Ruxolitinib in PV: The RESPONSE Trial

Jamile Shammo, MD, FASCP, FACP: Let’s move on to ruxolitinib and its role in the treatment of polycythemia vera [PV]. As many know, ruxolitinib is a Janus kinase [JAK] 1 and 2 inhibitors that have been shown to have clinical benefit in patients who have PV in the phase 2 studies. Ultimately, it was evaluated in a phase 3 study: the RESPONSE trial. This was an open-label phase 3 study that took patients who have polycythemia vera who happened to be phlebotomy-dependent and hadn’t had splenomegaly. They also had to be patients who had inadequate response or had unacceptable adverse effects from hydroxyurea. The trial took patients and randomized them to either ruxolitinib or to best available therapy in a 1:1 ratio.

The primary end point of that study was to look at a composite end point of freedom from phlebotomy, as well as 35% or more reduction in spleen volume at week 32. Freedom from phlebotomy was assessed from weeks 8 to 32. Obviously, you had to give the drug at least 8 weeks to kick in, but you were only allowed to have 1 phlebotomy from enrollment to week 8. That’s a set of stringent rules for freedom from phlebotomy. The patients were then allowed to crossover after week 32, and they were then monitored afterwards for the primary end point and many other points: safety, thrombotic events, and progression, of course.

There were over 200 patients who were randomized 1:1. As I’ve said, some went on to ruxolitinib, and the other half went on to best available therapy. Included in that were drugs like pipobroman, anagrelide immunomodulators, or no medications, for that matter. Please note that you need to know that chlorambucil, busulfan, and phosphorus-32 were prohibited.

Symptom assessment forms were also utilized to assess improvement based on hematology. The results were hugely in favor of ruxolitinib in that the composite end point was reached in about 20% of patients who were on ruxolitinib versus 0.9%, and the P value was less than 0.001. Notably, patients who became free from phlebotomy were 60% versus 20% in ruxolitinib versus standard of care, respectively, and also those who had reduction in their spleen volume in ruxolitinib group were 38% versus 0.9%. More importantly, the majority of patients, over 85%, crossed over from best available therapy to the ruxolitinib arm because of lack of efficacy reportedly.

When it comes to the dosing of ruxolitinib, the majority of the patients maintained at least 10 mg BID [twice daily] dosing, and only 10% were on 10 mg or less. For the practicing physician, it’s important to know that most of the dose modifications happened in the first 8 weeks of therapy. It is important when we are starting patients on ruxolitinib to monitor them very closely in the first 8 weeks of therapy. Another piece of information that we need to know is that herpes zoster infections were a bit more prevalent in the ruxolitinib arm: 6% versus a very low percentage. That is something about which we need to be cognizant. We need to monitor those patients.

There is no doubt, in the RESPONSE trial, ruxolitinib was found to be effective in controlling hematocrit, reducing spleen size, and improving symptoms in patients who have PV. In that analysis, it represented a very good option for patients who had intolerance or resistance to hydroxyurea, and this is a group of patients for whom this drug was approved. At that time, we did not have long-term data on this trial, but in 2020, Dr. Jean-Jacques Kiladjian and colleagues reported the long-term efficacy and safety of ruxolitinib versus the best available therapy, and that was published in Lancet Hematology. In that analysis, they gave an overview on the 5-year and final analysis of the RESPONSE trial, demonstrating that patients who were primary responders had a very good chance of sustaining the response. Those who became free from phlebotomy had a 74% chance of maintaining that, and even those who attained hematological remission had a 55% chance of maintaining complete hematological remission at 5 years.

At the 5-year data, you start to want to know about adverse effects and how those patients tolerated this treatment. It appears that anemia seemed to be the most common adverse effect, but even that was mild to moderate in severity. The non-hematological toxicities were lower with long-term ruxolitinib treatment than best available therapy, which was important. Thrombotic events were also lower in the ruxolitinib group than with best available therapy. There was no evidence that people on ruxolitinib had more progression, so that’s also very reassuring. In the analysis of 5-year data from the RESPONSE trial, the authors concluded that ruxolitinib is safe and effective for long-term treatment of patients with PV who are resistant or intolerant to hydroxyurea. That was very reassuring, clearly, for patients with PV who stayed on therapy with this agent.

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