did not receive a transplant entered the maintenance treatment period (120 in the midostauline group and 85 in the placebo group) (Figure 1)
.

There was no significant difference in the time to the start of maintenance treatment between the two study groups
.

Figure 1: CONSORT of patient outcomes Figure 2 CIR analysis The demographic and baseline characteristics of 441 CRind patients are shown in Table 1
.

The CR rate, median to CR time and range, and recurrence rate of the two treatment groups are shown in Table 2
.

If transplantation is not considered, compared with patients in the placebo group, midostauline has a significant improvement in CIR (P=0.
01)
.

If transplantation is considered, there is no significant difference in the risk of recurrence between midostauline and placebo group (P=0.
19); the CIR status of 182 patients receiving Allo-HSCT at CR1 is shown in Figure 2
.

Transplantation is of great significance in preventing the recurrence of AML
.

Analyze the CIR of each ELN risk group.
If transplantation is not considered, the hazard ratio of the mid-risk group is significantly better than that of the placebo group (P=0.
03), but in the good prognosis and poor prognosis groups, the There was no significant difference in hazard ratio between the indotalin group and the placebo group
.

If transplantation is considered, there is no significant difference in the risk of recurrence between the midostauline group and the placebo group in the three ELN risk groups
.

Table 2: Pre-treatment characteristics of 441 CRind patients and all 717 randomized patients Figure 2: According to the randomized treatment group, CIR status of patients receiving Allo-SCT at CR1 3 Maintenance treatment analysis of patients who entered and did not enter maintenance treatment The former characteristics are different: Compared with patients who have not entered the maintenance treatment period, the patients who enter the maintenance treatment period are slightly older, fewer women, and have a more favorable FLT3 mutation status (ie, low ITD allele mutation rate), cytogenetic And ELN risk stratification
.

However, among patients who actually started maintenance treatment, there was no significant difference between the pre-treatment characteristics of the two maintenance treatment groups
.

For patients who started maintenance treatment, there was no statistically significant difference in OS or disease-free survival (DFS) between the two treatment groups
.

During the entire treatment period after the start of maintenance treatment, there was no significant difference in CIR between the midostauline group and the placebo group (P=0.
93)
.

Within 12 maintenance periods, there was no significant difference in DFS between the two groups (hierarchical log rank P=0.
21)
.

For 120 patients who completed all planned maintenance treatments, there was no significant difference in DFS between the two groups from the end of treatment
.

Research conclusions Generally speaking, standard first-line chemotherapy with midostauline can reduce the CIR of AML patients with FLT3 mutations
.

References Richard A Larson, Sumithra J Mandrekar, Lucas J Huebner, et al.
Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.
Leukemia.
2021 Sep;35(9):2539-2551.
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