Biology and clinical use of MDM2 inhibitors in MPN

A review of the biology and clinical use of murine double minute 2 (MDM2) inhibitors for myeloid cancers, including myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML), was published in Leukemia by Al-Ali et al. The review integrates mechanistic foundations of the MDM2–p53 axis, clinical development of MDM2 inhibitors, resistance biology, safety considerations, and future directions for rational combinations and next-generation MDM2 degraders. 

Key data: MDM2 is a central negative regulator of p53 and a convergence point for oncogenic and inflammatory signaling in myeloid malignancies, particularly Janus kinase–signal transducer and activator of transcription (JAK–STAT)-driven MPN. Third-generation MDM2 inhibition in MPN is advancing beyond early clinical validation, with more potent and schedule-flexible agents being developed to deepen spleen and symptom responses and explore potential disease-modifying activity. Siremadlin was evaluated with ruxolitinib in the phase Ib/II ADORE trial (NCT04097821) in patients with myelofibrosis (MF) and suboptimal responses to ruxolitinib. Spleen volume reduction ≥35% (SVR35) was achieved in 30.4% of patients at Week 24, including 60% in the 30 mg cohort, while total symptom score reduction ≥50% (TSS50) was achieved in 21.7%. Navtemadlin has advanced into late-stage MF development through the phase III BOREAS trial (NCT03662126) and ongoing phase III POIESIS trial (NCT06479135). In BOREAS, navtemadlin vs best available therapy (BAT) numerically improved SVR35 (15% vs 5%; p = 0.08) and TSS50 (24% vs 12%; p = 0.05) in JAK inhibitor (JAKi)–relapsed/refractory (R/R) MF. Safety considerations focus on managing mechanism-driven Grade 3–4 cytopenias and gastrointestinal (GI) toxicity.  

Key learning: MDM2 has emerged as a biomarker-driven therapeutic target in MPN through its effects on p53 suppression and JAK–STAT signaling. Optimized dosing, rational combination strategies, and monitoring for cytopenias, GI toxicity, and clonal evolution will be important in defining its future role in clinical practice.