Evolving Role of JAK Inhibitors in Myelofibrosis and Beyond - Episode 6

Treatment After Ruxolitinib Failure in MPN

December 24, 2019

Rami Komrokji, MD:The other area we probably want to talk about a little: As we have more success treating patients, we are starting to talk also about the era of ruxolitinib failure. Both our institutions have published data on poor outcomes for those patients with a median survival of 14 months or less. Patients acquiring other mutations as their disease progressed. When I think of where we are moving down the road in clinical trials, I think of patients in what we call a primary RUX [ruxolitinib] failure, suboptimal RUX [ruxolitinib] response, and secondary RUX [ruxolitinib] failure. Maybe we can start talking about the suboptimal RUX [ruxolitinib] patients, where I think the trials are heading in the approach of combination therapies with ruxolitinib. I know this is a huge topic that could take a couple of hours to talk about, and you’ve led some of those studies. But can you just highlight some of the novel or exciting compounds for you to be combined with ruxolitinib or other JAK2 inhibitors?

Prithviraj Bose, MD:Suboptimal response to RUX [ruxolitinib] is an emerging concept and has been defined variously in different trials. One definition for example that I like was the 1 used in the parsaclisib trial, which is a PI3 kinase delta inhibitor in which you had to have had ruxolitinib for 6 months and with a stable dose over the preceding 8 weeks. But their spleen had to be bigger than either 10 cm or 5 to 10 cm with active symptoms, which tells you that the patient has had an adequate trial of RUX [ruxolitinib]. But still these problems persist, kind of the idea of suboptimal response.

Yes, there are many combinations being looked at. At the 2019 ASH [American Society of Hematology Congress], there were presentations on the bromodomain inhibitor, CPI-0610, in a trial called MANIFEST. This trial actually had different arms. You could use the drug alone in patients who were already off ruxolitinib. Or you could use it, as you were saying, as an add-on approach in patients deemed to have a suboptimal response to ruxolitinib. These data clearly show that it’s an active drug in terms of spleen, and symptoms, and anemia improvement. This is 1 to watch as the trial matures. They are going to be looking at this drug even in JAK-naïve patients as a combination with ruxolitinib. So that’s kind of a follow-on from the early data in the suboptimal setting.

Also, the first results from the navitoclax study were at ASH 2019, where navitoclax—the BCL-2, BCL-XL inhibitor that, as you know, kind of fell by the wayside a little because of the thrombocytopenia it caused by the on-target inhibition of BCL-XL—might be making a comeback in this space. It’s nice to see it being developed again. This was patients who had 12 weeks of ruxolitinib with suboptimal response, adding the navitoclax to that. And there is some science behind this. JAK2 has more to do with BCL-XL than BCL-2, so there’s a feeling that there’s also biological explanation for why inhibiting BCL-XL may be important. And this saw about a 29% spleen volume reduction at 24 weeks, so again activity was seen, and these are the first results. We’ll see where we go from here.

Rami Komrokji, MD:In practice now, in primary or secondary RUX [ruxolitinib] failure, I think obviously fedratinib is available as a choice for patients if they have like splenomegaly and constitutional symptoms.

Prithviraj Bose, MD:Absolutely.

Rami Komrokji, MD:Are there any novel agents you think will come as second line after JAK2 inhibitors that you’d like to highlight as well?

Prithviraj Bose, MD:Yeah, this is another huge area. There’s Imetelstat, the telomerase inhibitor. You did, both your group and our group, publishing that median survival after RUX [ruxolitinib] discontinuation is 13 to 14 months. However, in the Imetelstat trial, where these were all RUX [ruxolitinib] failure patients, they had a median survival of 30 months in the higher-dose arm. That attracted quite a bit of attention, and I believe later the company also looked at your historical data matched controls from Moffitt [Cancer Center] and showed that that survival advantage held up. That’s very intriguing. I don’t think we have seen something like that in terms of survival in the post—RUX [ruxolitinib] setting.

But then there are others. There is an LSD1 inhibitor now from Imago. It’s called IMG-7289. That has been exciting, and there have been other things looked at as well. Our group had looked at a SMAC [second mitochondrial-derived activator of caspases] mimetic called LCL161 from Novartis. Again, activity was seen with all these strategies. Tagraxofusp, which is the drug approved for BPDCN [blastic plasmacytoid dendritic cell neoplasm] has also been looked in postruxolitinib myelofibrosis. All these are active drugs. The trials are still early, and we have to see where things go.

Transcript edited for clarity.