Targeting JAK2 in Myeloproliferative Neoplasms - Episode 9

Alternative Dosing and JAK Inhibitors in the Second-Line Setting

Alternative dosing schedules and the use of JAK inhibitors for patients with MPNs in the second-line setting are explored.

Srdan Verstovsek, MD: The EXPAND study was published recently, as an update, and it seems that you can provide good benefit by an alternative dosing regimen, different than what is on the label. You start with 5 mg twice a day, that is what the label says. Then, you go 10 mg if you can. Hardly anybody can go higher because you do get some degree of myelosuppression, but with 10 mg twice a day you get good control of the spleen—it is not optimal but there is some control—so you do get good control of the quality of life. Improvement of quality of life is achieved. Perhaps it does not last as long in patients with high platelets because of the lower dose, but it is valuable to an extent. With fedratinib, you can give a full dose, 400 mg, even in patients with low platelets. Again, the question is, why change the standard and have these issues with the toxicity profile? It is a mixed bag here in patients with low platelets.

By the way, now that we are talking about alternative dosing regimens, anemia is the major problem in treatment of patients withJAKinhibitors in general. With ruxolitinib, we know—although there is no guidance on what to do in terms of the dose—that is the leading cause for dose adjustments, and is the leading cause of failing ruxolitinib. There is the potential, and it has been studied in Europe and projected to the public already, that if you do start with the lower dose of ruxolitinib because you are worried the anemia is there, you think you will now need to transfuse the patients, you start with 10 mg twice a day. If you can go from 10 to 15 to 20 to 25 mg—from low to higher—you may get as good, if not better, results than what you get with the standard practice of high to low. Is that not something that, perhaps if it is published, might be endorsed by NCCN [National Comprehensive Cancer Network] Guidelines in the future? I am just thinking out loud. It is friendly to everybody.

Andrew Kuykendall, MD:I think it comes down to practice dynamics, how you follow patients, and with what patients feel comfortable. I think starting at a high dose and not having consistent follow-up runs the risk of profound cytopenias, which you may not be able to control. Many physicians feel more comfortable starting low, but important thing we have always known is the response is very dose dependent. We need to try to make every effort to get to that higher dose. If you are going to start with a low dose, there needs to be a concerted effort to try to get to a higher dose as quickly as possible, as quickly as it can be tolerated. You do not want to just start at 10 mg twice a day for a patient who could tolerate a high dose and push that dose out without giving them a possibility of maximizing their spleen response.

Srdan Verstovsek, MD: Yes, that is a very good point. Quality of life comes first, spleen response second, and then as we said before, that may translate to the survival benefit. We need early intervention and higher doses, perhaps through alternative dosing regimens to optimize the care, not just to think, “Oh, it is not working,” and then move to the second-line setting. In the second-line setting, fedratinib might be the drug of choice. It is even in the NCCN guidelines. The guidelines say to use fedratinib over ruxolitinib as a first-line choice. We discussed this in detail, but in a second-line setting, it says fedratinib should be considered for people with spleen issues and symptoms, and with a good bone marrow reserve, because it does cause some myelosuppression. I think the results of the reanalysis of the JAKARTA2 study support fully its use after ruxolitinib.

Andrew Kuykendall, MD:The JAKARTA2 study has obviously some of the best data we have in the second-line setting for any agent in the post-ruxolitinib setting. Patients were required to be on at least 14 days of ruxolitinib, deemed to have an inadequate response or be intolerant, and then they were able to be treated with fedratinib. I think the interpretation of the study was challenged due to the clinical hold that was put on fedratinib during this process. But the reanalysis—using stringent criteria—does a great job of demonstrating that about 30% of patients were able to get spleen responses, and maybe slightly less were getting symptom responses. This is a really challenging population. I think we know this population historically does very poorly. They have poorer rates of survival. They, for a variety of reasons, do not have many options of therapy. The fact that we have data for a second-line agent with these response rates is really encouraging.

Transcript edited for clarity.