Discussion
We retrospectively analyzed the clinical features of pediatric vs. adult
patients with AE-AML. Our study revealed that both EML and c-KIT
mutations were more frequently seen in adult AE-AML. Accordingly, this
group of patients carried a higher risk of relapse, and had a lower rate
of DFS and OS compared to the pediatric counterparts.
In line with other’s study [13], the AML-M2 was the dominant
clinical subtype occurring in 88.2% of patients in our cohort. It was
even higher in up to 92.9% of adult patients. Apart from AML-M2
phenotypic dominance, high incidence of EML and c-KIT mutations were
other two features in AE-AML [1,3-4]. In our study, 22.5%(39/173)
patients presented with EML and 29.6%(42/142) carried a c-KIT mutation.
Subgroup analysis demonstrated that the occurrence of EML (29.6% vs.
13.3%, P=0.008) and c-KIT mutations (40.5% vs. 17.6%, P=0.003) were
at least doubled in adult group compared to pediatric cohort.
According to previous studies, both c-KIT mutations [7,11] and EML
[7,14-15] were associated with an increased expression of amyloid
precursor protein (APP), which adversely impacted the disease outcome in
AE-AML. APP is a type I integral membrane protein abundant in neurons
[16]. It was reported to be over-expressed in solid tumors,
including oral squamous cell carcinoma, pancreatic adenocarcinoma and
prostate cancer, promoting cell proliferation and metastasis therefore
adversely affecting the prognosis [17-19]. The APP gene is located
on 21q21.3. The app mRNA was over-expressed in AML with abnormal
chromosomal 21 [20], i.e. t (8;21) AML [21], as compared with
other AML subtypes. Jiang et al reported the role of APP in cell
migration through the APP/phosphorylated extracellular-signal-regulated
kinase (p-ERK)/c-Myc/matrix metalloproteinase (MMP)-2 pathway and its
involvement in the pathogenesis of EML [14-15]. Consistent with
other studies [22-23], the majority of EML in our study presented
with CNS infiltration in the form of either sarcoma within or beside the
spine (15/39, 38.5%) or CNSL (15/39, 38.5%). The CNS infiltration of
EML, in particular the sarcoma within or beside the spine, occurred at a
much higher rate in adults than that in children (adults 14/29, 48.3%
vs. children 1/10, 10.0%, P=0.032). In addition, in AE-AML the
overepression of APP was associated with both a higher incidence of
c-KIT mutations and a higher level of c-kit expression [7,11]. The
critical step of APP proteolysis in Alzheimer’s disease [16] which
is mainly an elders’ illness, and the overexpression of APP in certain
solid tumors which also mainly affect the elders made us speculate that
the expression of APP might increase with aging. Hence the variance in
EML and c-KIT mutations between the two age groups might reflect the
underlying difference in APP expression. Furthermore, the present study,
further supporting this hypothesis, from the clinical point of view,
showed that EML and c-KIT mutation negatively impacted on relapse, DFS
and OS, and the poor impact was only found in adult but not pediatric
patients by subgroup analysis, which was in agreement with the adverse
prognostic effect of APP in AE-AML [7,14-15].
EML has an adverse prognostic effect in adult patients with AE-AML
[7,14-15, 24-25]. However, its prognostic effect seems not so
important in pediatric AE-AML [9,26], though it might a poor
prognostic factor in pediatric patients with AML in the whole cohort
[11,27]. In the present study, EML was associated with a higher risk
of relapse (HR 2.20, 95% CI 1.11-4.35, P=0.024), and worse DFS (HR
1.88, 95% CI 0.97-3.64, P=0.048) and OS (HR 2.14, 95% CI 1.13-4.06,
P=0.020). However, the negative effects of EML on relapse and survival
were only seen in adult patients (P<0.05) but not in children
(P>0.05). Our results further supported that EML had
negative prognostic effect only in adult but not pediatric AE-AML. The
consolidation regimens did not improve the poor outcome in adults
presenting with EML.
Mutations in c-kit are one of most common genetic abnormalities,
especially in AE-AML. While most studies showed the presence of c-KIT
mutations adversely impacted the survival in AE-AML [1-3,28], some
research also reported that it did not influence the outcome especially
in pediatric patients [29-30]. In our study, the presence of c-KIT
mutations did not affect the whole cohort in terms of relapse (HR 1.80,
95% CI 0.92-3.50, P=0.088), DFS (HR 1.80, 95% CI 0.95-3.40, P=0.095)
and OS (HR 1.80, 95% CI 0.96-3.35, P=0.065). It was, however, an
unfavorable factor for relapse and survival in adults
(P<0.05), and the treatment regimens were not able to improve
the prognosis in this group of patients. Taken together, EML and c-KIT
mutations adversely affected the disease outcome only in adult but not
pediatric AE-AML.
When compared to SDAC-based regimens, median or high dose
cytarabine-based regimens have improved the survival and lowered the
relapse of AE-AML [12,31], and are the consolidation treatment
recommended by guidelines [32-34]. Our data further supported the
strength of MDAC-based regimen as the consolidation therapy irrespective
of patients’ age, with the only exception of those with either EML or
c-KIT mutations. The high CR in pediatric patients was mainly due to
intensive induction regimens, and the CR rates between the two age
groups became comparable when patients were given similar induction
regimens. Our study suggested that the patients with AE-AML could
benefit from intensive induction and consolidation regimens, but such
benefit was not seen in high-risk patients. Allogenic stem cell
transplantation should be recommended to adult patients with EML and
c-KIT mutations [35].