Photo courtesy of CDC
SAN DIEGO—Results from the ARETA trial suggest patients with essential thrombocythemia (ET) can benefit from early treatment even if they are not considered high-risk.
In this phase 3 trial, non-high-risk patients were less likely to experience ET-related cardiovascular events or disease progression if they received extended-release anagrelide rather than placebo.
Patients who received extended-release anagrelide were also less likely to become high-risk over time.
And extended-release anagrelide had a safety profile consistent with conventional anagrelide formulations, according to investigator Heinz Gisslinger, MD, of the Medical University of Vienna in Austria.
Dr Gisslinger reported final results of the ARETA trial at the 2016 ASH Annual Meeting (abstract 476).
The trial was sponsored by AOP Orphan Pharmaceuticals AG, the company developing the extended-release formulation of anagrelide, known as anagrelide retard (AR).
Dr Gisslinger noted that the goals of developing AR are to achieve lower peak plasma concentration of anagrelide, reduce the frequency and intensity of peak concentration related to adverse events (AEs), allow for an easier dosing scheme (once daily vs 2 to 3 times daily), and improve patient compliance.
He also pointed out that results of the phase 3 TEAM-ET trial suggest AR is non-inferior to the standard formulation of anagrelide (Thromboreductin, also a product of AOP Orphan Pharmaceuticals).
So with the ARETA trial, Dr Gisslinger and his colleagues set out to determine if AR would be beneficial as an early intervention in patients with non-high-risk ET.
Patients
The trial enrolled 146 patients who had platelet counts below 1000 G/L and met at least 1 of the following criteria:
- Age 40 to 60 years
- ET duration of more than 3 years
- Any risk factor for thrombotic complications (JAK2 mutation, protein C and/or S deficiency, antithrombin III deficiency, factor V Leiden or prothrombin mutation, or cardiovascular risk factors).
Seventy-seven patients were randomized to AR, and 69 were randomized to placebo. In both treatment arms, 100% of patients were Caucasian, and about 74% were female.
The mean age was 40.9 (range, 20-60) in the AR arm and 45.2 (range, 19-59) in the placebo arm. The median disease duration was 75.0 days (range, 1-2502) and 78.0 days (range, 1-2195), respectively. The mean platelet count was 748.6 G/L and 745.3 G/L, respectively.
A majority of patients in both arms had JAK2 mutations (62.7% in the AR arm and 63.8% in the placebo arm). Fewer had CALR mutations (22.7% and 13.6%, respectively) and MPL mutations (16.7% and 12.5%).
Treatment
Patients were stratified by JAK2 status and randomized to receive AR at 2 to 8 mg/day or placebo.
The dosing of AR started at 1 tablet (2 mg) per day during week 1 and was titrated up according to platelet response to 2 tablets in week 2. Dosing was further increased or decreased according to platelet response in weeks 3 and 4.
The maximum dose was 4 tablets (8 mg) per day. After week 4, the maximum dose to achieve optimal platelet counts (<450 G/L) was maintained, and patients continued with weekly visits through week 6.
After that, patients had visits every 3 months in both the main phase of this study and the extension phase. The main phase lasted 1 year, and the extension phase lasted up to 3 years.
Sixty patients (77.9%) in the AR arm and 52 (75.4%) in the placebo arm completed the main phase of the study.
Fifty-seven patients in the AR arm entered the extension phase, and 44 (57.1%) completed it. Thirty-four patients in the placebo arm entered the extension phase, and 21 (30.4%) completed it.
Efficacy
The primary endpoint was time to ET-related cardiovascular events (as confirmed by a blinded expert panel) or disease progression/worsening (platelet increase >1000 G/L).
The 1-year event-free rate (patients who did not meet criteria for the primary endpoint) was 87% in the AR arm and 69% in the placebo arm (hazard ratio=0.356, P=0.0008).
According to the expert panel, there were 12 ET-related events in 11 patients in the AR arm, as well as 17 such events in 14 patients in the placebo arm. This included major and minor arterial, venous, and bleeding events.
In total, there were 13 patients who had ET-related events or met platelet criteria in the AR arm (13 events) and 26 patients who had ET-related events or met platelet criteria in the placebo arm (30 events).
Nine patients in the AR arm (11.7%) and 18 in the placebo arm (26.1%) changed to high-risk status at some point during the trial (odds ratio=2.67, P=0.033).
Safety
The overall incidence of AEs was 88.3% in the AR arm and 69.6% in the placebo arm. The incidence of treatment-related AEs was 76.6% and 27.5%, respectively.
The incidence of treatment-related serious AEs was 1.3% and 0%, respectively. And the incidence of treatment-related AEs leading to withdrawal was 9.1% and 7.2%, respectively.
Treatment-related AEs occurring in more than 10% of patients in either arm (the AR and placebo arms, respectively) included headache (41.6% and 15.9%), dizziness (35.1% and 14.5%), palpitations (28.6% and 1.4%), and tachycardia (10.4% and 1.4%).
In closing, Dr Gisslinger noted that the primary endpoint of this study was met, and AR allowed for platelet count normalization and delayed progression to high-risk status.
Furthermore, the safety profile of AR is consistent with conventional anagrelide formulations, but AR allows for a more convenient dosing schedule.
Dr Gisslinger concluded, “[T]hese data from the ARETA study support an early treatment concept for all ET patients where platelet count or symptom reduction is a goal and those patients who can be attributed as intermediate-risk patients.”
