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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.
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
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 |
AMLSG historical cohort |
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. |
Figure 2. 2-year EFS and OS in the AMLSG 16-10 and AMLSG historical cohort*
*Adapted from Döhner et al.1
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 |
<0.001 |
0.56 |
<0.001 |
Age (per 10 years) |
1.17 |
<0.001 |
1.33 |
<0.001 |
NPM1-mutated |
0.48 |
<0.001 |
0.76 |
0.002 |
WBC |
1.21 |
0.011 |
1.23 |
0.015 |
18–60 years (n = 664) |
||||
AMLSG 16-10 |
0.59 |
<0.001 |
0.59 |
<0.001 |
Age (per 10 years) |
1.16 |
<0.001 |
1.30 |
<0.001 |
NPM1-mutated |
0.47 |
<0.001 |
0.76 |
0.010 |
WBC |
1.24 |
0.014 |
1.23 |
0.037 |
61–70 years (n = 191) |
||||
AMLSG 16-10 |
0.41 |
<0.001 |
0.47 |
<0.001 |
Female sex |
— |
— |
0.70 |
0.042 |
NPM1-mutated |
0.53 |
<0.001 |
— |
— |
CI, confidence interval; EFS, event-free survival; HR, hazard ratio; OS, overall survival; WBC, white blood cell. |
Table 3. Analysis of secondary endpoints*
Outcomes, % (unless otherwise stated) |
AMLSG 16-10 cohort |
Historical cohort |
||||
---|---|---|---|---|---|---|
All patients |
18–60 years |
61–70 years |
All patients |
18–60 years |
61–70 years |
|
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 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. |
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.
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