Challenges of Interpreting JAK Inhibitor Data for Real-World Myelofibrosis Care

Bart Scott, MD

Professor, Transplantation Program

Clinical Research Division

Miklos Kohary and Natalia Zimonyi Kohary Endowed Chair

Fred Hutchinson Cancer Center

Seattle, WA

Targeted Oncology: What limitations and key takeaways do you see regarding trials of different Janus kinase (JAK) inhibitors in patients with myelofibrosis?

BART SCOTT, MD: MOMENTUM [NCT04173494] didn’t have overall survival [OS] as an end point. It had total symptom score as its [primary] end point. PERSIST-2 [NCT02055781] was a subset analysis from a small number of patients. So although I believe the data support the use [of pacritinib (Vonjo)], if you look at the spleen volume responses in PERSIST-2, you’re talking about 31 vs 32 patients.¹ That’s a pretty [small] dataset. This is in the patients with a platelet count of less than 50,000/μL. It’s a limited data set from PERSIST-2 [whereas we have] much more robust data in the COMFORT-I [NCT00952289] and COMFORT-II [NCT00934544] trials [for ruxolitinib (Jakafi)].

I agree [with using pacritinib in patients with low baseline platelet count], but that’s because I think [physicians] suboptimally dose ruxolitinib. But patients also have to be alive in order for them to benefit. If somebody dies from bleeding, then of course they’re not going to benefit from JAK inhibitor therapy.

What is the significance of the OS data for ruxolitinib?

Both COMFORT-I and COMFORT-II had OS as a secondary end point, and it was recorded in the initial abstracts. Part of the issue with analyzing OS in both COMFORT-I and COMFORT-II is that the crossover rates after 24 weeks was very high in both. Critics of these survival [data] say “We’re basically looking at ruxolitinib early vs ruxolitinib late.” But still, they are able to show a survival benefit in the patients initially randomly assigned to ruxolitinib.²

How do you transition patients with declining platelet count from ruxolitinib to pacritinib? Is tapering required?

That truthful answer to the question is we don’t know. For the PAC-203 trial [NCT03165734], we did taper ruxolitinib, and we had a 2-week washout. Part of the problem with doing clinical trials…is that they don’t reflect what happens in the real world. In the real world, it would be inappropriate for someone to say, “I’m going to stop the medication that’s [partially] working for you, but it’s not so great, and then come back 2 weeks later, we’ll see what happens.” Because if you stop ruxolitinib, what do you think’s going to happen to their spleen? It’s going to start growing [as a rebound].

I’m not going to pretend that I know what the right answer is. I can only tell you about my anecdotal experience. But I have a lot of patients whom I cared for in PAC-203, and we were a good enroller for that study. PAC-203 was a follow-up for PERSIST-2 to determine the appropriate dose. We [enrolled patients in] PERSIST-2 as well. All those studies required a 2-week washout period of ruxolitinib. What I found is that as I tapered the ruxolitinib, there were a lot of patients who [told me], “Now that you’ve brought me down to 5 mg twice a day, I don’t want to come off ruxolitinib. Please put me back up on the higher dose.” That’s my anecdotal experience. Expert opinion is broad and differential in regard to this. I think it’s better to taper because a lot of patients who are saying that the ruxolitinib isn’t working for them anymore, once they start to taper [say] "Put me back on that drug.”

_References:

_{1. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818}

_{2. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7}