Treatment with Pegylated Interferon-Alfa-2A (PEG-IFN-α-2A; PEGASYS™) for Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV).
Authors: Quintas-Cardama Alfonso , Kantarjian Hagop , Giles Francis , Cortes Jorge , Richie Mary Ann , Borthakur Gautam , Verstovsek Srdan 
Published: April 2020

Patients (pts) with high-risk Philadelphia chromosome-negative myeloproliferative disorders (MPDs) are customarily treated with cytoreductive agents such as recombinant human interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in MPDs, responses have been frequently limited 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 increased serum half-life, decreased renal excretion, thus allowing for weekly administration while maintaining acceptable toxicity profile. Based on the superior pharmacokinetic and pharmacodynamic profile of PEG-IFN-α relative to IFN-α we designed a phase II study of subcutaneous (sc) PEG-IFN-α-2a (Pegasys™) for pts with ET and PV. A total of 23 pts have been enrolled so far (13 ET, 10 PV). First 3 pts received PEG-IFN-α-2a at 450mcg weekly but experienced toxicity and had to reduce the dose; next 3 pts started at 360mcg weekly and again had to reduce the dose due to toxicity; last 17 pts started at 270mcg weekly and tolerated therapy well. Dose modifications of 90 mcg are allowed according to response or toxicity. Median age is 54 years (range, 23 to 73), time from diagnosis to PEG-IFN-α-2a therapy 64 months (range, 1 to 282), Hb 13.5 g/dL (range, 8.9 to 18.5), WBC 5×109/L, (range, 4.3 to 49), platelets 592×109/L (range, 298 to 1000). All pts had prior therapies (median 2, range 1–6), including HU (n=17), AG (n=13), IFN-α (n=6: 4 oral and 2 sc), imatinib mesylate (n=2) and others (n=3). In addition, 8 PV pts had received phlebotomies. The JAK2 V617F mutation was detected in 6 (46%) of 13 ET pts and in 9 (90%) of 10 PV pts. All pts had diploid cytogenetics. After a median follow-up of 6 months (range, 1 to 15), 11 of 13 (85%) ET pts have achieved a complete response (platelets &lt;440×109/L, off HU and AG, in the absence of thromboembolic events); 2 pts without response received less than 2 months of therapy so far. Six of 10 (60%) PV pts achieved complete remission (Hb &lt;15 g/dL, off HU and AG, no phlebotomy, with disappearance of splenomegaly), 3 (30%) achieved partial response (no phlebotomy, off HU and AG, but still palpable spleen), and 1 have not responded so far (less than 3 months on the therapy), for overall response of 90%. The median time to response was 1.5 months (range, 0.5 to 5.6). While the first 6 pts on the study, that received high PEG-IFN-α-2a dose (450 or 360mcg weekly), experienced grade 3 toxicity, among last 17 pts that received 270mcg weekly, there were only 5 cases of grade 3 toxicity (anemia, increased liver function tests, and neutropenia x3) requiring dose reduction. However, to preserve pts quality of life, the dose of PEG-IFN-α-2a was also reduced for the persistent grade 2 toxicity (&gt; 2 weeks). Overall, 17 pts (74%) reduced the dose so far, while 6 pts (all on 270mcg weekly) remain at the same initial dose. Only 2 pts (1 ET, 1 PV) discontinued therapy, due to retinal infiltrates and depression after 8 and 6 months on therapy, respectively. In summary, therapy with PEG-IFN-α-2a has an acceptable toxicity profile and significant activity in pts with ET and PV. Updated clinical and molecular results will be presented.