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Core binding factor (CBF)* acute myeloid leukemia (AML) is present in 20–30% of pediatric cases and is associated with favorable outcomes. The co-occurrence of KIT mutations, found in 20–40% of patients, has been reported to be a negative prognostic factor in some studies, however, other contradictory studies reported no association between KIT mutation and clinical outcome.1 Whilst the European Leukemia Network (ELN) 2017 guidelines recognize that CBF AML with KIT mutations appear to be associated with a poorer prognosis, they do not recommend patients are assigned to a different genetic risk category.2
To better determine whether KIT mutations are of prognostic significance in CBF AML, Katherine Tarlock, Fred Hutchinson Cancer Research Center and Seattle Children’s Hospital, Seattle, US, and colleagues conducted a study, recently published in Clinical Cancer Research.1 They aimed to:
* CBF AML is associated with the cytogenetic abnormalities translocation (t)(8;21)(q22;q22) and inversion(16)(p13;1q22)/t(16;16)(p13;q22)
The KIT proto-oncogene encodes a transmembrane glycoprotein type III receptor tyrosine kinase (RTK). KIT mutations cause significant oncogenic events as they affect RTK activity. In some malignancies with KIT mutations, such as gastrointestinal stromal tumors, melanomas, and mastocytosis. TKIs have proven effective and have become standard-of-care for first-line therapeutic approaches.
Growth characteristics of transduced cells in vitro
Response of transduced cells to TKI in vitro
Clinical analysis
The prognostic significance of KIT mutations was analyzed by comparing outcomes between patients with KIT+ and KIT- CBF AML (Table 1).
In the Tables below, statistically significant results are indicated in a bold font.
Table 1. Comparison of outcomes to evaluate the impact of KIT mutations
|
KIT+ (%) |
KIT- (%) |
p value |
|
Five-year OS |
78 ± 12 |
81% ± 7 |
0.905 |
|
Patients in CR |
||||
DFS |
55 ± 14 |
73 ± 8 |
0.040 |
|
RR |
43 ± 14 |
21 ± 8 |
0.005 |
|
Treatment with conventional chemotherapy only |
||||
EFS |
44 ± 20 |
70 ± 11 |
0.021 |
|
DFS |
43 ± 20 |
69 ± 12 |
0.034 |
|
RR |
57 ± 21 |
28 ± 12 |
0.013 |
Table 2. Comparison of outcomes in patients with E17 KIT mutations, overall and by treatment
|
KIT+ (%) |
KIT- (%) |
p value |
E17 KIT+ versus KIT- |
|
|
|
OS |
72 ± 17 |
81 ± 7 |
0.478 |
DFS |
51 ± 18 |
73 ± 8 |
0.027 |
RR |
46 ± 19 |
21 ± 8 |
0.007 |
E17 KIT+ versus KIT- treated with GO |
|||
DFS |
67 ± 24 |
78 ± 11 |
0.396 |
RR |
27 ± 24 |
13 ± 9 |
0.207 |
E17 KIT+ versus KIT- treated with conventional chemotherapy |
|||
DFS |
35 ± 25 |
69 ± 12 |
0.021 |
RR |
65 ± 27 |
28 ± 12 |
0.010 |
Table 3. Comparison of outcome in E17 KIT+ by treatment type
|
GO (%) |
Conventional chemotherapy |
p value |
DFS |
67 ± 24 |
35 ± 25 |
0.161 |
RR |
27 ± 24 |
65 ± 27 |
0.062 |
Table 4. Comparison of outcomes in patients with E8 KIT mutations, overall and by treatment
|
KIT+ (%) |
KIT- (%) |
p value |
E8 KIT+ versus KIT- |
|
|
|
OS |
91 ± 12 |
81 ± 7 |
0.302 |
DFS |
60 ± 22 |
73 ± 8 |
0.305 |
RR |
40 ± 23 |
21 ± 8 |
0.072 |
E8 KIT+ versus KIT- treated with GO |
|||
OS |
100 ± 0 |
77 ± 10 |
0.092 |
DFS |
64 ± 29 |
78 ± 11 |
0.456 |
RR |
36± 31 |
13 ± 9 |
0.082 |
Advantages
Limitations
In vitro:
In vivo
References