Pegylated Interferon-alfa-2a (PEG-IFN-α-2A; PEGASYS™) for Essential Thrombocythemia (ET) and Polycythemia Vera (PV): An Update of an Ongoing Phase II Study.
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop , Garcia-Manero Guillermo , Cortes Jorge , Richie Marie Ann , Borthakur Gautam , Verstovsek Srdan 
Published: October 2019

Therapy for patients with high-risk Philadelphia chromosome-negative myeloproliferative disorders (MPDs) involves the use of cytoreductive agents such as recombinant human interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in MPDs, therapy with this agent is frequently hindered by poor tolerance and inconvenient dosing schedules. PEG-IFN-α is formulated by covalently attaching polymers of ethylene glycol to the native IFN-α molecule, which results in decreased renal excretion and increased serum half-life that allows for weekly administration with acceptable toxicity. Based on the superior pharmacokinetic profile of PEG-IFN-α-2a relative to conventional IFN-α, we designed a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) for patients with ET or PV. A total of 50 patients have been enrolled and treated thus far (22 ET, 28 PV). Median age is 53 years (range, 23–77) and time from diagnosis to PEG-IFN-α-2a 64 months (range, 1–348). Prior therapies (median 2; range 0–6) included HU (n=33), AN (n=22), phlebotomy (n=27), IFN-α (n=8: 5 oral and 3 sc), other (n=10). PEG-IFN-α-2a was the initial therapy in 4 patients. The JAK2 V617F mutation was detected in 11 (50%) of 22 ET and in 26 (93%) of 28 PV patients. Six (12%) patients had abnormal cytogenetics. Initial starting dose of PEG-IFN-α-2a was 450 mcg/week, but that was modified to the current starting dose of 90 mcg/week. Dose modifications are allowed according to response or toxicity. Patients are currently receiving 450 mcg (n=1), 360 mcg (n=1), 270 mcg (n=5), 180 mcg (n=11), 135 mcg (n=8), 90 mcg (n=9), and 45 mcg (n=5). After a median follow-up of 11 months (range, 2–28), 47 (94%) patients have responded. Complete response (CR) was achieved by 46 (92%) patients (for ET: platelets <440x109/L, off HU and AG, in the absence of thromboembolic events; for PV: Hb <15 g/dL, off HU and AG, no phlebotomy, with disappearance of splenomegaly) whereas 1 (2%) patient with PV had a partial response ([PR]; no phlebotomy, off HU and AG, but still palpable spleen). The mutant JAK2 V617F to total JAK2 ratio was determined by PCR (n=37) and by a quantitative pyrosequencing assay (n=30) prior to PEG-IFN-α-2a. JAK2 V617F mutational analysis was subsequently performed after 6 and 12 months into PEG-IFN-α-2a therapy in 20 and 10 patients, respectively. Nine (30%) of the 30 patients assessable for JAK2 V617V quantitation had >10% reduction in JAK2 V617F expression, including 2 (7%) in whom the mutant allele became undetectable. In addition, 4 (13%) patients had a 5%–10% reduction. JAK2 V617F quantitation has not been repeated yet in 9 patients. PEG-IFN-α-2a was well tolerated in most patients. Twenty-two episodes of grade 3–4 toxicity were reported, including neutropenia (n=11), elevated transaminases (n=4), and anemia, thrombocytopenia, depression, fatigue, infection, cardiac, and pain in 1 case each. Ten patients were taken off study, including 6 (12%) due to therapy-related toxicities: grade 3 neutropenia (n=1), fatigue (n=1), depression (n=1), ischemic retinopathy (n=1), dyspnea (n=1),and diarrhea (n=1). In summary, therapy with PEG-IFN-α-2a results in remarkable clinical activity and acceptable toxicity profile in patients with ET or PV. Significant reduction of JAK2 V617F allele burden occurred in a proportion of responders, suggesting selective targeting of the malignant clone.