In discussing the role of ruxolitinib in HU-resistant or intolerant PV, expert Prithviraj Bose, MD, highlights data from the RESPONSE and RESPONSE-2 clinical trials.
Prithviraj Bose, MD: There were 2 trials. One was called RESPONSE, and 1 was called RESPONSE-2. These were very similarly designed trials. The difference is that RESPONSE required patients to have splenomegaly, and RESPONSE-2 was done in patients without splenomegaly. These were phase 3 trials, large trials, done in a hydroxyurea-resistant and -intolerant population. The comparison was with standard therapy or best-available therapy, which ended up being hydroxyurea in a lot of these patients. Even though these were people failing hydroxyurea, many on the best-available-therapy arm got hydroxyurea simply because there aren’t good options in this setting. Of course, crossover was allowed after the primary end point had been assessed. As you might imagine, crossover was complete, with people switching over from the comparator arm to ruxolitinib [Jakafi].
In the RESPONSE trial, the 32-week primary end point, which was a composite of spleen volume reduction of 35% or greater, and hematocrit control to below 45% was achieved in 21% of patients on ruxolitinib and 1% of patients on the standard or best-available-therapy arm. If you broke down the primary end point into its components, then hematocrit control was achieved by 60% of the patients on ruxolitinib and 20% of the patients on the control arm. The spleen volume reduction was achieved by 38% of patients in the ruxolitinib arm and 1% of patients in the control arm.
Some other end points assessed at 32 weeks in this trial included symptom improvement as assessed by the TSS [Total Symptom Score] 50, the 50% or greater reduction in total symptom score. That was achieved by 49% of patients on the ruxolitinib arm and 5% of patients on the standard or best-available-therapy arm. The other end point assessed at this time point was the rate of CHR, or complete hematologic response, control of all 3 blood counts. That rate was 24% for the ruxolitinib patients and 9% for the patients on the control arm.
RESPONSE-2 was a very similar trial done in Europe. The only difference was that the patients didn’t have splenomegaly. The spleen volume reduction of 35% or more was not a relevant end point in this trial. It had remarkably similar results to RESPONSE, where the hematocrit control was 62% for ruxolitinib and 19% for best-available therapy. The complete hematologic response rate was 23% for ruxolitinib and 5% for best-available therapy. The 50% reduction in the TSS was 45% for ruxolitinib and 23% for best-available therapy. The spleen end point isn’t relevant to this trial. We have long-term follow-up from both trials. I’ll mention RESPONSE, which was the first trial. What’s reassuring and quite striking is that the benefit is sustained even at 5 years of follow-up, and no new adverse events show up. I’ll come to the adverse events in a bit. But the probability of maintaining these end points was quite impressive.
Seventy-three percent of patients in the ruxolitinib arm maintained their hematocrit control at 5 years, and 72% maintained that 35% or greater reduction in spleen volume, which is a robust duration of response and sustained response. The median duration of a complete hematologic response was 34 weeks. The probability of maintaining a complete hematologic response at 5 years was 55%. Speaking of adverse effects, 1 thing noticed in the RESPONSE trials were the occurrence of some excess basal cell and squamous cell carcinomas, more in patients with a history of the same. That’s something to be careful about. Another thing is the reactivation of [herpes] zoster, which was seen in about 6% of patients on RESPONSE. In my practice, I’ll give the shingles vaccine to all patients on ruxolitinib. Obviously, the response was very sustained with few discontinuations. In PV, ruxolitinib is much better tolerated from a cytopenia standpoint than in MF [myelofibrosis]. You don’t get the problems with cytopenia leading to interruptions and discontinuations that you might get a bit more of in MF, and that has to do with the disease biology.
Transcript edited for clarity.