A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia

Abstract

The goal of therapy for essential thrombocythemia (ET) and polycythemia vera (PV) patients is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for ET and PV patients at high-risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment naïve, high-risk ET/PV patients. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (p=0.80) at 12 months. At 24/36 months, CR was 20%/17% for HU and 29%/33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, while grade 3/4 adverse events were more frequent with PEG (46% vs. 28%). At 12 months of treatment there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment PEG was more effective in normalizing blood counts and reducing driver mutation burden, while HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk ET/PV patients. (Funded by the National Cancer Institute, 5P01CA108671-09; clinicaltrials.gov number (NCT01259856)

Cytoreductive treatment and association with platelet function and maturity in patients with essential thrombocythaemia

“…28 In addition, a recent study found that longer treatment with peg-IFN was more effective in normalizing levels of blood cells and reducing driver mutation burden, while hydroxycarbamide produced more histopathologic responses. 19 Our study shows for the first time that hydroxycarbamide and peg-IFN lead to alterations in activation-dependent granule markers in platelets. The mechanism of action of these drugs is still not fully understood.…”

“…However, it remains unknown if the risk of thromboembolic events differs between ET patients treated with different cytoreductive drugs. Some studies indicate that the risk may differ, 9,10,17,18 whereas a recent phase 3 study found no differences 19 . However, the study was not powered to detect a difference in the rate of thromboembolic events between hydroxycarbamide and peg‐IFN treated high‐risk ET patients 19 .…”

“…Some studies indicate that the risk may differ, 9,10,17,18 whereas a recent phase 3 study found no differences. 19 However, the study was not powered to detect a difference in the rate of thromboembolic events between hydroxycarbamide and peg-IFN treated high-risk ET patients. 19 It has been reported that peg-IFN is an effective treatment in ET patients refractory or intolerant to hydroxycarbamide therapy.…”

“…19 However, the study was not powered to detect a difference in the rate of thromboembolic events between hydroxycarbamide and peg-IFN treated high-risk ET patients. 19 It has been reported that peg-IFN is an effective treatment in ET patients refractory or intolerant to hydroxycarbamide therapy. 20 While no international consensus exists, younger ET patients (<40 years old) tend to receive peg-IFN rather than hydroxycarbamide as first line cytoreduction due to a theoretical increased risk of leukaemic transformation related to hydroxycarbamide.…”

“…In addition, the difference in platelet markers between treatment groups likely also reflects the diverse influence on megakaryopoiesis by hydroxycarbamide and peg‐IFN and the fact that cytoreduction may not reverse all abnormal platelet markers 28 . In addition, a recent study found that longer treatment with peg‐IFN was more effective in normalizing levels of blood cells and reducing driver mutation burden, while hydroxycarbamide produced more histopathologic responses 19 . Our study shows for the first time that hydroxycarbamide and peg‐IFN lead to alterations in activation‐dependent granule markers in platelets.…”