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Ruxolitinib, a selective inhibitor of Janus kinase 1/2 (JAK1/2), has proven to be beneficial to patients with Philadelphia-chromosome negative myeloproliferative neoplasms (MPN), in reducing spleen size and improving constitutional symptoms. However, 51% of patients discontinue therapy due to suboptimal response, disease progression, or anemia within 3 years after start. For this reason, there is a clinical need for treatment strategies to enhance tolerability and efficacy of ruxolitinib.
Somatic mutations in the JAK2, MPL, or CARL genes lead to the aberrant activation of JAK-STAT signaling, which is considered a hallmark in MPN. This in turn, results in the dysregulation of key downstream pathways, ultimately increasing the expression of cell cycle mediators such as CDC25A and the PIM kinases; thus, contributing to MPN pathogenesis.
A recent preclinical study by Raajit K. Rampal and colleagues investigated the therapeutic efficacy of a triple combination of ruxolitinib, the PIM kinase inhibitor PIM447, and the CDK4/6 inhibitor LEE011 in patients with MPN.1 We hereby provide a summary of the key results.
For the UKE-1 model:
BaF3-JAK2V617-mutant UKE-1 cell lines were grown.
In murine models of JAK2V617F and MPLW515L-mutant MPN, triple combination therapy (vs ruxolitinib alone if not stated):
Interestingly, disease burden was increased when doses of either LEE011 or PIM447 or all three agents were reduced. There was no significant difference in hemoglobin, hematocrit or platelet counts between ruxolitinib and triple combination in wildtype C57BL/6 mice; however, white blood cell counts were significantly reduced with triple therapy (p < 0.01), indicating limited effects on normal erythropoiesis and megakaryopoiesis.
The triple combination significantly reduced colony formation compared with ruxolitinib (p < 0.05 and p < 0.01 in different panels) in primary MPN patient samples. When investigated in normal human CD34+ cord blood cells, triple combination could significantly reduce colony formation compared with ruxolitinib but could not eliminate it.
Overall, these novel results suggest that the triple mechanism-based combination regimen of JAK1/2, pan-PIM, and CDK4/6 inhibition offers greater efficacy and potentially improved therapeutic responses compared with ruxolitinib monotherapy and ruxolitinib-based doublets for patients with MPN. Combined JAK/PIM/CDK inhibition significantly attenuated polycythemia vera and myelofibrosis disease phenotypes, although it did not fully eradicate the disease during the treatment duration. Notably, this approach could also better control MPN stem cell activity, contrary to JAK inhibition.
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