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ASH 2020 | Combined navitoclax and ruxolitinib therapy in R/R myelofibrosis

Naveen Pemmaraju, MD, University of Texas MD Anderson Cancer Center, Houston, TX outlines the results of the Phase II study (NCT03222609) of clinical outcomes following navitoclax (Nav), a BCL-xL inhibitor, plus ruxolitinib (Rux) combined therapy in high-risk relapsed/refractory (R/R) myelofibrosis. 34 patients with prior Rux failure and high-molecular-risk (HMR) mutations or high total number of gene mutations were enrolled. The results were promising, and analyses of the combination’s mechanism of action are ongoing. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.

Transcript (edited for clarity)

This is interesting area for development. Navitoclax is a novel agent. It’s oral. It’s a small molecule inhibitor of a pathway known as BCL-xL, so a cousin pathway different from BCL-2 of venetoclax, its cousin drug. So BCL-xL appears to be, in the lab and preclinical studies, a bit more important in myelofibrosis and MPNs, possibly than even the BCL-2 signal which now we know very well across myeloid malignancies...

This is interesting area for development. Navitoclax is a novel agent. It’s oral. It’s a small molecule inhibitor of a pathway known as BCL-xL, so a cousin pathway different from BCL-2 of venetoclax, its cousin drug. So BCL-xL appears to be, in the lab and preclinical studies, a bit more important in myelofibrosis and MPNs, possibly than even the BCL-2 signal which now we know very well across myeloid malignancies. So that’s the preclinical background. And then if you combine BCL-xL inhibition with JAK2 inhibition, again, pre-clinically, it appears that there may be some additive or even synergistic effect against these cells over JAK2 alone.

So with that premise, as a multicenter study, we sent out to investigate patients with myelofibrosis who are already on ruxolitinib JAK inhibitor, having a suboptimal response or failure, stay on the JAK inhibitor, and then we add in the BCL-xL inhibitor, the navitoclax. So it’s a very nice study, two oral agents. So far just over 30 patients have been treated, and we reported on that, but this abstract focuses on the built-in cytokine profile, so cytokine or messenger proteins that are analyzed, and what we found in this study is in-patients who are already having spleen size reductions, symptom benefit, we are seeing several of those patients also having what’s known as cytokine benefit. Some have been known before to correlate with MPN symptom burden benefit, but some are fairly new findings that of course require further ongoing study, other prospective validation. But I think it’s an exciting new aspect of this add-back or combination field of myelofibrosis.

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Disclosures

Naveen Pemmaraju, MD, has received research funding or grant support from Samus Therapeutics, Cellectis, Stemline Therapeutics, AbbVie, Plexxikon, LFB Biotechnologies, Novartis, SagerStrong Foundation, Affymetrix and Daiichi Sankyo; has received honoraria from Roche Diagnostics, Celgene, Stemline Therapeutics, DAVA Oncology, AbbVie, Incyte Corporation, Blueprint Medicines, Novaritis and MustangBio; and has done consultancy work for Pacylex Pharmaceuticals.

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