Targeted Treatments for Myeloproliferative Neoplasms - Episode 10

Novel Therapies Being Investigated in Myelofibrosis


Key opinion leaders provide a comprehensive review of agents under investigation, alone or in combination, in patients with myelofibrosis.


Pankit Vachhani, MD: Now we talked about a wide variety of JAK inhibitors and how to manage, which one to pick, the verse events. Dr Komrokji to discuss some of the novel therapies which are on the horizon for myelofibrosis? And this is a big area. If you can take us through some of these JAK inhibitors as well as non-JAK inhibitors therapies like for example navitoclax. There are many. Would you take us through these?

Rami S. Komrokji, MD:Absolutely. You and I could talk about those for hours. I will try to make it brief hitting some of the highlights for our audience. Maybe we can think of them first other JAK2 inhibitors. Momelotinib which hopefully is on the horizon for approval soon. Momelotinib is a JAK1, JAK2 inhibitor that also have activity against active and receptor or the ACV are that interferes with the hepcidin and could have an anemia response. As you alluded, there's some recent data showing that pacritinib also could affect that receptor. Momelotinib was already tested in simplify 1 and 2 studies but eventually try to highlight is the momentum study that was recently presented. They took patients for a second line after talks of failure that had splenomegaly and anemia. The momentum study showed that momelotinib was superior to danazol. It achieved spleen response, total symptom improvement and probably more importantly for our area that there were like patients that became transfusion independent, hemoglobin increased. In terms of toxicity, it was in general well tolerated. Originally, there were concerns about neuropathy with the momelotinib. In the momentum study, those were not seen. Momelotinib hopefully based on the momentum study is going to get approved and be available for our patients soon. Probably based on the momentum study, it's going to be as a second line for patients particularly with anemia, but I'm sure we're going to see more clinical trials really figuring out the role of momelotinib in MPN patients. Another JAK inhibitor is NS-018 or Ilginatinib. That's an early phase and it's been looked at in patients after other JAK2 failure. Another area is this combination therapy. We're going to have 4 JAK2 inhibitors, but there are efforts to improve still on that by a combination therapy and studies have either looked upfront or in patients that have suboptimal response. And I'm probably going to highlight 2 or 3 of those only given limitation of time. First is Pelabresib. This is the BET inhibitor. It's tested in a study called the Manifest. There are different arms. I think, you know, to highlight probably the up front arm or in patients that have suboptimal response that the addition of pelabresib to ruxolitinib has been demonstrating encouraging activity upfront almost approaching 60%, spleen volume reduction more than 35% or more, well iterated treatment, anemia response as well. And also, in the suboptimal certain responses seen. This is moving now into a phase 3 trial up front. We have the study, it's open. We are accruing patients to that. Navitoclax is a second generation venetoclax, but it's affects the BSL XL that is more important in patients with MPN. Again, similar study looked at patients with sub optimal response. Just published recently in the JCO 30 some patients where there were 20 to 30% responses. Again, some cytopenia response, maybe some change in the fibrosis. Encouraging data in a small-scale study. That also has moved now to a phase 3 up front randomizing patient with navitoclax. Parsaclisib is a PI3 Kinase inhibitor. They had presented data and updating them at Soho. It's also been looked in patients that have sub optimal response to ruxolitinib. It does have activity or returned the activity in patients with low platelets. The activity seems to be a little bit more modest than what's observed with the navitoclax or parsaclisib add on, but we have to see particularly now after failure of upfront combinations, maybe this drug will have role later on. Finally, do we have any options after all JAK2 inhibitor fails? This is obviously an area of unmet need. The group from MD Anderson and our group published that failure in the era before the other JAK2 inhibitor, the survival for those patients is 14 months. There are some studies on going there. Imetelstat a telomerase inhibitor that's been tested in MDS and myelofibrosis had been tested in myelofibrosis originally, you know, particularly in the patients after JAK2 failure. Although the responses were modest, there was a signal of survival advantage where the patients treated with imetelstat had a median overall survival approaching 30 months compared to historical of 15 month or so. Now there is ongoing phase 3 and patients post JAK2 failure with imetelstat which is the only study with overall survival endpoint in patients with myelofibrosis. There are other agents. You've taken the lead on the the MDM2 inhibitor. You just recently published data showing activity. It's been tested in- MDM inhibitors as you alluded have been tested in but they're also tested in myelofibrosis and there is a notion that they could alter the natural history or change fibrosis in the bone marrow as you recently published. The anti-SLAM7 antibody elotuzumab also had been looked at. Other several agents, I tend to think of them in those categories. Other novel JAK2 inhibitors. Momelotinib is the frontrunner for approval. Combination strategies navitoclax collaborative are the frontrunner post JAK2 failure is there. It's an exciting time that we have options on clinical trial to offer our patients more than the standard of care as well.

Transcript edited for clarity.