Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease
1
. Therefore, additional prognostic factors are needed in order to make risk-adapted
treatment approaches. KIT mutations are the most common mutations of t(8;21) AML patients,
and a spectrum of mutations has been detected to date
2–6
. Limited by sample size or the screening method, previous studies have usually analyzed
all types of mutations as a whole or just analyzed the most prevalent D816 mutation
2–7
. Thus, whether each type of mutation has similar adverse impacts remains unclear
to date. A reflection is that the existence of the KIT mutation brings t(8;21) AML
from low to intermediate risk regardless of mutation type in the National Comprehensive
Cancer Network guidelines
8
, whereas European LeukemiaNet has provided no further recommendation for those with
a KIT mutation
9
. Recently, Yui et al.
10
showed that the D816 mutation had a poorer prognosis than other mutations. Thus, it
is urgent to perform large-scale studies under modern treatment modes to comprehensively
evaluate the prognoses of the individual KIT mutation types.
A total of 275 consecutive adult patients with t(8;21) AML who were diagnosed and
received treatment in our institute from June 2005 to December 2017 were, retrospectively,
evaluated. Totally, 150 patients (54.5%) were male. The median age of the patients
at diagnosis was 36 (range: 16–69) years. As we previously reported, induction chemotherapy
comprised 1–2 cycles of induction with the “3 + 7” regimen or the homoharringtonine,
aclarubicin, and cytarabine regimen (homoharringtonine 2 mg/m2 per day, cytarabine
100 mg/m2, and aclarubicin 20 mg/day on days 1–7)
11,12
. Among the 263 patients achieving complete remission (CR), 142 received the intermediate-dose
cytarabine-based chemotherapy, 13 received chemotherapy followed by autologous-hematopoietic
stem cell transplantation (auto-HSCT), 108 received chemotherapy followed by allogeneic-HSCT
(allo-HSCT, human leukocyte antigen-identical sibling donor, n = 43; matched unrelated
donor, n = 7; haploidentical related donor, n = 58) as postremission therapy
13
. Dasatinib were used in some patients with KIT mutation if RUNX1–RUNX1T1 reduction
is less than 3-log after cycle 2 consolidation since 2015. Nine and one patients who
relapsed after chemotherapy and auto-HSCT received allo-HSCT as salvage therapy. The
study was approved by the Ethics Committee of the Peking University People’s Hospital.
Informed consent was obtained from all subjects in accordance with the Declaration
of Helsinki. The cutoff date for the follow-up was April 15, 2018. As we previously
reported, the complementary DNA was used to amplify KIT exons 17 and 8 and sequencing
4
, and TaqMan-based real-time quantitative polymerase chain reaction technology was
used to detect RUNX1–RUNX1T1 transcript levels
11
. The survival functions were estimated using the Kaplan–Meier method and were compared
using the log-rank test. The parameters with P < 0.20 by the univariate analysis were
entered into a multivariate model using a Cox proportional hazards model to identify
the most statistically significant parameters associated with relapse free survival
(RFS) and overall survival (OS). The SPSS 16.0 software package (SPSS Inc., Chicago,
IL) and GraphPad Prism 5 (GraphPad Software Inc., La Jolla, CA) were used for the
data analysis.
The median follow-up time was 20 (2–93) months. The 3-year RFS and OS rates were 61.5%
(95% confidence interval (CI), 53.9–68.2%) and 73.2% (95% CI, 67.3–80.4%), respectively.
Overall, 114 patients (41.5%) had KIT mutations, and a total of 22 types of mutations
were detected (Table 1). In all, 103 and 11 patients, respectively, had sole and compound
mutations (combination of 2 types), and 104 (37.8%) and 14 (5.1%) patients had a KIT
mutation in exon 17 and exon 8 (sole or compound), respectively. The most prevalent
mutation was exon 17 D816 (57.0% of the patients with KIT mutations), followed by
the exon 17 N822, exon 8 deletion–insertion and exon 17 D820 mutations (27.2, 12.3
and 4.4%). The one-course and two-course CR rates were similar between the patients
with KIT mutations and no mutation (P = 1.0 and 0.45). Patients with a KIT mutation
had significantly lower 3-year RFS and OS rates than those with no mutation (RFS:
P = 0.0002, 49.3% [95% CI: 37.0–60.5%] vs. 69.7% [95% CI 59.9–77.6%]; OS: P = 0.0055,
67.1% [95% CI: 55.0–76.6%] vs. 77.6% [95% CI: 68.3–84.5%]). Patients with sole D816V,
D816Y, and D816H mutation had similar 3-year RFS and OS rates (P = 0.57 and 0.087).
Patients with a sole D816 mutation had significantly lower 3-year RFS and OS rates
than those with no mutation (RFS, P < 0.0001, 33.7% [95% CI: 17.3–50.9%] vs. 69.7%
[95% CI: 59.9–77.6%], Fig. 1a; OS, P < 0.0001, 54.9% [95% CI: 37.9–69.1%] vs. 77.6%
[95% CI: 68.3–84.5%], Fig. 1b); Similar results existed if the patients who underwent
allo-HSCT were censored at the time of transplantation (RFS: P < 0.0001, 19.4% [95%
CI: 1.6–52.3%] vs. 57.7% [95% CI: 43.8–69.3%], Fig. 1c; OS: P = 0.0003, 53.7% [95%
CI: 23.9–76.3%] vs. 77.0% [95% CI: 63.2–86.2%], Fig. 1d). In addition, the 3-year
RFS and OS rates were similar among the patients with the sole N822 mutation, the
exon 8 mutation and no mutation (RFS: P = 0.47, 69.6% [95% CI: 46.1–84.4%] vs. 88.9%
[95% CI: 43.3–98.4%] vs. 69.7% [95% CI: 59.9–77.6%], Fig. 1a; OS: P = 0.70, 71.9%
[95% CI: 42.7–88.0%] vs. 83.3% [95% CI: 27.3–97.4%] vs. 77.6% [95% CI: 68.3–84.5%],
Fig. 1b). Likewise, the 3-year RFS and OS rates were similar if censoring at the time
of transplantation (RFS: P = 0.36, 52.6% [95% CI: 18.5–78.3%] vs. 80.0% [95% CI: 20.4–96.9%]
vs. 57.7% [95% CI: 43.8–69.3%], Fig. 1c; OS: P = 0.32, 0 [95% CI: 0–0] vs. 75.0% [95%
CI: 12.8–96.1%] vs. 77.0% [95% CI: 63.2–86.2%], Fig. 1d). Because of the similar prognoses
for the N822 and exon 8 mutations compared to no mutation, five patients with sole
or compound D820 mutation (Table 1) were analyzed together. Patients with the D820
mutation had significantly lower 3-year RFS rates than those with no mutation despite
of no censoring or censoring (no censoring: P = 0.0050, 20.0% [95% CI: 0.8–58.2%]
vs. 69.7% [95% CI: 59.9–77.6%], Fig. 1a; censoring: P < 0.0001, 0% [95% CI: 0–0%]
vs. 57.7% [95% CI: 43.8–69.3%], Fig. 1c). However, the D820 mutation had no impact
on OS (P = 0.73 and 0.72, Fig. 1b and d).
Table 1
KIT mutation patterns
Type of mutation
Number of patients (%)
Sole mutation
103 (90.4%)
Exon 17
92 (80.7%)
R815_D816delinsK
1 (0.9%)
R815_D816insT
1 (0.9%)
R815_D816insIR
1 (0.9%)
D816A
1 (0.9%)
D816H
8 (7.0%)
D816V
37 (32.5%)
D816Y
10 (8.8%)
D820G
3 (2.6%)
N822K
28 (24.6%)
N822Y
1 (0.9%)
A829P
1 (0.9%)
Exon 8
11 (9.6%)
T417_D419DelinsI
1 (0.9%)
T417_D419delinsY
1 (0.9%)
T417_R420DelinsG
1 (0.9%)
Y418delinsFFW
1 (0.9%)
Y418_D419delinsP
1 (0.9%)
Y418_R420delinsSW
1 (0.9%)
Y418_L421delinsTRVY
1 (0.9%)
D419del
1 (0.9%)
D419_R420delinsK
2 (1.8%)
D419_L421DelinsVEV
1 (0.9%)
Compound mutations
11 (9.6%)
D816V + D816H
2 (1.8%)
D816V + D816Y
3 (2.6%)
D816V + D820G
1 (0.9%)
D816V + D419del
1 (0.9%)
D816V + T417_L421delinsLPRF
1 (0.9%)
D816Y + N822K
1 (0.9%)
D820G + N822K
1 (0.9%)
D820G + D419del
1 (0.9%)
Total
114 (100%)
Fig. 1
RFS and OS of patients grouped by KIT mutation status and type.
a RFS, no censoring. b OS, no censoring. c RFS, censoring at the time of allo-HSCT.
d OS, censoring at the time of allo-HSCT
Next, patients with KIT D816 and D820 mutations were defined as the D816/D820 mutation
group (n = 70, 25.5%), whereas the N822 and exon 8 mutation and no mutation were defined
as the N822/exon 8/no mutation group (n = 201, 73.1%). Patients with the D816/D820
mutation had significantly lower 3-year RFS and OS rates than those with the N822/exon
8/no mutation (RFS: P < 0.0001, 33.1% [95% CI: 18.7–48.2%] vs. 70.5% [95% CI: 61.9–77.5%];
OS: P < 0.0001, 60.5% [95% CI: 45.3–72.7%] vs. 77.2% [95% CI: 68.8–83.6%]). Similar
results existed when censoring (RFS: P < 0.0001, 0% [95% CI: 0–0%] vs. 57.9% [95%
CI: 45.2–68.7%]; OS: P = 0.0002, 58.5% [95% CI: 31.9–77.7%] vs. 73.6% [95% CI: 60.3–83.1%]).
Multivariate analyses showed that the KIT D816/D820 mutation, a <3-log reduction in
the RUNX1–RUNX1T1 transcript levels at cycle 2 consolidation and treatment with chemotherapy
only/auto-HSCT were independent adverse prognostic factors for both RFS and OS (Table
S1).
In accordance with the majority of previous studies
2–7
, we confirmed that both the KIT mutation and the KIT D816 mutation were significantly
associated with lower RFS and OS rates in adult t(8;21) AML. We also showed that the
three common D816 mutations had similar clinical impacts. Furthermore, we demonstrated
that the N822 and exon 8 mutations had similar RFS and OS rates compared to no mutation,
whereas the D820 mutation had a significantly higher relapse probability than no mutation.
The results implied that we should stratify the patients not only according to the
existence of the KIT mutation but also according to the type of mutation. After regrouping,
the KIT D816/D820 mutation was shown to be an independent adverse prognostic factor
for both RFS and OS. The multivariate analyses result reflected that the pretreatment
factor, treatment response and treatment modality were all relevant to the outcome
of t(8;21) AML.
Consistent with the current clinical results, animal and in vitro studies show a functional
difference between KIT mutations. Nick et al.
14
used a murine model to illustrate that KIT
D814V promoted a more varied and aggressive leukemic phenotype than KIT
T417IΔ418–419 when coexpressed with RUNX1–RUNX1T1. Omori et al. demonstrated that
in addition to the common JAK/STAT signaling pathway, the D816V mutation activated
SRC family kinases, whereas N822K activated the MAPK pathway. The consequence was
that D816V had a greater cell-proliferative and antiapoptotic ability than the N822K
mutation
15
.
The limitation was that this was a retrospective study. The treatment regimens were
not uniform. Furthermore, we could not analyze the synergistic impact of the individual
KIT mutations with other gene mutations due to lack of data.
In conclusion, the individual KIT mutations had distinct prognoses in adult t(8;21)
AML. Exon 17 D816 and D820 mutation had an adverse prognosis, whereas the exon 17
N822 and exon 8 mutation had a similar prognosis to no mutation. This result is helpful
for a more precise stratification and for directing the appropriate treatment in t(8;21)
AML. Multicenter prospective studies with a large sample size are warranted.
Electronic supplementary material
Table S1