Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically

Complex karyotype (CK) with ≥3 abnormalities is detected in 10-12% of patients with acute myeloid leukemia (AML) and associated with poor prognosis. The most common unbalanced abnormalities found in CK result in loss of material from the 5q, 7q and/or 17p chromosome arms. The presence of 5q, 7q and/or 17p abnormalities denotes typical CK and their absence denotes atypical CK. Since molecular features of CK-AML are not well-characterized, we investigated mutational status of 81 leukemia/cancer-associated genes in 160 clinically well-characterized patients. They included 136 patients with ≥3 exclusively unbalanced chromosome abnormalities, 96 of whom had a typical CK and 40 atypical CK, and 24 patients with ≥1 balanced abnormality in addition to ≥2 unbalanced ones. Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P<0.001) and more often PHF6 (P=0.008), FLT3-TKD (P=0.02), MED12 (P=0.02) and NPM1 (P=0.02) mutations. They were younger (P=0.007), had higher WBC (P=0.001) and percentages of marrow (P<0.001) and blood (P=0.006) blasts, higher complete remission rates (P=0.02) and longer overall survival (P<0.001), thus indicating that atypical and typical CK-AMLs constitute distinct disease subtypes. We also identified smaller patient subsets within both typical and atypical CK-AML that differed molecularly and clinically.