Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group

Abstract

Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.

Graphical abstract

Figure 1.

Cytogenetics and fusion proteins in pediatric AEL versus other pediatric AMLs. Compared with all other centrally reviewed AMLs, AEL had fewer cytogenetic abnormalities of inv(16)/t(16;16), t(8;21), monosomy 7, and 11q23 abnormalities (the last being statistically significant). However, AEL was enriched in NUP98 fusions compared with the other subtypes of AML (analyzed from the AAML1031 cohort).

Figure 2.

Cytogenetic and molecular features of AEL. Cases are separated according to morphology of PEL and erythroid/myeloid subtypes, with 2017 WHO classification used for MDS and AML. *2017 WHO classification could not be determined, as the total percentage of myeloid blasts in all cells (not just nonerythroid cells) was not recorded. PM, point mutation; x, not performed.

Figure 3.

Kaplan-Meier curves. OS (A) and EFS (B) according to morphologic subtype. All other centrally reviewed leukemias were compared with the AEL of the pure erythroid subtype and the AEL of the erythroid/myeloid subtype. As shown, cases with PEL subtype had a significantly worse OS and EFS than those of the erythroid/myeloid subtype. OS (C) and EFS (D) of AEL cases according to the presence or absence of NUP98 fusion.