Incorporating cooccurring mutational data into 2017 ELN risk strata
| ELN 2017 category . | Genetic abnormality . | Concurrent mutation frequency . | Protective . | Deleterious . |
|---|---|---|---|---|
| Favorable | t(8;21)(q21;q22.1); RUNX1-RUNX1T1 (7%) | KIT 25%, NRAS ∼20%, cohesin ∼20%, | KIT, FLT3 increase relapse risk, | |
| ZBTB7A ∼20%, ASXL1* ∼10% | NRAS, KRAS decrease relapse risk26 ; cohesin/chromatin modifier genes predict adverse outcomes26 ; cooccurrence of >1 TK/RAS gene increases relapse risk28 | |||
| inv(16)(p13.1;q22)/t(16;16)(p13.1;q22) CBFB-MYH11 (5%) | NRAS 40%, KIT 35%, FLT3 TKD 20%, KRAS 15% | NRAS, KRAS decrease relapse risk26 | KIT/FLT3 increase relapse risk | |
| Cooccurrence of >1 TK/RAS gene increases relapse risk28 | ||||
| NPM1mutFLT3-ITDlow-wt | DNMT3A 50%, FLT3-ITD 40%, cohesin ∼20%, NRAS 20%, IDH1 15%, IDH2 R140 15%, TET2 15% | Cooccurrence of chromatin modifier mutations associated with favorable risk2 | Cooccurrence of NPM1, DNMT3A, FLT3 ITD mutations predicts poor prognosis12 | |
| Biallelic CEBPA(4%) | GATA2∼30%, NRAS∼30%, WT1 ∼20%, CSF3R∼20% | Germ line biallelic CEBPA-mutant patients at significant risk of postremission relapse and donor-derived leukemia33 | ||
| Intermediate | NPM1mutFLT3-ITDhigh | Mutations in chromatin modifiers (STAG2, BCOR, MLLPTD, EZH2, and PHF6) and RNA splicing factors (SRSF2, SF3B1, U2AF1, and ZRSR2) associated with MDS-like disease biology and poor outcome | ||
| NPM1wtFLT3-ITDlow-wt | ||||
| t(9;11)(p21.3;q23.3); MLLT3-KMT2A | ||||
| NOS favorable/adverse | ||||
| Adverse | t(6;9)(p23;q34.1); DEK-NUP214 (1%) | FLT3-ITD ∼70%, KRAS ∼20% | ||
| t(9;22)(q34.1;q11.2); BCR-ABL1 (1%) | ||||
| inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM(EVI1) (1%) | NRAS ∼30%, KRAS ∼15%, PTPN11 ∼20%, SF3B1 ∼20%, GATA2 15%, ETV6 5%, PHF6 ∼15%, BCOR ∼10%, RUNX1 ∼10%, ASXL1 ∼10%, NF1∼10% | |||
| t(v;11q23.3); KMT2A rearranged (4%) | KRAS ∼20%, NRAS ∼20% | |||
| −5 or del(5q); −7; −17/abn(17p) | ||||
| TP53mut or complex/monosomal (≥2 monosomies) karyotype 10% | BRCA1, BRCA2, CHEK2, PALB2 in up to 21% of patients with secondary AML40,41 | |||
| NMP1wtFLT3-ITDhigh | Adverse prognosis mitigated with upfront allo-SCT42,43 | |||
| RUNX1mut* | ||||
| ASXL1mut* |
| ELN 2017 category . | Genetic abnormality . | Concurrent mutation frequency . | Protective . | Deleterious . |
|---|---|---|---|---|
| Favorable | t(8;21)(q21;q22.1); RUNX1-RUNX1T1 (7%) | KIT 25%, NRAS ∼20%, cohesin ∼20%, | KIT, FLT3 increase relapse risk, | |
| ZBTB7A ∼20%, ASXL1* ∼10% | NRAS, KRAS decrease relapse risk26 ; cohesin/chromatin modifier genes predict adverse outcomes26 ; cooccurrence of >1 TK/RAS gene increases relapse risk28 | |||
| inv(16)(p13.1;q22)/t(16;16)(p13.1;q22) CBFB-MYH11 (5%) | NRAS 40%, KIT 35%, FLT3 TKD 20%, KRAS 15% | NRAS, KRAS decrease relapse risk26 | KIT/FLT3 increase relapse risk | |
| Cooccurrence of >1 TK/RAS gene increases relapse risk28 | ||||
| NPM1mutFLT3-ITDlow-wt | DNMT3A 50%, FLT3-ITD 40%, cohesin ∼20%, NRAS 20%, IDH1 15%, IDH2 R140 15%, TET2 15% | Cooccurrence of chromatin modifier mutations associated with favorable risk2 | Cooccurrence of NPM1, DNMT3A, FLT3 ITD mutations predicts poor prognosis12 | |
| Biallelic CEBPA(4%) | GATA2∼30%, NRAS∼30%, WT1 ∼20%, CSF3R∼20% | Germ line biallelic CEBPA-mutant patients at significant risk of postremission relapse and donor-derived leukemia33 | ||
| Intermediate | NPM1mutFLT3-ITDhigh | Mutations in chromatin modifiers (STAG2, BCOR, MLLPTD, EZH2, and PHF6) and RNA splicing factors (SRSF2, SF3B1, U2AF1, and ZRSR2) associated with MDS-like disease biology and poor outcome | ||
| NPM1wtFLT3-ITDlow-wt | ||||
| t(9;11)(p21.3;q23.3); MLLT3-KMT2A | ||||
| NOS favorable/adverse | ||||
| Adverse | t(6;9)(p23;q34.1); DEK-NUP214 (1%) | FLT3-ITD ∼70%, KRAS ∼20% | ||
| t(9;22)(q34.1;q11.2); BCR-ABL1 (1%) | ||||
| inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM(EVI1) (1%) | NRAS ∼30%, KRAS ∼15%, PTPN11 ∼20%, SF3B1 ∼20%, GATA2 15%, ETV6 5%, PHF6 ∼15%, BCOR ∼10%, RUNX1 ∼10%, ASXL1 ∼10%, NF1∼10% | |||
| t(v;11q23.3); KMT2A rearranged (4%) | KRAS ∼20%, NRAS ∼20% | |||
| −5 or del(5q); −7; −17/abn(17p) | ||||
| TP53mut or complex/monosomal (≥2 monosomies) karyotype 10% | BRCA1, BRCA2, CHEK2, PALB2 in up to 21% of patients with secondary AML40,41 | |||
| NMP1wtFLT3-ITDhigh | Adverse prognosis mitigated with upfront allo-SCT42,43 | |||
| RUNX1mut* | ||||
| ASXL1mut* |
Columns 1 and 2 display the revised 2017 World Health Organization guidelines for AML risk stratification, with percentage of total AML cases in each subset in parentheses. Columns 3, 4, and 5 display mutations observed within each subset and their implications.
allo-SCT, allogeneic stem-cell transplantation; MDS, myelodysplastic syndromes; NOS, not otherwise specified; TK, tyrosine kinase; WT, wild type.
Mutations in RUNX1/ASXL1 do not imply adverse outcomes when they cooccur within an otherwise favorable-risk subtype.