Genetic Abnormalities and Risk Status

The use of molecular profiling alongside cytogenetics is improving our ability to identify mutations that may have prognostic impact and predict response to therapy. Recent advances allow clinicians to distinguish patients with differing outcomes from the large cohort—even those with a normal-karyotype (NK) acute myeloid leukemia (AML) or a miscellaneous cytogenetic abnormality.1

European LeukemiaNet Risk Stratification by Genetics in Non-Acute Promyelocytic Leukemia (APL) AML2*

Risk Category Genetic Abnormality
Favorable t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Biallelic mutated CEBPA
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow‡
Intermediate Mutated NPM1 and FLT3-ITDhigh‡
Wild type NPM1 without FLT3-ITD or with FLT3-ITDlow‡ (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A§
Cytogenetic abnormalities not classified as favorable or adverse
Poor/adverse t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(a21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM(EVI1)
-5 or del(5q); -7; -17/abn(17p)
Complex karyotype,|| monosomal karyotype
Wild type NPM1 and FLT3-ITDhigh‡
Mutated RUNX1#
Mutated ASXL1#
Mutated TP53**

*Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient numbers are available, by specific genetic lesions indicated.
Prognostic impact of a marker is treatment-dependent and may change with new therapies.
Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by area under the curve “FLT3-wild type”; regardless of FLT3 allelic fractions, patients should be considered for bone marrow transplant, though recent studies indicate that AML with NPM1 mutation and FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients should not routinely be assigned to allogeneic hematopoietic-cell transplantation (alloHSCT). FLT3 allelic ratio is not yet pervasively used, and if not available, the presence of an FLT3 mutation should be considered high-risk unless it occurs concurrently with an NPM1 mutation, in which case it is intermediate risk. As data emerge, this measure will evolve.
§The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations.
||Three or more unrelated chromosome abnormalities in the absence of 1 of the World Health Organization (WHO)-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1.

Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding factor [CBF] AML).
#These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes.
**TP53 mutations are significantly associated with AML with complex and monosomal karyotype.

References: 1. Grimwade D, Hills RK. Independent prognostic factors for AML outcome. Hematology Am Soc Hematol Educ Program. 2009:385-395. 2. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.