Safety and tolerability

The most common nonhematologic adverse events at Week 32 in patients who received ruxolitinib in the Phase III RESPONSE trial were headache, diarrhea, pruritus, and fatigue (Table 3).22,112 The most frequent grade 3 or 4 nonhematologic adverse events in the ruxolitinib arm were dyspnea, asthenia, abdominal pain, headache, muscle spasms, and pruritus.22 Long-term treatment data indicated that the incidences of the most common nonhematologic adverse events were similar at Week 48 and in the 80-week analysis (headache, 20.9% and 21.8%; diarrhea, 20.0% and 19.1%; pruritus, 20.0% and 17.3%; fatigue, 17.3% and 17.3%, respectively).112


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(To view a larger version of Table 3, click here.)

Hematologic adverse events were primarily grade 1 or 2 at both the primary analysis (Table 3) and the 80-week analysis in the RESPONSE trial.22,112 The most common grade 3 or 4 hematologic adverse events in both randomized treatment arms were lymphopenia and thrombocytopenia. The US label for ruxolitinib indicates that thrombocytopenia, anemia, and neutropenia should be managed by dose reduction/interruption or transfusion.99

At Week 32, the rate of any grade 3 or 4 adverse events per 100 patient-years was lower in the ruxolitinib arm (28.8) than in the best available therapy arm (44.0) in the RESPONSE trial.22

Given the risks associated with thromboembolic events and disease transformation in patients with PV,14 it is important to consider such events when evaluating any new treatment option. The incidence of all-grade thromboembolic events at Week 32 was 0.9% in the ruxolitinib arm and 5.4% in the best available therapy arm (grade 3 or 4, 0.9% vs 1.8%, respectively).22 At the time of data cutoff in the primary analysis of RESPONSE, three patients in the ruxolitinib arm and one patient in the best available therapy arm developed MF after randomization; one patient in the ruxolitinib arm also developed AML. Two additional patients randomized to best available therapy experienced MF after cross over to ruxolitinib, one of whom progressed to AML.22

Other important adverse events of interest for patients being treated with ruxolitinib are nonmelanoma skin cancer and infections. At Week 32 in the RESPONSE trial, four patients in the ruxolitinib arm when compared with two patients in the best available therapy arm experienced newly diagnosed nonmelanoma skin cancer. All but one of these patients (best available therapy arm) had a history of precancerous skin lesions or nonmelanoma skin cancer.22 Melanoma skin cancer was diagnosed in zero patients in the ruxolitinib arm and one patient in the best available therapy arm during randomized treatment. The US prescribing information recommends periodic skin examinations for patients treated with ruxolitinib.99 In the RESPONSE trial, the incidence of any infection was similar in the ruxolitinib arm and the best available therapy arm at Week 32 (any grade, 41.8% vs 36.9%, respectively; grade 3 or 4, 3.6% vs 2.7%). However, herpes zoster infection was observed in 6.4% of patients in the ruxolitinib arm (all grade 1 or 2) at Week 32 compared to 0% of patients in the best available therapy arm.22 The US prescribing information states that patients should be advised about the early signs and symptoms of herpes zoster infection and to seek treatment as early as possible if herpes zoster infection is suspected.99

A long-term safety and tolerability evaluation of ruxolitinib was conducted in 241 patients (457 patient-years) who were resistant to or intolerant of hydroxyurea pooled from a Phase II study113 and RESPONSE (randomized and crossover patients).22,114 The most common nonhematologic adverse events were diarrhea, headache, and pruritus.114 Frequent grade 3 or 4 nonhematologic adverse events included dyspnea, herpes zoster, abdominal pain, back pain, headache, fatigue, and pyrexia.114 Hematologic adverse events were primarily grade 1 or 2; grade 3 or 4 anemia and thrombocytopenia were each reported in 3.7% of patients.114 Overall, seven patients had disease transformation to MF, and two patients had disease transformation to AML,114 a rate consistent with prior publications in similar patient populations with PV.21,84,115 The rate of thromboembolic events in the ruxolitinib group of this pooled analysis was 2.2/100 patient-years, whereas the rate in RESPONSE patients during randomized treatment with best available therapy was 8.2/100 patient-years.114

In Phase IIIb RELIEF trial, adverse events in the ruxolitinib arm were primarily grade 1 or 2.111 The most frequent nonhematologic adverse events were fatigue (20.4% [ruxolitinib arm] vs 10.7% [hydroxyurea arm]), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). Two patients receiving ruxolitinib had grade 3 or 4 neutropenia.111