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].