Clonal Heterogeneity in the 5q- Syndrome: NPMc+ and p53 Expressing Progenitors Are Insensitive to Lenalidomide Treatment and Expand at Disease Progression

Clonal heterogeneity has not been described in patients with myelodysplastic syndrome (MDS) of the 5q- syndrome subtype, for which lenalidomide has emerged as a highly potent treatment. Interestingly, transformation to acute myeloid leukemia (AML) occurs more frequently in patients without a cytogenetic response to lenalidomide. We describe two patients with classical 5q- syndrome with complete erythroid and partial cytogenetic response to lenalidomide, who evolved to high-risk MDS and AML, respectively, with complex karyotypes including del(5q). Immunohistochemistry of pre-treatment marrow biopsies revealed small fractions of progenitors with aberrant cytoplasmic nucleophosmin (NPMc+) expression and in one patient also a TP53 mutation. Both lesions may induce a state of genomic instability, and represent novel findings in 5q- syndrome. These subclones remained stable during response, but expanded at transformation, suggesting that pre-existing cells with more malignant genotype may be insensitive to lenalidomide and responsible for disease progression. We are currently investigating a larger patient material for the presence of subclones with molecular lesions in order to assess the potential impact on the risk of leukemic evolution.