Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy

Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (n = 371) and showed that EP MDS (n = 67, 18%) are characterized by higher TP53 (multihit TP53: 36% vs 17%, p = 0.004), BCOR and WT1 and lower ASXL1 and SRSF2 mutation frequencies compared to non-EP (NEP) MDS (n = 304, 82%). TP53-mutant variant allele frequencies and allelic states correlated with erythroid population expansions. EP MDS was characterized by 3 genetic subgroups with distinct survival (TP53 mutant: 11.4 months; splicing mutant: not reached; not otherwise specifiable (NOS): 19.5 months, p < 0.001). EP MDS had a higher incidence of leukemic transformation (32% vs 12%, p = 0.040) and worse survival (8.3 months vs not reached, p = 0.041) after HMA-venetoclax therapy among 112 HMA-venetoclax-treated MDS patients. Expansion of erythroid populations during venetoclax failure was observed in 11 (33%) patients. EP MDS had higher BCL-XL expression levels at the RNA and protein levels compared to NEP MDS. These data support the dynamic assessment of erythroid predominance in MDS and warrant evaluation of BCL-XL inhibitors in these patients.