Recent Advancements in Clinical Development for the Treatment of Myelofibrosis

At the 2023 Great Debates & Updates in Hematologic Malignancies conference in New York, New York, John Mascarenhas, MD, Mount Sinai, New York, New York, discussed recent advancements in clinical developments for the treatment of myelofibrosis, highlighting the use of JAK inhibitors.

Transcript: 
 
Hi, I'm John Mascarenhas, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York City. Today I'll be reviewing, in brief, the presentation at the Great Debates and Updates in Hematologic Malignancies in New York City.

The topic is exciting advances in myelofibrosis. Essentially, we reviewed the state-of-the-art, in terms of JAK inhibition, reviewing the data for ruxolitinib, fedratinib, now most recently pacritinib, and the anticipated approval of momelotinib, a JAK1, JAK2, ACVR1 inhibitor, in the summertime of 2023. It affords our patients a variety of different JAK inhibitor options that can be tailored to their particular platelet count and transfusional needs, and this really is an exciting period.

It is not always black and white when one drug may be advantageous over the other. There are certain niches that are obvious, like thrombocytopenia with pacritinib, and perhaps transfusion-dependent anemia with momelotinib. We await to see what that label from the FDA will look like. There's some overlap and redundancy in these drugs in terms of patient populations.

The 2nd part of the talk [reviews] the emerging combination therapy approaches, typically with a JAK inhibitor backbone. Ruxolitinib, plus pelabresib, the BET inhibitor, plus navitoclax, the Bcl-2/xl inhibitor, plus parsaclisib, the PI3 kinase inhibitor, are all exciting combination approaches, in large part trying to capitalize on complementary mechanisms of action that can attain deeper spleen responses, symptom improvement, and hopefully prolonged duration of response with ruxolitinib, either upfront, in JAK inhibitor-naive patients, such as the MANIFEST-2 trial, with pelabresib, or as second line and salvaging, such as the TRANSFORM-2 study with navitoclax.

We talked about non-JAK inhibitor therapeutic agents that are in late-stage development like navtemadlin, the MDM2 inhibitor, for wild-type P53 advanced myelofibrosis patients that have failed ruxolitinib. This is the BOREAS randomized phase 3 registration study. This is a very active drug with very compelling preclinical and phase 2 data.

And then imetelstat, the telomerase inhibitor for our refractory MF patients treated with ruxolitinib previously that are randomized to imetelstat versus best available therapy, which excludes JAK inhibitor with a primary endpoint of overall survival. This is based also on compelling preclinical data and compelling, randomized phase 2 data with imetelstat in this patient population. 

We are quickly seeing the paradigm shift, hopefully shift in a commercial sense, to combination therapies, non-JAK inhibitor-based therapies, and even treatments that are aimed at improving survival.

Lastly, luspatercept, the activin ligand trap, that's approved now most recently in transfusion-dependent MDS, for patients with myelofibrosis on ruxolitinib that have significant anemia and or transfusion dependence. This is based on the phase 2 data that inspired and informed the randomized phase 3 independence study to improve anemia with the subcutaneous injection.

There [are] a lot of different agents in clinical development. It is an exciting time to be in this field. I do think it will translate into advances for patients with myelofibrosis to improve their quality of life, their duration of life, and in some cases, perhaps extend their survival in a meaningful way as well.

That embodies my talk on exciting advances in the field of myelofibrosis. Thank you.

Source: 

Mascarenhas, J. Exciting advances in myelofibrosis. Presented at Great Debates & Updates in Hematologic Malignancies Conference; April 13-15, 2023; New York, NY.