Background
Amplification of mouse double minute 2 (MDM2) is a recurrent genetic alteration in p53-wild type tumors, leading to MDM2 overexpression and suppression of p53 function. Inhibition of MDM2 is therefore a promising anti-cancer strategy in these tumors and is under active investigation across a spectrum of malignancies. A major barrier to the development of MDM2 inhibitors is their associated myelosuppression, and while clinical studies have shown that these cytopenias can be mitigated through intermittent dosing strategies, it is unclear whether there are long-term consequences of this toxicity.
Case Discussion
We report the case of a 51-year-old female with MDM2-amplified, TP53-wild type adenoid cystic carcinoma who was treated with an MDM2 inhibitor and developed pancytopenia on treatment that persisted despite drug discontinuation. Her pancytopenia was associated with the presence of 20 distinct pathogenic TP53 mutations, detectable in peripheral blood and bone marrow but notably absent in drug-resistant tumor tissue. Plasma TP53 mutations were similarly detected in 4 other patients treated with an MDM2 inhibitor at our institution, with the number of mutations correlating strongly with duration of treatment.
Conclusion
This case suggests that MDM2 inhibitors are associated with TP53 clonal hematopoiesis, which may confer a risk of subsequent myeloid malignancy. As multiple clinical trials of MDM2 inhibitors are ongoing, our findings underscore the need for further investigation into the potential long-term deleterious effects of these inhibitors in the hematopoietic stem and progenitor compartment.