Prior treatment of patients with therapy-related myeloid neoplasms (t-MNs) with lenalidomide was associated with TP53 mutations, and these mutations were selected for by lenalidomide treatment of hematopoietic stem and progenitor cells (HSPCs) in animal models, according to the results of a study published in the journal Blood.
“Uncovering the exposure relationships that provide selective advantage to specific clonal hematopoiesis (CH) mutations is critical to understanding the pathogenesis and etiology of t-MNs,” the authors wrote in their report.
The study retrospectively evaluated data from 416 patients who were treated with lenalidomide prior to their t-MN diagnosis. Of these patients, 60% had myelodysplastic syndrome (MDS) and the remaining had acute myeloid leukemia (AML). The previous malignancy was nonhematologic or nonmyeloid hematologic in 63% and 37% of patients, respectively. There were 15% of patients whose primary malignancy was still active.
There were 85% of patients with at least 1 gene mutation, with the most common being TP53 in 37%, PPM1D in 19%, TET2 in 16%, DNMT3A in 15%, RUNX1 in 13%, ASXL1 in 13%, and SRSF2 in 10%. Of the TP53 mutations, 61% of cases demonstrated multi-hit changes.
Compared with 1021 patients with AML or MDS who did not have prior chemoradiotherapy exposure, patients in the t-MN cohort demonstrated a greater frequency of TP53 and PPM1D mutations.
Prior exposures were associated with specific genomic alterations. TP53 mutations were significantly associated with prior exposure to proteosome inhibitors (OR, 3.06; 95% CI, 1.52-6.15; FDR =.025) and thalidomide analogs, which primarily included lenalidomide (OR, 2.62; 95% CI, 1.36-5.05; FDR =.035). Exposure to platinum agents was significantly associated with complex karyotype (odds ratio [OR], 1.88; 95% CI, 1.23-2.89; FDR =.052), both alkylating agents (OR, 1.64; 95% CI, 1.08-2.49; FDR =.057) and platinum agents (OR, 1.65; 95% CI, 1.06-2.57; FDR =.057) were associated with chromosome 7 alterations.
In a mouse study, HSPCs treated with lenalidomide demonstrated selection of Trp53-mutated cells, but not other CH mutations. Furthermore, pomalidomide treatment did not select for Trp53 mutants.
The authors concluded that “these findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.”
Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.