Phase 2 Study of Pegylated Interferon in Patients with Essential Thrombocytopenia and Polycythemia Vera: Final Analysis Focused on the Two Diseases

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 24^th of August, 2023 (first patient enrolled 23^rd 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 < 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.