Long Term Results of Phase 2 Study of Pegylated Interferon in Patients with Essential Thrombocythemia and Polycythemia Vera: Median Follow-up of 15 Years

Introduction: Pegylated interferon alfa-2a [PEG-IFN] have been used for almost 3 decades in patients with polycythemia vera [PV] and essential thrombocythemia [ET], but long-term data from prospective studies are limited.

Objective: We present results of our single center, prospective, phase II study of PEG-IFN in patients with ET and PV with a median follow up of 183 months (range, 6-198, at data lock June 2022; previous data lock was May 2015).

Methods: The study enrolled patients with ET (n=40) or PV (n=43) over the age of 18, irrespectively of previous therapy (37% untreated). PEG-IFN dose modifications, monitoring, and response assessment were as published (Masarova et al, Lancet Haematology, 2017). Testing sensitivity for JAK2V167F mutation allele burden was 1% till 2018, and 0.1% since then. Molecular response [MR; assessed in patients with baseline JAK2 ≥20%] was defined as complete (CMR; undetectable), partial (PMR; decrease by ≥50% but detectable) and minor (mMR; decrease by 20-49%).

Results: Among 83 enrolled patients (median age 53 years, 29 males), after median follow up of 183 months (range, 6-198), 11 patients (13%) continue on active therapy on study. Current doses range from 45 mcg every 9 weeks to 180 mcg weekly. Forty-six (55%), 18 (22%) and 6 (7%) patients were treated for ≥5, ≥10 and ≥15 years, respectively. The overall median exposure to PEG-IFN (n = 83) was 95 months (range, 3-191).

Twenty-seven patients (41%) from the initial 66 hematologic responders [HR; 80%] were in HR at the time of their last follow-up, including 5 patients who lost but regained HR with longer therapy. Table 1 shows responses in patients who remained on study for 4+ years. Median duration of HR was 137 months (range, 2.2-189). Thirty-five (63%) of 55 JAK2 mutated patients with molecular sequencing achieved molecular response: 10 CMR (18%), 20 PMR (36%) and 5 mMR (9%). At the time of last follow-up on study, 24 patients remained in MR (67%). Only 17 treated patients underwent repeated molecular sequencing since the last study update; 3 of them experienced change: 1 lost PMR (JAK2: 38%->61%), 1 lost CMR (JAK2: 0%-6%) and 1 regained PMR (JAK2: 13%->7%). Median duration on study in months [range] was 127 [25-189], 91 [11-192], 15 [2-183] and 81.5 [6-187] for JAK2(+) patients who achieved CMR (n = 10), PMR & mMR (n = 25), without MR (n = 25) and in JAK2(-) (n = 23), respectively. Five patients with previous CMR had subsequent testing, 4 of them had detectable JAK2 allele in the range of 0.1%-0.5% using more sensitive assay. Median duration of MR was unreached in patients who achieved < 1% JAK2 and it was 96 months (range, 6-155) in patients with 20-99% JAK2 allele decrease.

Reasons for therapy discontinuation included treatment-related toxicities in 20 patients (24%; 11/13 for grade ≥3), patient's decision in 19 (23%), ET/PV progression or lack of response in 12 (14%), other reasons in 10 (12%, e.g., motor vehicle accident), transformation to myelofibrosis or acute leukemia [MF/AML] in 7 (8%) and death in 4 patients (5%, all unrelated). Medical reasons for discontinuation after 10 years on study included 3 carcinomas: 1 head squamous cell, 1 pancreatic and 1 ovarian; and 2 adverse events: grade 3 Sjogren syndrome and grade 2 recurrent transaminitis. Annual discontinuation rates are shown in graph.

There were no transformations to MF/AML on therapy since the last study update for a total number of cases of 7. No additional vascular thrombotic events occurred with overall incidence of 0.9 / 100 person-years. Five patients experienced new adverse events after 10 years on therapy: mild flu-like symptoms, fatigue or diarrhea (3); grade 2 transaminitis (1) and Sjogren syndrome (1).

Twenty-five patients continued on active follow-up after PEG-IFN discontinuation until the current data lock with a median follow-up off therapy of 92 months (range, 8-132). Twenty patients are alive (on cytoreductive therapy in 11), 5 died (acute leukemia in 2, other medical condition, bleeding, stroke for 1 each). As of last follow-up, 25% (n = 21) of originally enrolled patients died. Median overall survival (n = 83) since enrollment was unreached.

Conclusions: Our 15 years of follow-up of pegylated interferon in patients with ET and PV confirms durability of responses and disease control in patients who are able to tolerate long therapy and an acceptable safety profile.

Bose:Sierra Oncology (now GSK): Consultancy; Blueprint Medicines Corporation: Honoraria, Research Funding; Telios: Research Funding; Astellas: Research Funding; Disc Medicine: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Pharma Essentia: Honoraria; Novartis: Honoraria; AbbVie: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Cogent: Honoraria, Research Funding; Kartos: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Honoraria, Research Funding; Pfizer: Research Funding; Ionis: Research Funding; CTI BioPharma: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Borthakur:Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Kantarjian:KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Takeda: Honoraria. Verstovsek:Novartis: Consultancy, Research Funding; Constellation Pharmaceuticals: Consultancy; Roche: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Genentech: Research Funding; CTI BioPharma Corp.: Research Funding; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Pragmatist: Consultancy.

Pegylated interferon alfa 2a is an off-label product used in patients with polycythemia vera and essential thrombocythemia.