Dr Vachhani on the Rationale for Evaluating Navtemadlin Plus Ruxolitinib in R/R Myelofibrosis

"When these 2 drugs are used together, we…get the cell killing function that we derive through TP53 [and] downregulation of the JAK/STAT pathway, [as well as] the typical spleen volume responses and symptom improvements that we see with JAK inhibitor use."

Pankit Vachhani, MD, associate professor, medicine; associate scientist, experimental therapeutics, University of Alabama at Birmingham, discusses the rationale for evaluating the novel MDM2 inhibitor navtemadlin (KRT-232) in combination with ruxolitinib (Jakafi) for patients with relapsed/refractory myelofibrosis.

The TP53 pathway plays a critical role in apoptosis, particularly in myelofibrosis, Vachhani begins. However, this apoptotic pathway is often impaired due to the overexpression of MDM2, a key negative regulator of TP53, he says. MDM2 suppresses TP53 activity through multiple mechanisms, including direct inhibition of its transcriptional activity, nuclear export, and proteasomal degradation, Vachhani details. This dysregulation creates an environment where malignant cells evade apoptosis, contributing to disease progression, he explains. He adds that the upregulation of MDM2 in myelofibrosis provides a strong rationale for targeting this pathway therapeutically.

Navtemadlin is a potent oral MDM2 inhibitor designed to restore TP53 function by preventing its degradation, thereby promoting apoptosis in malignant cells, Vachhani states. Preclinical studies have demonstrated elevated MDM2 levels in myelofibrosis samples, suggesting that MDM2 suppression could be beneficial in this disease setting, he notes.

Furthermore, combining navtemadlin with ruxolitinib, a JAK inhibitor, offers a synergistic approach, Vachhani continues. Although navtemadlin enhances TP53-mediated apoptosis, ruxolitinib downregulates JAK-STAT signaling, contributing to reductions in spleen volume and symptom burden—key therapeutic goals in myelofibrosis management, Vachhani emphasizes. The dual mechanism of action shifts cellular behavior away from cell cycle arrest and toward apoptosis, maximizing the therapeutic benefit and showing potential for improved disease control in patients with myelofibrosis, he concludes.