Ruxolitinib Effective for Long-Term Treatment of Polycythemia Vera After Hydroxyurea

Ruxolitinib (Jakafi) was found to be safe and effective for long-term treatment of patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (Hydrea), according to the 5-year follow-up data from the phase III RESPONSE trial recently published inThe Lancet Haematology.

“We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population,” the study authors, led by Jean-Jacques Kiladjian, MD, wrote in the published report.

Half of the 222 patients in the study population were randomized to receive ruxolitinib (n = 110), and the other half received the best available therapy (n = 112). The groups had balanced baseline characteristics.

The primary end point of composite response among patients who achieved both hematocrit control without phlebotomy and reduction from baseline in spleen volume by 35% or more was achieved in 23% of patients (n = 25). The probability of maintaining the primary composite response at 5 years was 74% (95% CI, 51%-88%). The primary analysis showed that 60% of patients in the ruxolitinib arm had hematocrit control versus only 19% of patients who received the best available therapy (n = 21). Reduction in spleen size was observed in 40% of patients in the ruxolitinib group (n = 44) and in only 1% of those who received the best available therapy (n = 1).

Progression was defined as having been eligible for phlebotomy and/or progression of splenomegaly. Twenty-four percent (n = 6) out of the 25 primary responders progressed during the study at the time of data cutoff. The duration rate of maintaining primary response at 224 weeks was 74% (95% CI, 51%-88%), but the median duration of primary response was not reached.

At 224 weeks, there was a 55% (95 CI, 32%-73%) duration rate of complete hematological remission. Thirty-eight percent (n = 10) of the 26 patients who had early complete hematological remission progressed by week 256. Progression by week 256 also occurred in 24% of the 66 patients who had hematocrit control by week 32 (n = 16), with a duration rate of hematocrit control of 73% (95% CI, 60%-83%).  

Of the participants in the ruxolitinib arm, 83% of 94 patients were evaluable after week 80 through week 256 and did not require any phlebotomies (n = 78). Six percent of the ruxolitinib patients required 3 or more phlebotomies after week 80 through the time of the week 256 clinic visit.

Crossover from the best available therapy arm to the ruxolitinib arm was allowed. The median time to crossover from best available therapy to ruxolitinib was 34.7 weeks (95% CI, 33.9-35.3). Out of 79 patients total, 87% of those who crossed over to ruxolitinib were evaluable after week 80 through week 256 and remained phlebotomy free, with the exception of 8% who needed 3 or more phlebotomies (n = 6), similar to what was observed with the main ruxolitinib group. Compared to the best available therapy arm, few phlebotomies were needed overall among the ruxolitinib and ruxolitinib-crossover populations.

White blood cell (WBC) counts and platelet counts were measured at baseline. Of the patients who presented with a WBC count greater than 10 × 10⁹/L at baseline, 41% had a WBC count of less than 10 × 10⁹/L at week 256 (n = 36). Additionally, 46% of patients who presented with a platelet count greater than 400 × 10⁹/L at baseline had a reduced platelet count by week 256.

Sixty-four percent of patients had an overall clinicohematological response to treatment. Disease progression occurred in 30% of those patients (n = 21) by week 256.

The study investigators determined that the probability that patients would maintain clinicohematological response was 67% (95% CI, 54%-77%), with the median duration of clinicohematological not reached. The likelihood that patients would maintain at least a 35% reduction in spleen volume at week 224 was calculated to be 72% (95% CI, 34%-91%).

In the ruxolitinib arm, 89% of patients had a 25% reduction in spleen volume, as did 85% of patients who crossed over to ruxolitinib. In the best available therapy arm, only 55% of patients had a 25% reduction in spleen volume.

During the study or the survival follow-up phase, there were a total of 10 deaths in the ruxolitinib group and 8 in the best available therapy group. In the intention-to-treat analysis, excluding the crossover population, the overall survival rate at 5 years per Kaplan-Meir was estimated to be 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group and 91.0% (95% CI, 82.8%-95.4%) in the best available therapy group (HR, 0.95; 95% CI, 0.38-2.41).

Mean allele burden among the 94 patients who presented withJAK2Val617Phe was also monitored in the study. The investigators observed a decrease in the mean allele burden from baseline among patients who were given ruxolitinib. At the time the study was completed, the mean percentage of change from baseline in allele burden was −38% (standard deviation [SD], 38.64; n = 66). Among patients who crossed over to ruxolitinib, the reduction in allele burden was −23% (SD, 40.5; n = 64). Among patients who received the best available therapy, the mean percentage change from baseline in theJAK2Val617Phe allele burden was 1.18 (SD, 25.33; n = 80). Also, according to the Pruritus Symptom Impact Scale, patients in the ruxolitinib group experienced an improvement in quality of life. 

The safety analysis showed that 110 patients in the ruxolitinib arm, 111 in the best available therapy arm, and 98 crossover patients experienced any-grade adverse events (AEs). In the ruxolitinib arm, the most common non-hematologic AEs were pruritus (7.0% per 100 patient-years), diarrhea (7.0%), increased weight (6.1%), and headache (5.8%). In the best available therapy arm, the most common non-hematologic AEs were pruritus (32.6%), headache (28.5%), fatigue (23.1%), and abdominal pain (17.7%), In crossover patients, the most common non-hematologic AEs were pruritus (6.1%), dizziness (6.1%), back pain (5.5%), and hypertension (4.5%). The hematological AEs observed in the study were anemia and thrombocytopenia, which occurred in 8.9% and 4.4% of patients in the ruxolitinib arm, 8.0% and 3.2% of patients in the best available therapy arm, and in 8.8% and 1.2% of patients who crossed over to ruxolitinib, respectively.

The rate of serious AEs per 100 patient-years of exposure was 10.3 in the ruxolitinib group versus 13.6 in the best available therapy group and 13.0 in the crossover population.

The international, multicenter, randomized, open-label RESPONSE study was launched to compare the efficacy and safety of ruxolitinib and the best available therapy in patients with PV. Patients in the study were treated at 109 sites across North America, South America, Europe, and the Asia-Pacific region. As treatment, patients in the experimental arm received ruxolitinib at a starting dose of 10 mg BUD, which could be increased up to 25 mg BID, based on safety and efficacy. In the best available therapy arm, patients received the investigator’s choice of either hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, lenalidomide (Revlimid), pomalidomide (Pomalyst), or observation only.

The primary end point of the study was the percentage of participants achieving a primary composite response at week 32. The key secondary end points, which were assessed at weeks 32 and 48, were primary response, complete hematological remission, spleen volume reduction, duration of primary response, and overall clinicohematologic response.

“These 5-year findings showed that the primary response, complete hematological remission, and overall clinicohaematological response were maintained with long-term ruxolitinib therapy. In addition, modest reductions inJAK2Val617Phe allele burden and improvements in quality of life parameters were observed with longer-term ruxolitinib use, indicating greater overall benefits with the long-term treatment,” Kiladijan et al wrote.

Reference:

Kiladijan JJ, Zachee O, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study.Lancet Haematol. 2020; 7: e226—37. DOI: 10.1016/S2352-3026(19)30207-8.