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Internal tandem duplication (ITD) mutations in FLT3 are present in approximately 25–35% of adult patients with acute myeloid leukemia (AML) and are associated with an adverse prognosis due to a high rate of relapse, especially in those with a high mutant: wild-type allelic ratio. Tyrosine kinase domain (TKD) point mutations are present in ~8% of patients with de novo AML, with an unknown impact on prognosis. Data from the RATIFY study (NCT00651261) demonstrated an overall survival (OS) and event-free survival (EFS) benefit with the addition of midostaurin—a multi-targeted kinase inhibitor that inhibits FLT3 signaling—to standard first-line chemotherapy in a genotypically-defined subgroup of patients with FLT3-ITDs.1 Risk of death was reduced by 22%, with a clinical benefit seen in patients with either high or low mutant allelic fractions or with the TKD mutation. These results led to approval of midostaurin for patients with FLT3-mutated AML by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
A post hoc analysis of the impact of midostaurin on the cumulative incidence of relapse (CIR) and outcomes of patients who received 12 4-week cycles of midostaurin maintenance therapy was recently published in Leukemia,2 and is summarized below.
Of the 717 patients with newly diagnosed AML randomized to midostaurin (n = 360) or placebo (n = 357), 214 were FLT3-ITD-high (allelic ratio ≥0.7), 341 were FLT3-ITD-low (allelic ratio <0.7), and 162 were FLT3-TKD. Patient characteristics are shown in Table 1.
Table 1. Demographics and pretreatment characteristics*
Characteristic |
All induction CRs (CRind)† |
All randomized patients |
|
---|---|---|---|
Midostaurin |
Placebo |
||
Median age, years (range) |
47.8 (20–60) |
49.9 (18–60) |
48 (18–61) |
Female, % |
49 |
58 |
56 |
FLT3 mutation, % |
|||
TKD (No ITD) |
24 |
23 |
23 |
ITD (ratio <0.7) |
50 |
45 |
48 |
ITD (ratio ≥0.7) |
27 |
32 |
30 |
ELN 2017 group, % |
|||
Favorable |
50 |
51 |
45 |
Intermediate |
24 |
30 |
28 |
Adverse |
26 |
18 |
27 |
Pretreatment WBC, median × 103/μl (range) |
35 (0.6–421.8) |
31.3 (0.8–308.8) |
34.9 (0.6–421.8) |
CR, complete response; CRind, CR during induction; ELN, European LeukemiaNet; ITD, internal tandem duplication; TKD, tyrosine kinase domain; WBC, white blood cell count. |
During induction and four cycles of consolidation, 50 mg of midostaurin or placebo was given twice daily on Days 8–21. During the 12 maintenance cycles, administration was increased from 14 days every 4 weeks to 28 days continuously.
Table 2. Complete remission and relapse rates*
Characteristic |
Midostaurin |
Placebo |
p value† |
---|---|---|---|
CRind‡, % |
65 |
58 |
0.05 |
Median time to CR, days (range) |
36.5 (20–99) |
36 (20–108) |
— |
Relapses, % |
42 |
49 |
0.15 |
Median time to maintenance therapy initiation, months |
6.9 |
7.5 |
0.17 |
CR, complete response; CRind, CR during induction; ELN, European LeukemiaNet; ITD, internal tandem duplication; TKD, tyrosine kinase domain; WBC, white blood cell count. |
With transplantation not taken into account, CIR was improved in patients treated with midostaurin compared with placebo (CRind patients [n = 441], HR, 0.71; 95% CI, 0.54–0.93; p = 0.01). However, when allo-HSCT was considered a competing risk, relapse risks in patients treated with midostaurin and placebo were similar (HR, 0.81; 95% CI, 0.60–1.10; p = 0.19), although CIR was lower in both arms.
Furthermore, the following points were observed:
In total, 58% patients assigned to midostaurin and 60% to placebo completed maintenance therapy (n = 120). Maintenance was well-tolerated and median duration of exposure was the same (48 weeks, as planned) in both treatment arms. Discontinuation due to adverse events was also similar (midostaurin, 8%; placebo, 6%). Relapse occurred in 27% patients treated with midostaurin and 35% with placebo, with one death in each treatment arm.
Survival outcomes were as follows:
The authors concluded that midostaurin decreased the risk of relapse in patients with untreated FLT3-mutated AML, with a transplantation in first CR also important for preventing relapse. However, it was noted that it was difficult to isolate any clinical benefit gained from a single cause as the survival benefit was observed in patients receiving allo-HSCT. Additionally, relapses were found to be more frequent during the first 6 months after midostaurin maintenance completion, suggesting midostaurin may suppress but not eradicate measurable residual disease (MRD), resulting in relapse. Further limitations included the small size of each subgroup and the lack of re-randomization at the start of the maintenance treatment. The trial also provided no information on any benefit in older patients.
Overall, 12 4-week cycles of midostaurin maintenance therapy were shown to be well-tolerated, but the precise impact of maintenance with midostaurin, or any other targeted agent, requires further investigation.
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