Long Term Clinical and Molecular Responses in Patients with Polycythemia Vera and Essential Thrombocytosis Receiving Pegylated Interferon-Alpha Therapy
Authors: Diebolt Leah , Twardowski Nicole , Esplund Jayda , Wu Jianzheng , Pal Mudaranthakam Dinesh , Yacoub Abdulraheem 
Published: December 2024

Background:Polycythemia Vera (PV) and Essential Thrombocytosis (ET) are myeloproliferative neoplasms (MPNs) that are characterized by excessive hematopoiesis, high burden of symptoms, increased risk of thrombosis and hemorrhage, and variable risk of transformation to higher risk myeloid neoplasms. Cytoreductive therapy, most commonly with hydroxyurea, aims at controlling disease symptoms and thrombohemorrhagic complications. Multiple trials have demonstrated significant therapeutic response rates with pegylated interferon-2a (PEG). These studies were limited by heterogeneity of patients and treatment approach, relatively short follow up, and limited molecular response data. The significance of this study is to characterize PEG dosing intensity, and to describe clinical and molecular outcomes in patients who have received PEG therapy under the same protocol at a single cancer center over prolonged duration of treatment.
Methods: This is a single center, retrospective review of 56 patients with either PV or ET who have received monotherapy with PEG. Clinical outcomes included achievement of complete hematologic response (CHR), hematocrit control without phlebotomy in PV, and platelet control &lt; 400 in ET. Molecular response (MR) was evaluated by reduction in driver mutation variable allele frequency (VAF). PEG was administered at a starting dose of 45 µg weekly and titrated for response up to a maximum of 180 µg/w. After achievement of CHR, the dose was gradually titrated down while maintaining response to mitigate adverse events.
Results: Fifty-six patients were included in the final analysis, 21 (38%) had PV, and 35 (63%) had ET. The median duration of disease prior to therapy was 20 months (IQR 6-73; range 0-240). Driver mutations were JAK2 in 40 patients, MPL in 3 patients, and CALR in 9 patients, while 4 patients had none. The median duration of PEG therapy in this sample was 39.4 months (IQR 17.0-74.6; range 0.5-122.7), and the majority remain on ongoing therapy. PEG was escalated to achieve CHR or to the maximum dose successfully in all subjects. Mean maximum dose of PEG achieved was 128 µg/w and median dose for long term maintenance was 81 µg/w. CHR was achieved in 37 patients (66%) (11/21 PV (52%) patients and 26/35 ET (74%) patients). Mean time to achievement of CHR was 8.3 months. Smaller spleen size (p=.033) was predictor of CHR on univariate analysis. Age at diagnosis (p=0.640) and duration of PEG therapy (p=0.06) were not predictors of CHR in this cohort. Interferon dose was not significantly associated with CHR, but in patients with CHR, long term PEG dose needed for maintenance was lower (45.0 µg/w vs. 135.0 µg/w, p=0.037).
MR was observed in 24 of 29 (83%) evaluable patients (24 had JAK2, 2 had MPL, and 3 had CALR). The median reduction of VAF was 53% (82% in PV and 29% in ET). Of those who achieved MR, 16/24 patients (67% achieved CHR). Five patients (8.9%) in this cohort discontinued therapy due to side effects. There were no thrombotic events noted while on PEG therapy. Transformation to myelofibrosis occurred in 2 patients.
Conclusion: PEG therapy was very active and achieved CHR in the majority of patients. In addition, PEG demonstrates molecular responses in all three driver mutations, that correlated with CHR, with deeper MR observed with extended duration of therapy. With over 340 patient-years of follow up, very few transformations to MF were observed (0.6/100 person-year) and no transformation to blast phase was observed. This approach of dose up-titration then de-escalation was feasible and was associated with low discontinuation rate and feasibility of delivering for extended durations, and we propose as a preferred PEG dosing schedule. Additional clinical and molecular responses will be available at the time of presentation.