Phase 2 Study of Pegylated Interferon in Patients with Essential Thrombocytopenia and Polycythemia Vera: Final Analysis Focused on the Two Diseases
Authors: Masarova Lucia , Bose Prithviraj , Pemmaraju Naveen , Borthakur Gautam , Verstovsek Srdan , Yin C. Cameron , Patel Keyur P. , Kantarjian Hagop M. 
Published: December 2024

Introduction: Long-term data from prospective studies of the use of pegylated interferon alfa-2a [PEG-IFN] in polycythemia vera [PV] are more widely available compared to similar data for patients with essential thrombocythemia [ET].
Objective: We present final analysis of our single center, prospective, phase 2 study of PEG-IFN in patients with ET and PV, focusing on disease subtypes.
Methods: The study enrolled adult patients with ET and PV in a need for therapy (37% previously untreated). Study details were as previously published (Masarova et al, Lancet Haematology, 2017). The study was terminated on 24th of August, 2023 (first patient enrolled 23rd of June, 2005).
Results: 40 ET (median age 52, range 39-62, 30% males) and 43 PV (median age 54 years; range 44-63, 40% males) patients (pt) were treated with PEG-IFN for a median of 79 (range, 2-201) and 93 (range, 6-202) months, respectively. Relevant discontinuation reasons included: study termination (5 ET, 4 PV), no response (3 ET, 9 PV); progression to myelofibrosis or acute leukemia (MF/AML; 4 ET, 4 PV), other malignancy (4 PV); drug-related toxicity (11 ET, 9 PV), deaths (unrelated, 4 PV). Unprovoked vascular events on PEG-IFN occurred in 3 ET and 3 PV pts, respectively.
ET driver mutations included 19 (48%) JAK2+, 9 (23%) CALR, 9 (23%) undetectable (triple negative, TN) and 3 (7%) MPL. Age at PEG-IFN start was the highest in MPL pt (median years [range]) of 58 [38-67]) vs 53 [19-75] JAK2, 54 [39-66] CALR, 48 [23-72] TN. Median weekly dose of PEG-IFN was 45 mcg for JAK2, CALR and MPL pt and 90 mcg for TN pt. Six patients did not achieve hematologic response (HR): 4 JAK2, 1 MPL, 1 TN (HR 85%); and 10 lost their HR during PEG-IFN: 8 JAK2, 1 CALR, 1 TN. JAK2+ pt had the shortest duration of PEG-IFN (median, months [range]) of 59 [6-205]; compared to CALR = 78 [10-208]; TN = 93 [36-143] and MPL = 82 [12-88]. However, JAK2+ pt who achieved ≥20 reduction in JAK2% (molecular response, MR) had equally long therapy as JAK- pt, median of 81 months (range, 30-205). Eleven pt (58%) achieved ≥ 50% JAK2 reduction (2 pt with 100% JAK2% reduction) with a median decline in JAK2% of 89% (range, -69%, -100%). PEG-IFN therapy for ≥ 5 years received 10 (53%), 5 (67%), 5 (59%) and 2 (67%) of JAK2, CALR, TN and MPL pt, respectively. Four JAK2 pt and 2 CALR pt were on PEG-IFN for ≥15 years. Progression to MF/AML on PEG-IFN was noticed in 1 JAK2 pt, 2 CALR pt; and 1 TN pt, respectively. Additional molecular mutations (Add. Mut.) on myeloid gene panel were in 7 JAK2 (37%), 7 CALR (78%), 3 MPL and 3 TN (33%) pt; the most common were DNMT3A (5), ASLX1 (5) and TET2 (4). Among 23 ET pt with repeated bone marrow assessment (11 JAK2, 5 CALR, 5 TN, 2 MPL), 12 (52%) had improved marrow fibrosis and/or morphology: 5 JAK2, 4 CALR, 1 TN and 1 MPL.
All 43 PV pt were JAK2+. JAK2% reduction by 100% (CMR), between 50-99% (PMR) and between 20%-49% (mMR) were achieved in 7, 15 and 1 patient, respectively. Twenty patients had &lt; 20% JAK2% reduction or were not evaluable (no-MR). Eleven patients (26%, all no-MR) did not achieve HR; and 15 pt (1 CMR, 10 PMR and 4 no-MR) lost it doing their therapy. Median [range] duration of PEG-IFN for CMR, PMR and no-MR pt was 186 [25-201], 93 [45-185] and 23 [3-158] months, respectively. Median weekly PEG-IFN dose was 45, 90, 135 mcg for CMR, PMR, no-MR pt, respectively. Median decline in JAK2% in PMR pt was -90% (range: -74%, -98%) and it was -17% (null, -19%) for no-MR. Age (median in years, [range]) at PEG-IFN initiation was the highest among no-MR pt of 61 [24-68] vs 44 [25-58] for CMR and 50 [33-78] for PMR. PEG-IFN for ≥5 years received 86% CMR pt (n 5), 87% PMR pt (n 13), 1 mMR pt and 25% no-MR pt (n 5). 5 CMR and 2 PMR pt were treated for ≥15 years. Progression to MF/AML on PEG-IFN was detected in 1 PMR and 3 no-MR pt. Add. Mut. were in 3 CMR (43%), 10 PMR (66%), and 13 mMR & no-MR (62%) pt; the most common were TET2 (15), DNMT3A (9), ASLX1 (4). Among 18 PV pt with repeated bone marrow assessment (6 CMR, 8 PMR, 4 no-MR), 11 (61%) had improved marrow fibrosis and/or morphology: 5 CMR, 5 PMR, 1 no-MR.
Conclusions: Our phase 2 study proves pegylated interferon as a viable and durable treatment option for patients with ET and PV.