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Long-term effects of midostaurin in FLT3-mutant AML: the RATIFY trial

Nov 4, 2021
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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.

Study design

Primary study

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)
(n = 441)

All randomized patients
(N = 717)

Midostaurin
(n = 234)

Placebo
(n = 207)

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.
*Adapted from Larson et al.2
CRind patients achieved a CR at any time during their induction period, prior to starting consolidation.

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.

Current study

  • Median follow-up was 59 months for surviving patients.
  • Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in first complete remission (CR) in ~28% patients (n = 101) assigned to midostaurin and ~23% assigned to placebo (n = 81).
  • Both CR per protocol by day 60 (CR60) and CR following one or two cycles of induction chemotherapy prior to commencing consolidation (CRind) were used for CIR analyses, alongside disease-free survival (DFS; time from maintenance therapy initiation to first death or relapse).

Results

  • In total, 403 patients (56%) reached CR60; similar results were seen between those treated with midostaurin (59%) and placebo (54%; p = 0.15).
  • CR at any time was achieved by 504 patients (70%), and 441 patients reached CRind.
    • More patients assigned to midostaurin achieved CRind compared to placebo (Table 2).
    • 63 additional patients were included upon response to consolidation chemotherapy.
  • Of these, 172 underwent allo-HSCT during their first CR and 130 left the study before starting maintenance therapy due to disease relapse, alternative therapy, or adverse events.
    • Three patients had CR with incomplete hematologic recovery (CRi)
  • Patients who reached CR/CRi at any time and did not receive allo-HSCT (n = 205) entered the maintenance phase of treatment (midostaurin, n = 120; placebo, n = 85).
  • Median time to maintenance therapy initiation was similar between patients assigned to midostaurin and placebo (Table 2).

Table 2. Complete remission and relapse rates*

Characteristic

Midostaurin
(n = 360)

Placebo
(n = 357)

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.
*Adapted from Larson et al.2
Two-sided Fisher’s exact p value.
CRind patients achieved CR at any time during induction, prior to starting consolidation.

Cumulative incidence of relapse

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 patients undergoing allo-HSCT in first CR (n = 182), CIR was reduced with midostaurin compared to placebo (HR, 0.59; 95% CI, 0.34–1.01), suggesting allo-HSCT was important in preventing relapse.
  • Within the 282 evaluable CIR patients, when allo-HSCT was not considered, HR was improved for patients treated with midostaurin compared to placebo in the European LeukemiaNet (ELN) ‘intermediate’ risk group (HR, 0.49; 95% CI, 0.26–0.94; p = 0.03), but not for ‘favorable’ or ‘adverse’ risk groups.
    • With allo-HSCT included, the relapse risks were comparable between treatment arms across all ELN risk groups.
    • Overall, CIR was greater in patients in the ELN ‘favorable’ risk group compared to ‘intermediate’ (HR, 1.79; 95% CI, 1.02–3.16) or ‘adverse’ risk groups (HR, 2.15; 95% CI, 1.17–3.96; p = 0.04, with ‘favorable’ as the reference group).

Maintenance treatment

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:

  • CIR was comparable between treatment arms during maintenance therapy (HR, 0.98 for midostaurin; 95% CI, 0.65–1.49; p = 0.93).
  • No significant difference in DFS was observed (HR, 0.74; 95% CI, 0.45–1.19; p = 0.21) or from the last dose of study drug (HR, 1.55; 95% CI, 0.69–3.49; p = 0.28).
  • DFS at 1-year from the end of maintenance was worse in patients assigned to midostaurin (77%; 95% CI, 65–85%) than placebo (92%; 95% CI, 80–97%), with more early relapses observed within 6 months after study drug completion.
  • During follow-up, there were 26 post-maintenance or DFS events, including 17 relapses in the midostaurin arm, and seven relapses and two deaths in the placebo arm.
    • These occurred in 20% patients with FLT3-TKD, 29% with FLT3-ITD-low, and 22% with FLT3-ITD-high; p = 0.61.

Conclusion

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.

  1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454-464
    DOI: 1056/NEJMoa1614359
  2. Larson RA, Mandrekar SJ, Huebner LJ, et al. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial. 2021;35(9):2539-2551. DOI: 10.1038/s41375-021-01179-4

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