Jean-Jacques Kiladjian, M.D., Ph.D. from Saint-Louis Hospital and Paris Diderot University in France speaks about the ASH abstract – 481 Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: 5-Year Results from a Randomized Controlled Study and Its Extension.
Introducing:
Life-long care is required in patients with polycythemia vera (PV) in order to avoid thromboembolic events and minimize the risk of progression. By selectively targeting the malignant clone, ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) will eventually alter the natural history of PV. In the PROUD-PV/CONTINUATION-PV trials, long-term ropeg therapy was contrasted with normal cytoreductive therapy for thromboembolic and other adverse reactions, as well as for a five-year evolution of hematologic and molecular parameters.
Methodology:
Enrolled were patients aged 18 years or older and diagnosed with PV according to WHO 2008 requirements who were either cytoreduction-naïve or hydroxyurea (HU)-pre-treated for < 3 years. In the initial study, a total of 257 patients were randomized to receive ropeg or HU at individualized doses for 12 months at 1:1 (stratified by age > 60 years, previous thromboembolic incidents, and HU pre-treatment) (PROUD-PV). Patients in the HU arm were allowed to turn to the best available care in the extension study (CONTINUATION-PV). Hematological parameters, phlebotomy requires, JAK2V617F allele pressure, and molecular response identified by updated ELN criteria were included in the efficacy assessments. When all patients completed 5 years of treatment, an interim review was conducted; efficacy data for patients involved in the extension study and all available safety data were analyzed.
Outcomes:
Ninety-five patients joined the extension study in the ropeg arm, and 76 in the control arm. Much of the control arm patients continued to receive HU (88 percent at month 60). 70 patients in the ropeg arm and 57 in the control arm remained in the study at the time of this 5-year analysis; discontinuation rates were balanced between the treatment arms; (ropeg: 26.3 percent; control: 25.0 percent ).
In 81.8 percent of patients in the ropeg arm, haematocrit <45 percent was sustained without the need for phlebotomy in the fifth year of treatment, which was significantly higher than the 63.2 percent rate observed in the control group (p=0.01). A major thromboembolic adverse effect was encountered by very few patients (4.2 percent [1.2 percent -patient year] of patients in the ropeg arm and 6.6 percent [1.2 percent -patient-year] of patients in the control arm during the entire treatment period).
The median allele load decreased from 37.3 percent at baseline to 7.3 percent over 5 years of care in the ropeg arm with respect to the causative JAK2V617F mutation, while the median allele load increased in the control arm from 38.1 percent to 42.6 percent over the same duration (p<0.0001). The 5-year molecular response rate was also substantially higher for ropeg-treated patients than for the control arm (69.1% vs. 21.6%; RR: 3.2 [95% CI: 2.1 to 4.9; p<0.0001]). Low risk of disease progression followed the sustained molecular response observed in ropeg-treated patients; only 1 case of progression to myelofibrosis (0.20 percent -patient-year) was recorded during the entire study period and no leukemic transformation occurred. In comparison, in the control arm, there were 2 cases of progression to myelofibrosis and 2 cases of transition to acute leukemia (1.0 percent -patient-year in total).
Further research was carried out on combined hematological and molecular parameters, which are known to affect the risk of thrombosis and PV progression. 58.5 percent of patients receiving ropeg had well-controlled hematocrit (<45 percent) without phlebotomy and molecular response at the 5-year visit, compared with 17.3 percent on standard therapy (RR: 3.52 [2.13 to 5.81]; p<0.0001).
As for protection and tolerability, in the fifth year, no new signals were found. In 25.6 percent and 24.2 percent of patients in the ropeg and control arms respectively, treatment-related adverse effects were registered, and one patient in each arm withdrew because of drug-related toxicity. In the fifth year, three patients (3.8 percent) in the ropeg arm reported grade ⇠3 treatment-related adverse events; in each research arm, the grade ⇠3 drug-related adverse event rate was the same over the entire treatment period (16.5 percent ).
Findings:
Ropeg therapy has successfully regulated hematocrit in a randomized controlled setting and minimized the occurrence of thromboembolic events in PV patients. During long-term treatment with ropeg, disease progression was very rare and this potential improvement in the natural history of the disease appears to be due to profound and enduring molecular responses selectively obtained with ropeg.