Biological and clinical influences of NPM1 in acute myeloid leukemia patients with DNMT3A mutations

Figures & data

Table 1 Biological and clinical characteristics

Characteristic	DNMT3A^mut/NPM1^wild, median (range) or n/%	DNMT3A^mut/NPM1^mut, median (range) or n/%	t/χ^2	P
Age (years)	63 (42–81)	57 (21–81)	1.700*	0.095
<60	10/43.5	17/60.7
≥60	13/56.5	11/39.3
Gender			0.440§	0.580
Male	12/52.2	12/42.9
Female	11/47.8	16/57.1
AML FAB subtypes
M0	3/13.0	0	3.880§	0.085
M1	7/30.4	6/21.4	0.539§	0.529
M2	5/21.7	6/21.4	0.001§	1.000
M4	5/21.7	7/25.0	0.075§	1.000
M5	2/8.7	9/32.1	4.104§	0.084
M7	1/4.3	0	1.242§	0.451
Karyotype
Normal	10/43.5	23/85.2	9.628§	0.003
Complex	3/13.0	1/3.7	1.472§	0.322
Trisomy 8	4/17.4	1/3.7	2.585§	0.167
−7/7q	2/8.7	0	2.446§	0.207
Others	4/17.4	2/7.4	1.172§	0.395
Risk (cytogenetics)			3.224§	0.121
Good	0	0
Intermediate	17/73.9	25/92.6
Poor	6/26.1	2/7.4
WBC count (×10^9/L)	14.9 (1.2–202.7)	69.8 (2.6–298.4)	1.948*	0.057
<50	19/82.6	13/46.4
≥50	4/17.4	15/53.6
BM blasts	62 (32–99)	81.5 (41–100)	2.531*	0.015
<70	14/60.9	7/25.0
≥70	9/39.1	21/75.0
PB blasts	32 (0–97)	49 (0–91)	0.692*	0.492
<70	17/73.9	18/66.7
≥70	6/26.1	9/33.3
Relapse	11/47.8	17/60.7	0.847§	0.407
Mutated recurrent genes	6 (2–10)	5 (2–11)	1.569*	0.123
<5	5/21.7	10/35.7
≥5	18/78.3	18/64.3
FLT3			9.785§	0.004
FLT3-ITD	2/8.7	10/35.7
FLT3-TKD	2/8.7	7/25.0
Wild type	19/82.6	11/39.3
IDH2			6.749§	0.014
Mutation	5/21.7	0/0
Wild type	18/78.3	28/100
IDH1			0.506§	0.514
Mutation	6/26.1	5/17.9
Wild type	17/73.9	23/82.1
TET2			4.015§	0.079
Mutation	5/21.7	1/3.6
Wild type	18/78.3	27/96.4
NRAS			0.058§	1.000
Mutation	2/8.7	3/10.7
Wild type	21/91.3	25/89.3
CEBPA			0.599§	0.583
Single mutation	1/4.3	1/3.6
Double mutation	1/4.3	0/0
Wild type	21/91.3	27/96.4
PTPN11			2.618§	0.242
Mutation	0/0	3/10.7
Wild type	23/100	25/89.3
KRAS			0.042§	1.000
Mutation	2/8.7	2/7.1
Wild type	21/91.3	26/92.9
U2AF1			0.599§	0.583
Mutation	2/8.7	1/3.6
Wild type	21/91.3	27/96.4
SMC1A			0.178§	1.000
Mutation	1/4.3	2/7.1
Wild type	22/95.7	26/92.9
SMC3			0.066§	1.000
Mutation	3/13.0	3/10.7
Wild type	20/87.0	25/89.3
RAD21			0.178§	1.000
Mutation	1/4.3	2/7.1
Wild type	22/95.7	26/92.9
HSCT			2.208§	0.166
Yes	13/56.5	10/35.7
Allo-HSCT	11/47.8	8/28.6
Auto-HSCT	2/8.7	2/7.1
No chemotherapy	10/43.5	18/64.3

Notes:

* Student’s t-test.

§ Chi-square test.

Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; FAB, French-American-British classification; HSCT, hematopoietic stem cell transplantation; PB, peripheral blood; WBC, white blood cell.

Figure 1 Mutational spectrum of all genes with >5% mutation frequency.

Note: NPM1 was the most frequently combined mutation gene (n=28, 54.9%), followed by FLT3 (n=21, 41.2%), IDH1 (n=11, 21.6%), TET2 (n=6, 11.8%), SMC3 (n=6, 11.8%), IDH2 (n=5, 9.8%), NRAS (n=5, 9.8%), KRAS (n=4, 7.8%), MT-CYB (n=4, 7.8%), CEBPA (n=3, 5.9%), PTPN11 (n=3, 5.9%), U2AF1 (n=3, 5.9%), SMC1A (n=3, 5.9%), and RAD21 (n=3, 5.9%).

Table 2 Kaplan–Meier analysis for EFS and OS between different biological and clinical character groups

Characteristic	EFS (months)				OS (months)
	DNMT3A^mut/NPM1^wild	DNMT3A^mut/NPM1^mut	χ^2	P	DNMT3A^mut/NPM1^wild	DNMT3A^mut/NPM1^mut	χ^2	P
Age (years)
<60	14.90	8.70	0.019	0.891	21.50	12.00	0.018	0.892
≥60	17.20	2.50	1.863	0.172	8.40	6.30	2.319	0.128
Risk (cytogenetics)
Intermediate	9.30	18.00	0.279	0.598	16.40	10.20	0.330	0.565
Poor	4.00	0.60	2.527	0.112	4.00	0.60	1.232	0.267
WBC count (×10^9/L)
<50	9.30	8.00	0.517	0.472	20.10	10.20	0.677	0.410
≥50	4.00	7.50	1.632	0.201	6.60	7.90	0.739	0.390
BM blasts (%)
<70	9.60	7.80	1.153	0.283	20.20	10.20	1.188	0.276
≥70	5.20	7.50	0.424	0.515	8.10	7.80	0.500	0.479
PB blasts (%)
<70	9.30	8.00	0.091	0.763	17.40	10.20	0.063	0.802
≥70	4.00	5.70	0.072	0.789	6.60	7.50	0.020	0.888
Mutated recurrent genes
<5	8.50	5.30	0.363	0.547	20.20	7.50	0.443	0.506
≥5	8.60	8.20	0.059	0.807	15.80	10.20	0.055	0.815
FLT3-ITD/TKD
Present	4.00	6.90	1.443	0.230	6.60	7.90	1.817	0.178
Absent	9.60	8.00	0.269	0.604	20.10	10.20	0.551	0.458
IDH1
Mutation	4.90	13.80	1.134	0.287	5.20	24.80	1.781	0.182
Wild type	9.30	6.90	1.620	0.203	16.40	7.50	1.910	0.167
HSCT
Yes	14.90	10.20	0.006	0.938	21.50	16.30	0.005	0.942
No	5.90	5.30	0.006	0.940	7.70	6.30	0.071	0.790

Abbreviations: BM, bone marrow; EFS, event-free survival; HSCT, hematopoietic stem cell transplantation; OS, overall survival; PB, peripheral blood; WBC, white blood cell.

Figure 2 Comparison of EFS and OS between different biological and clinical character groups.

Notes: (A and B) EFS and OS of DNMT3A^mut/NPM1^wild vs DNMT3A^mut/NPM1^mut in all of the 51 patients. (C and D) EFS and OS of DNMT3A^mut/NPM1^wild vs DNMT3A^mut/NPM1^mut in 28 patients with chemotherapy. (E and F) EFS and OS of DNMT3A^mut/NPM1^wild vs DNMT3A^mut/NPM1^mut in 23 patients with HSCT.

Abbreviations: EFS, event-free survival; HSCT, hematopoietic stem cell transplantation; OS, overall survival.

Figure 3 Comparison of chemotherapy and HSCT in different mutation groups.

Notes: (A and B) EFS and OS of all the 51 patients. (C and D) EFS and OS of the 23 patients with DNMT3A^mut/NPM1^wild. (E and F) EFS of the 28 patients with DNMT3A^mut/NPM1^mut.

Abbreviations: EFS, event-free survival; HSCT, hematopoietic stem cell transplantation; OS, overall survival.

Figure 4 Influences of FLT3-ITD/TKD to the cohort.

Notes: (A and B) EFS and OS of DNMT3A^mut/FLT3^wild/NPM1^wild vs DNMT3A^mut/FLT3^mut/NPM1^mut vs DNMT3A^mut/FLT3^mut/NPM1^wild; P1 for comparison between DNMT3A^mut/FLT3^wild/NPM1^wild and DNMT3A^mut/FLT3^mut/NPM1^mut; P2 for comparison between DNMT3A^mut/FLT3^wild/NPM1^wild vs DNMT3A^mut/FLT3^mut/NPM1^wild.

Abbreviations: EFS, event-free survival; OS, overall survival.