JAK2 and IRAK1 in Myelofibrosis - Episode 10
Expert hematologist-oncologists comment on the optimization of JAK inhibitor therapies, including ruxolitinib, momelotinib, fedratinib, and pacritinib, in myelofibrosis treatment.
Ruben Mesa, MD: With pacritinib it’s been a very interesting journey, and these most recent studies come from what we learn early on. He clearly saw that the drug is active—spleen symptoms and can be given safely for people with marked thrombocytopenia. We did learn that the optimal dose was probably not the dose we had used in the PERSIST-1 study, but the 200-mg twice a day might be a bit safer and efficacious. With the PAC203 study, from the earliest studies, there was a signal that there was a subset of people with MAC [mycobacterium avium complex] thrombocytopenia who were having issues in terms of bleeding or cardiovascular events. There was a natural question: Was that the drug, comorbidities, or their underlying state with the disease? We learned that it was probably not the therapy but patient selection. There were very high-risk patients, other situations, so we defined a perhaps cleaner group by eligibility of participants, as well as learning optimization in terms of dosing, that 200-mg twice a day was beneficial as we saw in PERSIST-1 and then validated in PAC203.
As the inaugural panel chair for the NCCN [National Comprehensive Cancer Network] Guidelines, I’ve rotated off the committee since then, but we clearly identified that in that group with a platelet count under 50,000 per mm3, we don’t have very good options. Clinically, they receive ruxolitinib off-label typically with fairly homeopathic doses of 5 mg twice a day or 5 once a day, without much success. But there aren’t a lot of options for these folks. The aggregate of this data, including data from the hopefully soon-to-complete accrual and the report out of the PACIFICA study. That will be a natural niche for pacritinib, but the niche will be broader without question. There’s a broader group of individuals with thrombocytopenia who will be a natural consideration. It will set itself up well for any number of potential combinations with other drugs that cause thrombocytopenia. Ruxolitinib and navitoclax have benefit, but thrombocytopenia is an issue with both drugs. It might be more natural fit with pacritinib or other drugs where we see that combination.
As I’m sharing for folks, people ask me at work, “We have 4 drugs approved. Is that too many?” No, not even close. One, patients are heterogeneous. Two, each JAK inhibitor would have its own profile, potential niche, and patients who are optimal responders. I envision it likely that many patients have the question of which JAK inhibitors to start with. How do we optimize that? If that’s not successful, do we add in another drug, or do we adjust the JAK inhibitor? There will be your JAK inhibitor base. Is another drug added? As you’ve mentioned are several, whether it’s bomedemstat, or other agents that have been tested more in isolation, like imetelstat. Would that be helpful in combination? What do you think, John? If all 4 JAK inhibitors are out there—let’s say pacritinib is approved—what are the niches? When do we evaluate patients on their first JAK inhibitor to see whether we should make a change?
John Mascarenhas, MD: I would 100% agree with you in the sense that I’d welcome multiple JAK inhibitors to the commercial space. This is because it gives us opportunity to personalize and tailor the therapy accordingly, whether it’s platelet count or anemia. As I’ve said, there are data that JAK2 V617F VAF [variant allele frequency] may influence decision-making. We’ve seen that the effects of SVR [spleen volume reduction] appear to be constant across the core tiles of JAK2 VAF compared with ruxolitinib. As we go on, we may realize that certain patient profiles may be optimal for certain drugs beyond simply hard platelet counts of 50,000 per mm3. Having multiple agents is great because, as we’ve seen with fedratinib, you can cycle these drugs and salvage responses that may have been suboptimal or lost with the previous JAK inhibitor. The promise of having multiple inhibitors and the potential for a more personalized approach going forward is quite exciting.
Transcript edited for clarity.