Ropeginterferon Alfa-2b (ROPEG) and Peginterferon Alfa-2a (PEG) at Low Dose with Response-Based Titration (LDRT) Have Comparable Efficacy and Tolerability in Polycythemia Vera (PV)
Authors: Lee Neville , Erdos Katie , Abdul Rahman Aqib , Silver Richard T. , Scandura Joseph M. , Abu-Zeinah Ghaith 
Published: December 2024

Background: Interferon alfa, in the form of ROPEG or PEG, is an effective first-line treatment (Rx) for patients (pts) with PV, associated with disease-modifying activity and favorable survival outcomes. ROPEG was approved by the FDA for PV in November 2021 but has not been directly compared to PEG, which has been used off-label for decades. In absence of randomized trials, a real-world propensity score matched (PSM) retrospective study is necessary to compare the efficacy and tolerability of ROPEG to PEG when both are dosed similarly at LDRT. This comparison is important because current ROPEG trials rapidly escalate to the maximum dose (MD), whereas PEG has traditionally been started at a low dose and titrated based upon patient (pt) response.

Methods: In this single-center retrospective study, pts with PV who started ROPEG at LDRT (50-100mg every 2 weeks (q2w) with 50mg uptitration) were compared to those on PEG similarly managed using LDRT (45mg weekly with 45mg uptitration). The Weill Cornell MPN Research Data Repository (RDR) was queried to identify all pts treated for PV with ROPEG monotherapy and a control PEG cohort, propensity score matched (PSM) by age, sex, thrombosis history, and hematocrit (HCT). Automated tools retrieved demographics, labs, dosing, adverse events (AEs), thrombosis, progression to myelofibrosis or blast-phase (progression), and spleen size, which were then manually validated. Hematologic response (HR) (complete or partial: CHR or PHR) was defined using the revised response criteria by European LeukemiaNet (ELN) and IWG-MRT (Barosi et al. Blood 2013), as phlebotomy-free control of HCT and normalization of platelet and white blood cell counts for at least 3 months. AEs were categorized according to the Common Terminology Criteria for AEs (CTCAE) version 5. Efficacy was assessed by HR, thrombosis incidence, spleen response, and molecular response (MR) as available (MR defined as JAK2 mutant allele frequency (MAF) relative reduction &gt; 20% from baseline). Tolerability was assessed by frequency of AEs. Since ROPEG has been approved for only 3 years (yr), only the first 3yr of PEG were considered.

Results: A total of 44 pts with PV on ROPEG were identified and PSM to 44 pts on PEG. Baseline values of ROPEG and PEG pts were the following, respectively: median age 54 vs 58 yr; history of thrombosis 14% vs 16%; ELN high-risk 43% vs 48%; median HCT 44% vs 43%; splenomegaly 18% vs 36%; median spleen size when palpable 7.0 vs 2.5 cm below costal margin; and median time on Rx was 9 vs 30 mo (p&lt;0.001). All p-values &gt;0.05 except where indicated. The 3-mo HRs were higher for ROPEG vs PEG (CHR/PHR 39/61% vs 18/68%, p=0.02) but subsequent HR rates were similar. HRs at 6-mo were 37/57% vs 34/54% (p=0.9), respectively. HRs at 12-mo were 55/40% and 56/42% (p&gt;0.9), respectively. The 3,6,12-mo median doses were 100, 100, 150 mg for ROPEG and 45, 68, 90 mg for PEG. PV-related events were rare, with only one patient (2.3%) experiencing thrombosis (deep vein) within 3 yr (at 0.3 mo on ROPEG). Progression was not observed in either group within 3 yr. Of pts with palpable splenomegaly at start of therapy, 4 of 8 (50%) on ROPEG and 10 of 16 (63%) on PEG normalized palpable spleen size within a yr (p=0.9). MR was achieved in 4 of 9 (44%) ROPEG pts and 13 of 18 (72%) PEG pts (p=0.22), with median time to MR of 7 vs 15 mo, respectively (p=0.03). AEs were similar except for significantly lower flu-like symptoms with ROPEG (n=3, 6.8%) compared to PEG (n=11, 25%) (p=0.02).

Discussion: Using an LDRT strategy, HR rates were high for both ROPEG and PEG with CHR attained a bit faster with ROPEG. Incidence of PV-related events (thrombosis and progression) was too low for meaningful comparison, reflecting the efficacy of both at LDRT. MR was not different but time to test varied significantly and additional follow-up is required for assessment of MR with ROPEG. While these results do not address whether MD ROPEG could yield superior efficacy (HR, thrombosis, MR), the already excellent outcomes with LDRT ROPEG suggests that MD strategy risks worsened tolerability with an undefined benefit over LDRT.

Conclusion: For treatment of pts with PV, ROPEG used at LDRT yields high HR rate within 12 mo and very low thrombosis incidence, similar to PEG. ROPEG offers the advantage of less frequent dosing and a lower rate of flu-like symptoms at LDRT compared to PEG. These results challenge the rationale for rapid ROPEG dose escalation to MD given the high efficacy of ROPEG at LDRT.