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Navtemadlin + ruxolitinib is an investigational combination therapy for myelofibrosis, currently in phase 2 and phase 3 clinical trials. Navtemadlin is an oral, potent, and selective inhibitor of mouse double minute 2 (MDM2), restoring p53 tumor suppressor activity, promoting apoptosis via pro-apoptotic Bcl-2 family proteins in TP53 wild-type myeloblasts. Ruxolitinib is an oral inhibitor of Janus kinase 1 and 2 (JAK1, JAK2), targeting aberrant cytokine signaling involved in myeloproliferative neoplasms. Combined, these drugs target complementary escape mechanisms in myelofibrosis, with preclinical and clinical studies showing synergistic effects, including reduced spleen volume, improved symptom burden, and modulation of p21-driven cell-cycle arrest and anti-apoptotic protein expression[1][2][4][6].
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