Ruxolitinib Outperforms Standard Therapy in Polycythemia Vera

Wayne Kuznar
Published: Thursday, Jul 24, 2014
Dr. Srdan Verstovsek
Srdan Verstovsek, MD, PhD

Professor, Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, TX

In the first pivotal phase III study of a Janus-associated kinase (JAK) inhibitor for the treatment of polycythemia vera (PV), ruxolitinib (Jakafi) was superior to best available therapy (BAT) in maintaining control of hematocrit without the need for phlebotomy and in reducing spleen size in patients with an inadequate response to or intolerance of hydroxyurea.

The responses to ruxolitinib were durable in the open-label randomized trial, announced Srdan Verstovsek, MD, PhD, at the 2014 American Society of Clinical Oncology Annual Meeting in June. Ruxolitinib was also associated with superior symptom management compared with BAT. “An interesting observation…is that the rate of thromboembolic events appears to be lower in the ruxolitinib group so far,” said Verstovsek.

Ruxolitinib, which inhibits JAK1 and 2, was approved in 2011 for the treatment of patients with intermediate or high-risk myelofibrosis, including post-PV myelofibrosis. The oral agent is being evaluated in several tumor types, including uncontrolled PV, according to Incyte Corporation, which is developing ruxolitinib.

The JAK/STAT pathway is known to be overactivated in PV. The disease is characterized by erythrocytosis, debilitating symptoms, and cardiovascular complications due to thrombosis or hemorrhage. “Hematocrit control is a key therapeutic goal,” said Verstovsek, a professor at The University of Texas MD Anderson Cancer Center, Houston. “It has been shown before in many studies that maintaining hematocrit to below 45% significantly decreases the risk of cardiovascular death and major thrombotic events.”

In a phase II trial, ruxolitinib was well tolerated, effectively controlled hematocrit, reduced spleen size, and improved the symptom burden in patients with PV.

RESPONSE Study Shows Benefit

The phase III trial, known as RESPONSE, evaluated ruxolitinib versus BAT in 222 patients with PV and splenomegaly who were resistant to or intolerant of hydroxyurea. Patients randomized to ruxolitinib were started at 10 mg twice daily and titrated up to a maximum of 25 mg twice daily. BAT was at the investigator’s discretion, and could include hydroxyurea, interferon/pegylated interferon, anagrelide, pipobroman, immunomodulators, or observation. If patients did not respond to BAT or experienced toxicity, their therapy could be changed.

BAT patients were allowed to cross over to ruxolitinib at week 32 if they failed to meet the primary endpoint (achievement of hematocrit control at week 32 and a ≥35% reduction from baseline in spleen volume), or later if they required phlebotomy or had progression of splenomegaly. All patients received low-dose aspirin unless contraindicated.

RESPONSE Trial Results at Week 32

Clinical Outcomes Ruxolitinib
(n = 110)
(n = 112)
Patients who achieved both spleen response and Hct control 21% (P <.0001) 1%
≥35% reduction in spleen volume 38% 1%
Hct controla 60% 20
CHRb 23.6% 8.9%

aNo phlebotomy eligibility from week 8-32 with no more than 1 postrandomization eligibility up to week 8; eligibility defined as Hct >45% and ≥3% higher than baseline or >48%.
bCHR consists of Hct control, platelet count ≤400 x 109/L, and white blood count ≤10 x 109/L.
BAT indicates best available therapy; CHR, complete hematologic remission; Hct, hematocrit.

At baseline, 35.5% in the ruxolitinib arm and 29.5% in the BAT group had a prior thromboembolic event, and their mean hematocrit was 43.6% and 43.9%, respectively. Some 30.9% of ruxolitinib recipients and 42.0% of the BAT group had ≥3 phlebotomies in the 24 weeks prior to study entry.

Spleen volume was a median of 1195 cm3 in the ruxolitinib arm and 1322 cm3 in the BAT arm. About two-thirds of patients assigned to BAT had some exposure to hydroxyurea.

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