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On Saturday, June 1 2019, during the American Society for Clinical Oncology (ASCO) annual meeting in Chicago, US, Mark J. Levis, from Johns Hopkins University School of Medicine, Baltimore, US, discussed the effect of gilteritinib on the survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) AML who have common AML co-mutations or a high FLT3-ITD allelic ratio.
FLT3 mutations occur in approximately 30 % of patients with AML and are often associated with poor survival. Gilteritinib was recently approved by the FDA for the treatment of patients with R/R AML based on interim data from the randomized phase III ADMIRAL study (NCT02421939) which showed that the oral FLT3 inhibitor, gilteritinib provides superior response and overall survival (OS) compared with salvage chemotherapy (SC) in patients (pts) with FLT3mut+ R/R AML.
Characteristics |
Gilteritinib |
Salvage chemotherapy |
Total |
---|---|---|---|
Median age, years (range) |
62 (20-84) |
61.5 (19-85) |
62 (19-85) |
Female, n (%) |
131 (53) |
70 (56) |
201 (54) |
Cytogenetic risk, n (%) |
|
|
|
Favorable |
4 (2) |
1 (1) |
5 (1) |
Intermediate |
182 (74) |
89 (72) |
271 (73) |
Unfavorable |
26 (11) |
11 (9) |
37 (10) |
Other |
35 (14) |
23 (19) |
58 (16) |
Centrally-confirmed FLT3 mutation status, n (%) |
|
|
|
FLT3-ITD alone |
215 (87) |
113 (91) |
328 (88) |
FLT3-TKD alone |
21 (9) |
10 (8) |
31 (8) |
FLT-ITD and FLT3-TKD |
7 (3) |
0 |
7 (2) |
Table 1
-NPM1 : 47.9% (n = 173/361)
-DNMT3A: 31% (n = 115/361)
-DNMT3A/NPM1: 23.8% (n = 86/361)
-WT1: 18.0% ( n= 65/361)
Treatment outcomes according to FLT3-ITD allelic ratio |
||||
---|---|---|---|---|
High allelic ratio |
||||
|
Gilteritinib |
Salvage chemotherapy |
|
P - value
|
Median OS, months |
7.1 |
4.3 |
HR=0.492 (95% CI: 0.339, 0.714) |
0.0001 |
CR/CRh, n (%) |
30 (27.5) |
6 (10.0) |
Risk difference 17.5% (95% CI: 4.9, 30.1) |
0.010 |
Low allelic ratio |
||||
Median OS, months |
10.6 |
6.9 |
HR = 0.795 (95% CI: 0526, 1.200) |
0.2719 |
CR/CRh, n (%) |
45 (39.8) |
10 (18.9) |
Risk difference: 21.0% (95% CI: 5.7, 36.2) |
0.0081 |
Table 2
Patients |
CR/CRh (%) |
|
Median OS |
|||
---|---|---|---|---|---|---|
|
Gilteritinib |
SC |
Gilteritinib |
SC |
HR |
P value |
ITT population (n=371) |
34.0 |
15.3 |
9.3 |
5.6 |
0.637 |
0.0007 |
|
Co-mut+ cohorts |
|
|
|
||
NPM1 (n=173) |
32.2 |
12.1 |
8.3 |
5.1 |
0.419 |
<0.0001 |
DNMT3A(n=115) |
37.3 |
12.5 |
9.1 |
5.5 |
0.504 |
0.0031 |
DNMT3A/NPM1(n=86) |
40.0 |
9.7 |
10.8 |
5.0 |
0.252 |
<0.0001 |
WT1 (n=65) |
35.6 |
5.0 |
9.1 |
3.4 |
0.309 |
0.0001 |
Table 3
Dr. Levis concluded that the clinical benefit of gilteritinib was maintained regardless of the presence of NPM1, DNMT3A, and WT1 co-mutations. Relative to the other co-mutated cohorts, patients with both NPM1 and DNMT3A co-mutations had the greatest survival benefit with gilteritinib.
In patients with a high FLT3-ITD allelic ratio, OS was significantly longer in patients treated with gilteritinib compared with those treated with salvage chemotherapy. In the gilteritinib arm, the low FLT3-ITD allelic ration cohort had a survival advantage when compared with the high FLT3-ITD allelic cohort
These findings of the ADMIRAL trial further support the use of gilteritinib in the R/R AML treatment paradigm irrespective of co-mutation status and FLT3-ITD allelic ratio.
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