Whether to generally define HHK AML as CK AML or classify HHK AML into the adverse risk category is a matter of debate. Considering the heterogeneity and the inconsistency of the outcome of HHK AML in different studies and the fact that few studies have been conducted, we hereby thoroughly analyzed the data from our center to demonstrate the clinical and biological characteristics of HHK AML.
Previous studies showed that 10%-12% AML have complex karyotypes [10], while HHK is more rare and only presents in < 2% AML cases [11]. HHK was identified in 1.31% (133/10131) of AML cases from our center, which was consistent with previous studies [5].We reported the largest cohort of HHK in China so far and we compare the prognosis and biological features of three separate HHK subgroups. Patients from NUM and STR groups had significantly higher WBC counts and BM blasts compared to the ADV group, while patients in the ADV group were older and had a higher proportion of MDS history. The results are consistent with the study by Chilton et al. [5]. A study focusing on childhood AML reported a connection between the FAB type M7 and hyperdiploidy [12]. Another study involving 38 purely numerical HHK AML cases reported no correlation between any FAB subtypes and HHK [4]. However, we found that 41.7% NUM and 46.5% STR cases were M5 while only 9.5% ADV cases were M5. In our study, the distribution of modal chromosome numbers and the percentage of gaining of different chromosomes were similar between the NUM and STR group. Whereas more differences were found in the ADV group with higher modal numbers and gaining of chromosome 1, 2, 6, 10, 11, 20 and 22 in a higher proportion (P < 0.05). Therefore, we speculated that the NUM and STR groups were more alike, with dominate M5 and high WBC and BM blasts upon diagnosis, although they were classified into different risk categories by ELN. The ADV group, probably due to their MDS-related abnormalities, had lower WBC counts and blasts. No particular FAB type was found associated with the ADV group, showing the heterogeneity of this group.
Our findings of MN of chromosomes and gaining of chromosomes were partially consistent with the previous study but we found a more obvious similar cytogenetic pattern of the NUM and STR group and a more distinct pattern of the chromosome abnormalities of ADV cases. Previous studies identified chromosomes 8 and 21 as the most commonly gained chromosomes in HHK AML [4, 5], and this pattern was similar to our results. Chromosome 8 was the most frequently gained chromosome in all 3 groups, a study reported that gaining of chromosome 8 in AML patients did not affect the disease outcome and we had the same result [13]. The second most commonly gained chromosomes was chromosome 21, which was found to have no impact on disease outcomes of AML as well, we also reached the same conclusion [14]. It was reported that, AML with trisomy 19 and 4 as a sole abnormality or within karyotypes characterized by trisomies only had a significantly better outcome [15, 16]. However, probably due to the fact that many other chromosome abnormalities were combined, we found no significant differences in OS between cases with or without gaining of chromosome 19 or 4, both in all cases and in NUM cases only. This may suggest that, although as the sole or dominant abnormality, trisomy 19 and 4 are associated with a better disease outcome, but when being part of a more complex karyotype like HHK, the impact of a single chromosome gaining is weakened.
Chilton et al.[5] reported that gaining of chromosome 1 was rare in NUM cases but more common in STR and ADV cases (7% vs 32% and 20%), while we found that gaining of chromosome 1 was significantly more frequent in the ADV group compared with the MUN and STR groups (40.5% vs 2% and 14%).However, hardly any studies were conducted on chromosome 1 gaining and AML except for an early case reporting trisomy AML associated with eosinophilia[17]. A study incorporated 3 AML cases with trisomy 1q resulting from unbalanced translocations, and they believed that trisomy 1q as a sole abnormality were sufficient for leukemogenesis [18]. Another study of 7 myeloproliferative neoplasm patients with trisomy 1q found that 6 of these patients progressed into AML [19]. Although we didn’t find a significant difference between the OS of ADV cases with or without chromosome 1 gaining, the 2-year survival rate of ADV cases with trisomy 1 was 0%, and we believed that gaining of this chromosome may have an impact on disease development.
Similar to chromosome 1, chromosome 11 gaining was infrequent in patients from the NUM and STR group while detected in 35.7% of the ADV cases. By comparing OS of ADV case with/without this abnormality, we found that gaining of chromosome 11 was associated with a worse outcome (P = 0.036). Researchers retrospectively studied 15 AML patients with trisomy 11 (among which trisomy 11 was the sole abnormality in 8 patients) and found it to be associated with an unfavorable prognosis [20]. Unlike the previously described chromosomes 1, 19 and 4, we found gaining of chromosome 11 to be associated with a poorer outcome, even in a complicated cytogenetic situation of HHK with adverse abnormalities. This may suggest an important role of chromosome 11 in leukemogenesis and disease progression. Adding its significantly higher frequency in the ADV group, we speculated that it may be associated with the poor survival rate of this group.
Notably, previous studies on HHK AML did not include the mutational pattern and we are the first to demonstrate it. Several studies found that TP53 mutation is frequent (70%-83%) in ELN defined CK AML [6, 21]. This proportion is consistent with our finding in the ADV group, in which 68.8% patients had TP53 mutation. However, although also classified as CK AML, not a single patient from the STR group had TP53 mutation, and this is more similar to the NUM group (only 1 patient had mutant TP53). Mutations associated with signaling pathway like KRAS, NRAS, JAK2 and FLT3 were commonly found in NUM and STR groups, but the ADV cases seldom had this type of mutation. This agreed with the higher WBC counts and blasts in the NUM and STR group compared with the ADV group. It seemed that the first two group had similar pathogenic factor at the genetic level while the driver of disease was basically TP53 mutation for ADV patients at the genetic level.
There was no statistical difference among the OS of the three groups. The clinical outcomes of all three groups are poor, with a 5-year survival rate of less than 15%. Because the lines of NUM and STR group largely overlapped, we combined these two groups to one and compared it with the ADV group. Even though there still was no statistical difference, the survival curve showed that the ADV cases had relatively worse outcome. Our findings were more similar to the 2016 study conducted by Stölzel et al., in which they concluded that HHK AML patients with only numerical changes had an adverse risk [3]. A study conducted by Chilton et al. in 2013 reported that the OS of HHK AML with adverse chromosome abnormalities were significantly worse than those without adverse abnormalities [5]. However, they studied cases from 1988–2009 and they did not mention the influence of HSCT while we found that HSCT could significantly improve the OS of HHK AML patients (p < 0.001). Our cases were more recent and probably had higher HSCT rate, which may increase the prognosis and decreased the differences of OS between the two groups.
Furthermore, we found that both in all patients and in NUM patients only, cases harboring 49–50 chromosomes had a significantly better OS than those with ≥ 51 chromosomes (P = 0.033). Although patients with only numerical changes were classified into the intermediate risk group, we found that the prognosis of NUM cases was similar to STR and ADV case. Moreover, NUM cases with ≥ 51 chromosomes had a worse outcome than those with 49–50 chromosome, indicating heterogeneity among these patients, and they may not be generally classified into the intermediate risk group. The UK National Cancer Research Institute Adult Leukaemia Working Group defined ≥ 4 aberrations as a cut-off of poorer outcomes in CK AML [3].We defined that ≥ 51 chromosomes, which means ≥ 5 chromosome gains, as a cut-off of worse outcomes for HHK AML, which to some extent compensated for the previously defined cut-off for CK AML.