Novel Non-JAK-Inhibitor Therapeutic Options for Patients With Myelofibrosis

Anthony Hunter, MD, Emory University, Atlanta, Georgia, explores options and the use of non-JAK-inhibitor regimens for the treatment of patients with myelofibrosis. 

Transcript:

My name is Anthony Hunter and I'm an assistant professor in the leukemia group here at Winship Cancer Institute of Emory University where I’m particularly focused on myeloproliferative neoplasms. 

I’m speaking a little bit today about non JAK-inhibitor agents that are coming out in myelofibrosis. JAK inhibitors have really been our mainstay for quite some time now, and certainly play a key role in the disease, but we’re really starting to see an emergence now of a number of non-JAK inhibitor therapies, agents targeting novel targets.

Now, none of these necessarily that are specifically approved yet, but a number are in advanced phases of clinical development. So, I can review a couple of these shortly here right now. Probably one of our most advanced right now is pelabresib. This is an agent that inhibits the BET proteins, which are involved in epigenetic regulation and some inflammatory pathways. Pelabresib has been presented at a number of recent meetings, a couple of the ASH conferences as well, showing data there. 

Studies have included patients in monotherapy cohorts after ruxolitinib failure, have included addition of this agent onto suboptimal response to ruxolitinib as well as frontline cohorts. All of them demonstrated some efficacy in those settings, and certainly advanced now onto phase 3 testing. So, we're waiting to see those final results, but certainly a very promising agent both from pre-clinical rationale from this agent, as well as some of the early data that we've seen with the ability to improve on spleen and symptom response rates, and some ability to potentially improve anemia as well.

One of the more difficult problems that we see with a number of this kind of combination approaches potentially is thrombocytopenia. That'll be certainly something to watch for, but certainly an exciting option right now is the emergence of BET inhibitors like this.

Another one that's fairly advanced in clinical testing is Navitoclax, so a BCL-2 as well as BCL-XL inhibitor. This is also demonstrated data already published from the phase 2 and the suboptimal response setting for ruxolitinib. So, ongoing studies that have been in the phase 3 setting for frontline as well as second-line settings. The frontline study has finished enrolling, and waiting to see that final data as well, but it has certainly shown promising early data, again with good pre-clinical rationale, seems to really have the potential to improve on spleen rates as well as symptomatology. And certainly in some of the earlier studies we've seen, it seems to be pretty active in patients with higher molecular risk profiles as well, which is an important feature. These are 2 of the most exciting agents that we have in the non-JAK inhibitor pathway right now.

Another one that's a little bit more unique is imetelstat, which is a telomerase inhibitor. This was studied initially in phase 2 studies and now with an advanced phase 3 study going on as well. A little bit unique here compared to the others, this is a monotherapy study, so looking at this agent not in combination with a JAK inhibitor, and uniquely, and moving the bar in myelofibrosis study is, it's actually looking at survival as the final end point of this study.

Imetelstat really have been looked at and showing some promise in a number of diseases in the myeloid space. It has shown some good data in lower-risk myelodysplastic syndromes (MDS) patients in the ability to improve anemia. Obviously studying here in myelofibrosis where it's shown, I would say modest spleen response rates in early phase studies, but certainly improvements in symptomatology, improvements in anemia, we do see some allele reductions and things as well.

So, really excited to see some of the results from these advanced phase 3 studies that are hopefully going to be reading out in the relatively near future here to see some of these novel options to really move us beyond the JAK inhibitor space and really start to use some of these combination approaches, whether it be in the frontline or second-line setting as well. Beyond these 3, there are a number of other agents targeting multiple pathways in earlier phase studies as well that will be exciting to see as more of these results come out in the future.