Table 4.
Studies reporting clinical outcome of karyotypically normal AML patients according to the NPM1 mutational status
| Prognostic significance | Independent prognostic factor on MVA | AML type | No. of pts (no. with/no. without alteration)* | Age range, y (median) | Median follow-up | Differences in pretreatment features | Source |
|---|---|---|---|---|---|---|---|
| Cytoplasmic localization of NPM1 vs nucleolar localization of NPM1 | |||||||
| CR rate: no significant difference in univariable analysis (77% vs 62%): independent favorable prognostic factor for CR achievement (odds ratio 2.98, CI: 1.2-7.43; P = .019) | Yes | De novo | 126 (79/47) | 19-60 (52/42)† | NA | Older age | Falini et al12 |
| NPM1+ versus NPM1− | |||||||
| CR rate: significantly higher in NPM1+ pts (70.5% vs 54.7%; P = .003) | ND | De novo (93%), secondary (7%) | 401 (212/189) | 17-82 (56/58)† | 484 d | More often women; higher WBC; lower CD34, CD133, and MPO expression | Schnittger et al21 |
| OS: no significant difference (1012 vs 549 d) | — | 401 (212/189) | |||||
| EFS: significantly longer (median, 428 vs 336 d; P = .012). | Yes | 401 (212/189) | |||||
| RFS: no significant difference (median, 473 vs 386 d) | — | 226 (136/90) | |||||
| OS: no significant difference | — | De novo (86%), secondary (8%), unknown (6%) | 300 (145/155) | 16-60 (NR) | 46 mo | More often women, higher WBC, higher platelet counts, higher LDH, higher percentage of BM blasts, more FAB M4/M5, more extramedullary, involvement and lymphadenopathy, lower CD34 expression | Döhner et al79 |
| RFS: significantly longer for NPM1+ pts (P = .002) | NR | 217 (111/106) | |||||
| CR rate: no significant difference (86% vs 88%) | — | De novo | 106 (50/56) | 17-65 (43/46)† | NR | Higher WBC, more FAB M4/M5, less FAB M0, and less common CEBPA mutations | Boissel et al37 |
| OS: no significant difference (6-year OS rates, 43% vs 37%) | No | 106 (50/56) | |||||
| EFS: no significant difference (6-year EFS rates, 32% vs 26%) | No | 106 (50/56) | |||||
| RFS: no significant difference (6-year RFS rates, 47% vs 34%) | — | 92 (43/49) | |||||
| OS: no significant difference | — | De novo and secondary | 658 (298/360) | 15-87 (NR) | 20.2 mo‡ | More often women, lower CD34 expression‡ | Thiede et al47 |
| DFS: significantly longer for NPM1+ pts (P = .043) | NR | 301 (166/135) | |||||
| CR rate: significantly higher in NPM1+ pts (86.4% vs 64.3%; P = .037) | Yes | De novo | 79 (37/42) | 15-85 (58/47)†§ | NR | Older age, higher WBC, higher percentage of PB blasts, less FAB M2§ | Suzuki et al81 |
| OS: no significant difference | No | 79 (37/42) | |||||
| RR: significantly higher in NPM1+ pts (P = .032) | Yes | 59 (32/27) | |||||
| NPM1+/FLT3-ITD− versus NPM1+/FLT3-ITD+ versus NPM1−/FLT3-ITD+ versus NPM1−/FLT3-ITD− | |||||||
| CR rates: a significant difference according to the NPM1 and FLT3-ITD mutational status (86% vs 63% vs 76% vs 68.5%; P < .001) | Yes‖ | De novo (86%), secondary (8%), unknown (6%) | 300 (86/59/38/117)¶ | 16-60 (49/47/43/49)¶ | 46 mo | WBC, LDH, percentage of PB and BM blasts highest in NPM1+/FLT3-ITD+ pts, WBC, LDH, percentage of PB and BM blasts lowest in NPM1−-/FLT3-ITD− pts | Döhner et al79 |
| OS: significantly longer for NPM1+/FLT3-ITD− pts compared with the 3 other groups (P = .001) | Yes‖ | 300 (86/59/38/117)¶ | |||||
| RFS: significantly longer for NPM1+/FLT3-ITD− pts compared with the 3 other groups (P < .001) | Yes‖ | 217 (74/37/28/78)¶ | |||||
| CR rate: a significant difference according to the NPM1 and FLT3-ITD mutational status (61% vs 52.8% vs 50% vs 42.1%; P < .001) | NR | De novo and secondary | 709 (182/142/76/309)¶ | 15-87 (NR) | 20.2 mo‡ | NR | Thiede et al47 |
| OS: significantly longer for NPM1+/FLT3-ITD− pts compared with NPM1+/FLT3-ITD+ (P = .001) NPM1−/FLT3-ITD+ (P = .032) and NPM1−/FLT3-ITD− (P = .03) pts | Yes‖ | 658 (169/129/70/290)¶ | |||||
| DFS: significantly longer for NPM1+/FLT3-ITD− pts compared with NPM1+/FLT3-ITD+ (P = .04), NPM1−/FLT3-ITD+ (P < .001), and NPM1−/FLT3-ITD− (P = .04) pts | Yes‖ | 301 (103/63/31/104)¶ | |||||
| CR rate: no significant difference (68.8% vs 57.7% vs 68.9% vs 60.2%) | — | De novo | 352 | < 60 (NR) | 20.2 mo‡ | NR | Thiede et al47 |
| OS: significantly longer for NPM1+/FLT3-ITD− pts compared with NPM1+/FLT3-ITD+ (P = .003) and NPM1−/FLT3-ITD− (P = .02) pts; no difference between NPM1+/FLT3-ITD− and NPM1−/FLT3-ITD+ pts | Yes‖ | 359 (74/95/46/144)¶ | |||||
| DFS: significantly longer for NPM1+/FLT3-ITD− pts compared with NPM1+/FLT3-ITD+ (P = .02), NPM1−/FLT3-ITD+ (P < .001) and NPM1−/FLT3-ITD− (P = .006) pts | Yes‖ | 204 (43/67/26/68)¶ | |||||
| CIR: significantly reduced for NPM1+/FLT3-ITD− pts compared with the 3 other groups (40-mo CIR 25% vs 57.2% vs 51.3% vs 32.7%; P = .004) | NR | 204 (43/67/26/68)¶ | |||||
| NPM1+/FLT3-ITD− versus NPM1−/FLT3-ITD− | |||||||
| OS: significantly longer for NPM1+/FLT3-ITD− pts (median, 1183 vs 601 d; P = .022) | NR | De novo and secondary | 264 (126/138) | 17-82# (NR) | 484 d# | NR | Schnittger et al21 |
| EFS: significantly longer for NPM1+/FLT3-ITD− pts (median, 773 vs 365 d; P = .001) | NR | 264 (126/138) | |||||
| NPM1+/FLT3-ITD− versus NPM1+/FLT3-ITD+ | |||||||
| OS: significantly longer for NPM1+/FLT3-ITD− pts (median, 1183 vs 321 d; P = .014) | NR | De novo and secondary | 212 (126/86) | 17-82# (NR) | 484 d# | NR | Schnittger et al21 |
| EFS: significantly longer for NPM1+/FLT3-ITD− pts (median, 773 vs 234 d; P = .001) | NR | 212 (126/86) | |||||
| NPM1−/FLT3-ITD+ versus NPM1+/FLT3-ITD+ | |||||||
| OS: no significant difference (median, 405 vs 321 d) | — | De novo and secondary | 131 (45/86) | 17-82# (NR) | 484 d# | NR | Schnittger et al21 |
| EFS: no significant difference (median, 279 vs 234 d) | — | 131 (45/86) | |||||
| NPM1+/FLT3-TKD+ versus NPM1−/FLT3-TKD− | |||||||
| OS: no significant difference (median, not reached vs 676 d) | — | De novo and secondary | 173 (20/153) | 17-82# (NR) | 484 d# | NR | Schnittger et al21 |
| EFS: significantly longer for NPM1+/FLT3-ITD+ (median, not reached vs 336 d; P = .014) | NR | 173 (20/153) |
MVA indicates multivariable analysis; pts, patients; CR, complete remission; NPM1+, patients with mutations of the NPM1 gene; NPM1−, patients without mutations of the NPM1 gene; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; DFS, disease-free survival; RR, risk of relapse; FLT3-ITD−, patients without FLT3-ITD; FLT3-ITD+, patients with ITD of the FLT3 gene; CIR, cumulative incidence of relapse; FLT3-TKD+, patients with mutations in the tyrosine kinase domain (TKD) of the FLT3 gene; FLT3-TKD−, patients without FLT3-TKD mutations; NA, not applicable; —, no significant difference in univariable analysis (MVA not performed); ND, not done; WBC, white blood cell count; MPO, myeloperoxidase; NR, not reported; LDH, serum lactate dehydrogenase level; BM, bone marrow; FAB, French-American-British; and PB, blood.
Numbers of patients for whom clinical data were available.
Median age of patients with NPM1 mutations/patients without NPM1 mutations.
Number and median follow-up and differences in pretreatment features reported for all 1485 patients, including 709 with a normal, 686 with an abnormal, and 90 with an unknown karyotype.
Age range and median and differences in pretreatment features reported for all 190 patients, including 79 with a normal, 87 with an abnormal, and 24 with an unknown karyotype.
NPM1+/FLT3-ITD− is an independent prognostic factor.
Number and median age of patients with NPM1+/FLT3-ITD−/patients with NPM1+/FLT3-ITD+/patients with NPM1−/FLT3-ITD+/patients with NPM1−/FLT3-ITD−.
Age range and median follow-up reported for all 401 patients studied.