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T. Kaburagi et al.
Table 3. Univariate and multivariate Cox regression analyses of overall survival and event-free survival.
HR
Overall survival
NF1 4.104 PTPN11 2.027 CBL 2.145 NRAS 0.305 KRAS 1.201 RUNX1-RUNX1T1 0.173 CBFB-MYH11 0.000 Monosomy 7 1.655 Complex karyotype 2.230 FLT3-ITD 3.051 5q– 2.442 FUS-ERG 10.19 NUP98-NSD1 5.232 PRDM16 high expression 3.427
Event-free survival
NF1 1.794 PTPN11 2.142 CBL 1.215 NRAS 0.506 KRAS 0.966 RUNX1-RUNX1T1 0.466 CBFB-MYH11 0.422 Monosomy 7 1.539 Complex karyotype 1.926 FLT3-ITD 2.250 5q– 5.587 FUS-ERG 4.179 NUP98-NSD1 8.056 PRDM16 high expression 2.797
HR: hazard ratio; CI: confidence interval.
Univariate analysis
Multivariate analysis
HR 95%CI
Inferior
1.492 0.880 0.676 0.111 0.379 0.075 0.000 0.522 1.270 1.833 0.339 3.671 2.605 2.203
0.664 1.157 0.387 0.280 0.396 0.306 0.186 0.569 1.222 1.460 1.366 1.533 4.180 1.990
95%CI P-value Superior
11.29 0.006 4.670 0.097 6.800 0.195 0.833 0.021 3.808 0.756 0.398 <0.001
Inf 0.995 5.250 0.392 3.916 0.005 5.076 <0.001 17.60 0.376 28.26 <0.001
10.510 <0.001 5.331 <0.001
4.852 0.249 3.965 0.015 3.813 0.739 0.914 0.024 2.359 0.940 0.708 <0.001 0.956 0.039 4.161 0.395 3.037 0.005 3.469 <0.001 22.86 0.017 11.39 0.005 15.53 <0.001 3.931 <0.001
Inferior 4.109 1.471
0.694 0.260 2.617 0.794 0.309 0.112 2.064 0.618 0.250 0.106 0.000 0.000 2.617 0.781 1.812 0.991 1.853 0.985 1.627 0.207 6.007 2.096 2.941 1.366 1.921 1.165
1.621 0.588 1.239 0.616 1.527 0.471 0.530 0.293 1.084 0.432 0.659 0.420 0.603 0.255 2.275 0.786 1.810 1.111 1.236 0.716 4.441 1.009 3.191 1.144 5.017 2.463 2.172 1.489
Superior
11.48 1.851 8.630 0.849 6.892 0.590 Inf 8.775 3.312 3.486 12.82 17.22 6.331 3.168
4.469 2.494 4.948 0.961 2.725 1.035 1.427 6.589 2.948 2.133 19.54 8.903 10.220 3.167
P-value
0.007 0.466 0.114 0.023 0.239 0.002 0.995 0.119 0.054 0.056 0.644 0.001 0.006 0.010
0.351 0.548 0.480 0.037 0.863 0.070 0.250 0.130 0.017 0.447 0.049 0.027 <0.001 <0.001
Sanger sequencing,6-9 it appears to be lower than that of the recent pediatric report by targeted deep sequencing.1 Next, there were a small number of patients harboring NF1 alter- ations. Further investigation is needed to determine the clinical significance of NF1 alterations in pediatric AML. Since there have been few reports on NF1 alterations, espe- cially in pediatric AML (Online Supplementary Table S5), our results might be valuable for future analysis. Lastly, we could not analyze germline alterations because of the lack of non-hematopoietic cells. Congenital alterations of RAS pathway genes are known as RASopthies predisposing to hematological malignancies.54 Especially for NF1 and CBL, it is difficult to distinguish between somatic and germline mutations because the mutation hotspots overlap. While it is sometimes difficult to diagnose RASopathy because of minor clinical symptoms, patients with distinct clinical fea- tures of AML predisposing diseases, such as neurofibro- matosis, Noonan syndrome, or CBL syndrome were excluded from the AML-05 trial according to its eligibility criteria. Also, we estimated that most of NF1 and CBL mutations might be somatic from online databases and pre- vious reports. Since there have been few reports of detailed
analysis on NF1 and CBL alterations in pediatric AML (Online Supplementary Tables S5 and S6), further analyses are needed.
In conclusion, NF1 alteration is possibly a poor prognos- tic factor and NRAS mutation is a favorable prognostic fac- tor in pediatric patients with AML. Pediatric AML patients with PTPN11 mutations may show a greater tendency for relapse and induction failure. Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel ther- apeutic molecular targets related to this signal transduction pathway.
Disclosures
No conflicts of interest to disclose.
Contributions
TK, GY, NS, and YH designed and performed the research, analyzed the data, and wrote the paper; YHayashi designed the research, led the project, and wrote the paper; KY, YS, SM, and SO performed the research; KT performed the research and bioin- formatics analysis; KO, MS, HA, HM, AS, TTabi, NK, DT, KH,
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haematologica | 2022; 107(3)