Background
Methods
Study design and patient population
Clinical end points and response criteria
Detection of somatic mutations in AML
Statistical analysis
Results
Clinical characteristics and follow-up
Clinical features | Total (n = 870) | R882 wild-type (n = 796) | R882 mutation (n = 74) | P value |
---|---|---|---|---|
Agea, years | 42 ± 15 | 41 ± 15 | 48 ± 11 |
6.64 × 10
−6
|
Age ≥ 60 years, n (%) | 103 (11.84) | 94 (11.81) | 9 (12.16) | 0.928 |
Male, n (%) | 476 (54.71) | 443 (55.65) | 33 (44.59) | 0.068 |
FAB classification, n (%) | ||||
M2 | 445 (51.15) | 428 (53.77) | 17 (22.97) |
3.99 × 10
−7
|
M4 | 180 (20.69) | 162 (20.35) | 18 (24.32) | 0.420 |
M5 | 173 (19.89) | 139 (17.46) | 34 (45.95) |
4.31 × 10
−9
|
Other subtypes or undetermined | 72 (8.28) | 67 (8.42) | 5 (6.76) | |
Parameters at diagnosisa | ||||
WBC count, ×109/L | 39.19 ± 62.25 | 37.56 ± 62.48 | 56.72 ± 57.27 |
0.012
|
RBC count, ×1012/L | 2.32 ± 1.53 | 2.32 ± 1.58 | 2.25 ± 0.66 | 0.710 |
Hemoglobin, g/L | 73.48 ± 21.11 | 73.45 ± 21.50 | 73.82 ± 16.36 | 0.858 |
Platelets count, ×109/L | 58.21 ± 83.94 | 55.99 ± 84.15 | 82.71 ± 78.02 |
0.010
|
Neutrophil count, ×109/L | 12.69 ± 32.04 | 12.53 ± 32.67 | 14.45 ± 24.10 | 0.630 |
LDH, U/L | 555.17 ± 694.61 | 553.00 ± 713.95 | 578.29 ± 441.34 | 0.771 |
Bone marrow blasts, % | 64.23 ± 21.40 | 63.97 ± 21.50 | 67.08 ± 20.19 | 0.244 |
Risk stratificationsb, n (%) | n = 759c | n = 696 | n = 63 | |
Intermediate risk | 384 (50.59) | 355 (51.01) | 29 (46.03) | |
Low risk | 202 (26.61) | 190 (27.30) | 12 (19.05) | 0.467d |
High risk | 173 (22.79) | 151(21.70) | 22 (34.92) | 0.051d |
FLT3-ITD, n (%) | n = 733c | n = 670 | N = 63 | |
Negative | 637 (86.90) | 591 (88.21) | 46 (73.02) | |
Positive | 96 (13.10) | 79 (11.79) | 17 (26.98) |
0.001
|
Karyotype, n (%) | n = 789c | n = 721 | n = 68 | |
Normal cytogenetics | 479 (60.71) | 425 (58.95) | 54 (79.41) | |
Non-normal cytogenetics | 310 (39.29) | 296 (41.05) | 14 (20.59) |
0.001
|
HSCT, n (%) | 161 (18.51) | 151 (18.97) | 10 (13.51) | 0.248 |
Chemotherapy cycles | Total CR/n (%) | R882 wild-type CR/n (%) | R882 mutation CR/n (%) | OR (95% CI) | P value |
---|---|---|---|---|---|
One cycle | 357/864 (41.32) | 336/791 (42.48) | 21/73 (28.77) | 1.829 (1.081–3.094) |
0.023
|
Two cycles | 601/864 (69.56) | 556/791 (70.29) | 45/73 (61.64) | 1.472 (0.897–2.417) | 0.124 |
Comparison of clinical features between DNMT3A R882 mutation groups
Comparison of response to induction chemotherapy according to DNMT3A R882 mutant status
Influence of DNMT3A R882 mutations on chemosensitivity to anthracyclines
Induction cycles | Anthracyclines | Total CR/n (%) | R882 wild-type CR/n (%) | R882 mutation CR/n (%) | OR (95% CI) | P value |
---|---|---|---|---|---|---|
First cycle | Aclarubicin | 95/187 (50.80) | 92/173 (53.18) | 3/14 (21.43) | 4.165 (1.122–15.451) |
0.022
|
Daunorubicin | 28/84 (33.33) | 27/78 (34.62) | 1/6 (16.67) | 2.647 (0.294–23.821) | 0.653 | |
Idarubicin | 90/203 (44.33) | 83/183 (45.35) | 7/20 (35.00) | 1.541 (0.589–4.041) | 0.376 | |
Mitoxantrone | 114/287 (39.72) | 107/264 (40.53) | 7/23 (30.43) | 1.558 (0.620–3.915) | 0.343 | |
Pirarubicin | 21/74 (28.38) | 20/69 (28.99) | 1/5 (20.00) | 1.633 (0.172–15.524) | 1.000 | |
First or second cycle | Aclarubicin | 243/379 (64.12) | 229/349 (65.62) | 14/30 (46.67) | 2.181 (1.030–4.619) |
0.038
|
Influence of DNMT3A R882 mutations on AML prognosis
Variables in the model | Overall survival (n = 870) | Disease-free survival (n = 688) | ||
---|---|---|---|---|
HR (95% CI) | P value | HR (95% CI) | P value | |
DNMT3A R882 mutations | 1.725 (1.221–2.437) |
0.002
| 1.694 (1.114–2.577) |
0.014
|
Age, years | 1.018 (1.010–1.026) |
7.47 × 10
−6
| 1.005 (0.997–1.014) | 0.229 |
WBC count, ×109/L | 1.002 (1.001–1.004) |
0.007
| 1.002 (1.000–1.004) | 0.051 |
Platelets count, ×109/L | 0.997 (0.995–0.999) |
0.011
| 0.999 (0.997–1.001) | 0.159 |
Risk stratifications |
6.80 × 10
−22
|
9.13 × 10
−7
| ||
Low vs. intermediate | 0.681 (0.512–0.907) |
0.009
| 0.693 (0.522–0.920) |
0.011
|
High vs. intermediate | 2.729 (2.146–3.469) |
2.53 × 10
−16
| 1.794 (1.323–2.433) |
1.68 × 10
−4
|
Effect of DNMT3A R882 mutation allele ratio on prognosis of AML
Variables in the model | Overall survival (n = 74) | Disease-free survival (n = 51) | ||
---|---|---|---|---|
HR (95% CI) | P value | HR (95% CI) | P value | |
DNMT3A R882 mutation ratio, % | 1.029 (0.998–1.061) | 0.066 | 1.026 (0.990–1.063) | 0.159 |
Age, years | 1.047 (1.006–1.090) |
0.025
| 1.031 (0.984–1.081) | 0.197 |
WBC count, ×109/L | 1.005 (0.999–1.010) | 0.088 | 1.005 (0.998–1.012) | 0.171 |
Platelets count, ×109/L | 0.999 (0.995–1.003) | 0.757 | 1.001(0.996–1.005) | 0.709 |
Risk stratification |
0.027
|
0.032
| ||
Low vs. intermediate | 1.055 (0.362–3.075) | 0. 921 | 0.618 (0.185–2.071) | 0.436 |
High vs. intermediate | 2.758 (1.288–5.904) |
0.009
| 3.351 (1.183–9.494) |
0.023
|