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Efficacy and safety of midostaurin in younger and older patients with FLT3-ITD AML

Jun 14, 2022
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Learning objective: After reading this article, learners will be able to identify the impact of midostaurin treatment on survival in both younger and older patients with FLT3-ITD-mutated AML

Midostaurin is a FLT3-ITD inhibitor approved by the U.S. Food and Drug Administration (FDA) and European Commission (EC) for newly diagnosed AML in adult patients with FLT3-mutated AML. This decision followed results from the RATIFY trial which demonstrated midostaurin and intensive chemotherapy improved event-free survival (EFS) and overall survival (OS) compared with placebo. In the recent phase II AMLSG 16-10 trial (NCT01477606), older patients aged 61–70 years old were included in the treatment cohort with midostaurin. Interim study results have been previously reported by the AML Hub. Here, we summarize the key efficacy and safety results, published by Döhner et al.1, in Blood Advances.

Methods

The AMLSG 16-10 was a single arm, phase II study1 conducted at 54 centres in Austria and Germany. The outcomes of patients enrolled in this trial were compared with those of a historical control cohort (AMLSG). Patient inclusion criteria and study endpoints are shown in Figure 1.

Figure 1. Overview of the phase II AMLSG 16-10 trial*

Allo-HSCT, allogeneic hematopoietic stem cell transplant; AML, acute myeloid leukemia; CBF-AML, core-binding factor AML; CID, cumulative incidence of death; CIR, cumulative incidence of relapse; CR/CRi, complete remission/complete remission with incomplete hematologic recovery; CTCAE, Common Terminology Criteria for Adverse Events; RFS, relapse-free survival.
*Adapted from Döhner et al.1

Results

Patient characteristics for the AMLSG 16-10 and AMLSG historical cohort are shown in Table 1.

Table 1. Patient characteristics*

Characteristic

AMLSG 16-10 cohort
(n = 440)

AMLSG historical cohort
(n = 415)

p value

Median age, years (range)

54.1 (18–70)

50.5 (18–70)

< 0.001

Female, %

57

54

 

ECOG PS, %

< 0.0001

              0

38

22

 

              1

50

61

 

              2

12

16

 

WBC, × 109/L

              Median (range)

41.8 (0.3–420)

44.8 (0.2–439)

 

              Missing, n

3

3

 

Hb, g/dL

              Median (range)

9.0 (4.1–18.1)

9.0 (3.1–16.6)

 

              Missing, n

4

3

 

Platelet count, × 109/L

              Median (range)

59 (5–681)

58 (6–734)

 

              Missing, n

3

2

 

BM blasts, %

              Median (range)

80 (0–100)

85 (2–100)

 

              Missing, n

46

25

 

PB blasts, %

              Median (range)

52 (0–100)

60 (0–100)

 

              Missing, n

30

20

 

AML type, %

< 0.0001

              De novo

89

91

 

              Secondary

7

1

 

              Therapy-related

4

3

 

              Missing, n

1

 

Cytogenetics, %

0.02

              Intermediate-I

69

78

 

              Intermediate-II

25

17

 

              Adverse

6

5

 

              Missing, n

28

0

 

FLT3-ITD, %

              Allelic ratio ≥0.5

55

56

 

              Missing, n

2

121

 

FLT3-TKD present, %

4

4

 

              Missing, n

22

 

BM, bone marrow; Hb, hemoglobin; ECOG, Eastern Cooperative Oncology Group; PB, peripheral blood; WBC, white blood cell.
*Table from Döhner et al.1

Efficacy

  • The median follow-up for the AMLSG 16-10 and historical cohort was 40.4 months and 76.3 months, respectively
  • The 2-year EFS and OS were greater in the AMLSG 16-10 cohort treated with midostaurin compared to the historical cohort (Figure 2)
    • The AMLSG 16-10 cohort also showed improved EFS and OS when assessing via subgroup analysis for younger (18–60 years) and older (61–70) patients

Figure 2. 2-year EFS and OS in the AMLSG 16-10 and AMLSG historical cohort*

*Adapted from Döhner et al.1

  • In a multivariate analysis, midostaurin treatment in the AMLSG 16-10 trial was associated with significantly improved OS and EFS compared with the historical cohort (Table 2)
    • This effect was again observed in both younger and older patients.

Table 2. Multivariate analysis*

Variable

EFS

OS

HR (95% CI)

p value

HR (95% CI)

p value

All patients (N = 855)

AMLSG 16-10

0.55
(0.47–0.65)

<0.001

0.56
(0.47–0.68)

<0.001

Age (per 10 years)

1.17
(1.09–1.25)

<0.001

1.33
(1.23–1.44)

<0.001

NPM1-mutated

0.48
(0.41–0.57)

<0.001

0.76
(0.63–0.91)

0.002

WBC

1.21
(1.05–1.40)

0.011

1.23
(1.04–1.44)

0.015

18–60 years (n = 664)

AMLSG 16-10

0.59
(0.49–0.71)

<0.001

0.59
(0.47–0.73)

<0.001

Age (per 10 years)

1.16
(1.06–1.27)

<0.001

1.30
(1.17–1.45)

<0.001

NPM1-mutated

0.47
(0.39–0.56)

<0.001

0.76
(0.61–0.94)

0.010

WBC

1.24
(1.04–1.47)

0.014

1.23
(1.01–1.49)

0.037

61–70 years (n = 191)

AMLSG 16-10

0.41
(0.29–0.59)

<0.001

0.47
(0.33–0.67)

<0.001

Female sex

0.70
(0.49–0.99)

0.042

NPM1-mutated

0.53
(0.38–0.74)

<0.001

CI, confidence interval; EFS, event-free survival; HR, hazard ratio; OS, overall survival; WBC, white blood cell.
*Adapted from Döhner et al.1

  • In a sensitivity analysis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) slightly reduced the treatment effect compared to the multivariate model without considering allo-HSCT (EFS: HR 0.63 and 0.62 vs 0.55; OS: HR 0.72 and 0.66 vs 0.57)
  • When comparing patients from AMLSG 16-10 with the RATIFY trial, the treatment effect of midostaurin remained significant (HR, 0.71; p = 0.005)
  • Treatment with midostaurin produced significantly greater complete remission/complete remission with incomplete hematologic recovery (CR/CRi) compared with the historical cohort, and lower cumulative incidence of relapse (CIR) and rates of refractory disease
    • The 2-year RFS rate in the AMLSG 16-10 trial was 52% and in the historical population was 32%, and multivariate analysis revealed treatment within the AMLSG 16-10 trial (HR, 0.50; p < 0.001) and NPM1 mutation (HR, 0.63; P < 0.001) as significant favorable factors, while older age (HR per 10 years, 1.02; p < 0.001) was an adverse factor.

Table 3. Analysis of secondary endpoints*

Outcomes, % (unless otherwise stated)

AMLSG 16-10 cohort

Historical cohort

All patients
(N = 440)

18–60 years
(n = 312)

61–70 years
(n = 128)

All patients
(N = 415)

18–60 years
(n = 352)

61–70 years
(n = 63)

CR/CRi

74.9

75.9

72.4

64.6

66.5

54.0

CIR

28.0

24.0

37.0

57.0

54.0

74.0

CID

20.0

20.0

19.0

12.0

12.0

12.0

RD

19.2

20.6

15.8

30.6

28.4

42.9

ED/HD

5.9

3.5

11.8

4.8

5.1

3.2

Missing, n

2

1

1

CID, cumulative incidence of death; CIR, cumulative incidence of relapse; CR/CRi, complete remission/complete remission with incomplete hematologic recovery; ED, early death; HD, hypoplastic death; RD, refractory disease.
*Table from Döhner et al.1

Safety

  • Midostaurin treatment was interrupted at least once in 40% of patients, mostly due to toxicity (73%)
    • The most frequent adverse events (AEs) leading to treatment discontinuation were thrombocytopenia, nausea/vomiting, graft-versus-host disease (GvHD), hepatobiliary disease/increase of transaminases, and infections
  • Grade ≥3 AEs are summarized in Table 4.
    • Metabolism and nutrition disorders (p = 0.003), vascular disorders (p = 0.04), cardiac disorders (p = 0.08), and respiratory, thoracic, and mediastinal disorders (p = 0.07) were more common in older (61–70 years) patients

Table 4. Grade ≥3 AEs occurring in >10% of patients*

AEs, %

Patients (N = 440)

Blood and lymphatic system disorders

95

Infections and infestations

66

Gastrointestinal

39

General disorders

34

Investigations

30

Metabolism and nutrition disorders

27

Respiratory, thoracic, and mediastinal

17

Vascular

15

Renal and urinary

12

Nervous system

10

Cardiac

10

Skin and subcutaneous tissue

10

AEs, adverse events.
*Table from Döhner et al.1

Conclusion

Results from the phase II study1 showed the benefits of midostaurin in patients with FLT3-ITD-mutant AML. In line with the previous RATIFY trial, compared to historical controls, treatment with midostaurin significantly improved the survival outcomes in older and younger patients with FLT3-ITD-positive AML with a manageable safety profile.

  1. Döhner H, Weber D, Krzykalla J, et al. Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications. Blood Adv. 2022;bloodadvances.2022007223. DOI: 1182/bloodadvances.2022007223

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