Ruxolitinib Shows Superiority Over BAT in Second-Line, Inadequately-Controlled Polycythemia Vera

Based on 5-year findings from the phase 3 RESPONSE-2 clinical trial, the use of ruxolitinib (Jakafi) as second-line treatment for patients with inadequately-controlled polycythemia vera (PV) without splenomegaly is supported over best available therapy.¹

In the study, ruxolitinib demonstrated superiority vs BAT in terms of hematocrit control, normalizing blood cell counts, and improving PV symptoms at week 28.

“The 5-year results from RESPONSE-2, together with the results from RESPONSE, provide long-term, clinical trial data for ruxolitinib in patients with polycythemia vera. RESPONSE-2 showed that ruxolitinib is effective and well tolerated during long-term treatment, thereby supporting the use of ruxolitinib as the second-line therapy of choice after hydroxyurea in a broad population of patients with polycythemia vera,” wrote the study author lead by Francesco Passamonti, MD of the Università degli Studi dell’Insubria in Varese, Italy.

RESPONSE-2 (NCT02038036) is a prospective, multi-center, open-label, randomized, phase 3b study that evaluated the efficacy and safety of ruxolitinib vs BAT in patients with PV. The study was conducted in 48 hospitals or clinical across Asia, Australia, Europe, and Canada. Patients treated with ruxolitinib in the study received a staring dose of 10 mg twice daily (BID), then based on efficacy and safety, the dose was adjusted to a maximum of 25 mg BID. In the comparator arm, BAT consisted of either hydroxyurea, pegylated-interferon, pipobroman, anagrelide, immunomodulatory imide drugs, or observation. Patients in the BAT arm who did not respond by week 28 were eligible to crossover to the ruxolitinib arm.

In RESPONSE-2, the primary end point was the proportion of patients with hematocrit control at week 28. The key secondary end point investigated during the study was the proportion of patients who achieved complete hematological remission at week 28.

Secondary end points explored during the study included the proportion of patients who achieved durable hematocrit control at week 260, the proportion of patients who achieved durable complete hematological remission at week 260, median hematocrit over time as well as the number of phlebotomies over time. In the study, investigators also looked at several other end points, including change in spleen length, change in ECOG status, the proportion of patients who achieved partial remission, overall survival, event-free survival, symptom improvement, spleen length at week 260, improvements in pruritus, patients’ perception of their health, and safety determined by adverse events (AEs) of special interest.

A total of 149 patients were randomly assigned in RESPONSE-2 to receive either ruxolitinib (n = 74) or BAT (n = 75). Median follow-up in the study was 67 months (interquartile range, 65-70). Overall, 80% of the ruxolitinib arm completed 260 weeks of therapy, while 15 patients discontinued. Among patients in the BAT arm, no patients remained on treated after week 80, and 77% crossover to the ruxolitinib arm.

At baseline, characteristics of patients in both treatment arms were balanced. The population enrolled had a median age of 63 years (range 26-82 years) in the ruxolitinib arm and 67 years (range, 34-87 years) in the BAT arm. The majority of patients were men, including 53% of the ruxolitinib arm and 63% of the BAT arm. Patients in the population predominantly identified as White. Specifically, 91% of the ruxolitinib arm was White vs 88% of the BAT arm.

The average hematocrit level in the ruxolitinib arm at baseline was 43% (range 40%-45%), and white blood cell (WBC) count was 8 x 10⁹ cells per L. Platelets were 296 x 10⁹ platelets per L in the ruxolitinib arm, and 78% of patients had ≥ 2 phlebotomies within 24 weeks prior to screening. In the BAT arm, hematocrit level and WBC counts matched the ruxolitinib arm, but platelet counts were 350 x 10⁹ platelets per L, and 76% of patients had 4 or more phlebotomies within 24 weeks before screening.

Among the 58 patients who crossed over from the BAT arm to the ruxolitinib arm, the hematocrit levels matched the other 2 groups. The WBC count was 9 x 10⁹ cell per L, platelet count was 362 x 10⁹ platelets per L, and 72% of patients in the crossover arm had ≥ 2 phlebotomies within 24 weeks before screening.

Among 97 patients who were treated with ruxolitinib until week 260, 22% (95% CI 13%-33%) achieved hematocrit control. The estimated duration of hematocrit control was not reached (NR) in the study (95% CI, 144 to NR). The 5-year follow-up data also show that the median hematocrit level in the ruxolitinib arm remained below 45%. In terms of phlebotomies, 74 patients treated with ruxolitinib required phlebotomies in 260 weeks compared with 106 phlebotomies among the 75 patients in the BAT arm.

Survival data from the long-term analysis showed a 5-year OS rate of 96% (95% CI, 87%-99%) with ruxolitinib vs 91% (95% CI, 80%-96%) with BAT.

In terms of safety, the most common grade 3/4 AEs in the ruxolitinib arm vs the BAT arm, respectively, were hypertension (2.4% vs 5.6%), thrombocytopenia (0.3% vs 5.6%), and thrombocytosis (0 vs 7.5%). In the ruxolitinib arm, there were exposure-adjusted any-grade thromboembolic events in 5 patients compared with 2 patients in the BAT arm. No deaths related to study treatment were observed during the study.

The data from RESPONSE-2 add to previous findings from the RESPONSE trial (NCT01243944), which demonstrated the efficacy of ruxolitinib in patients with PV. The 2 studies show that there is an option for the roughly 40% of patients with PV who become intolerant or resistant to hydroxyurea, which is a common treatment used in the front-line setting for this patient population.

_REFERENCE:

_{Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Hematol. 2022;9(22):S2352-3026. doi: 10.1016/S2352-3026(22)00102-8}