Abstract
Introduction: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by aberrant JAK-STAT signaling via the acquisition of a somatic “driver” mutation, most commonly JAK2 V617F. The variant allele frequency (VAF) of JAK2 correlates with phenotypic features and the risk of thrombosis and progression. Interferons (IFNs) are immunomodulatory cytokines that have demonstrated the potential to reduce VAF, a feature rarely seen with conventional therapies. However, this data is derived from a limited number of clinical trials, with a paucity of real-world data. We aimed to evaluate outcomes of patients (pts) treated with IFN in real-world practice, with a focus on evaluating the impact of IFN therapy on JAK2 allele burden.
Methods: This single center, retrospective study evaluated consecutive pts treated with pegylated interferon alfa-2a (peg-IFN) or ropeginterferon alfa-2b (ropeg), regardless of line of therapy. Eligible pts had a diagnosis of essential thrombocytosis (ET), polycythemia vera (PV), or prefibrotic myelofibrosis (pre-MF) by WHO 2022 criteria. Data was abstracted from medical records at time of diagnosis, IFN initiation (baseline), and throughout treatment.
Serial assessment of JAK2 V617F VAF was evaluated by allele-specific RQ-PCR in peripheral blood, with limit of detection of 0.1%. A subset of pts underwent assessment of additional somatic mutations by next generation sequencing using a 75-gene panel.
Descriptive analyses were performed. Fishers exact test was used to compare categorical variables and the Mann-Whitney test for continuous variables. The Kaplan-Meier method was used for time-to-event analyses. This study was approved by institutional review board at Emory University.
Results: A total of 82 pts were included with median age of 50.5 years (20-71); 73.4% were women. At baseline, 14 (17.1%) had ET, 63 (76.8%) had PV, and 5 (6.1%) had Pre-MF. Among ET/Pre-MF and PV pts, 11 and 29 pts had conventionally high-risk disease, respectively, with prior thrombosis in 21 (25.6%) pts. One pt had a JAK2 exon 12 mutation. Prior therapy included hydroxyurea, anagrelide, and ruxolitinib in 36 (43.9%), 2 (2.4%), and 8 (9.8%) pts, respectively; 44 had not received prior cytoreductive therapy. IFN therapy included peg-IFN (43), ropeg (22), or both (17).
Median duration of follow up was 92 months (mos) from diagnosis and 59 mos from IFN initiation. Median duration of therapy was not reached, with 82% of pts remaining on IFN at 48 mos. At last follow up, 17 pts had discontinued therapy (12 intolerance, 2 lack of response, and 3 treatment-free remission [TFR]). One death occurred during follow up (not disease/treatment related).
Complete hematologic remission (CHR) was achieved in 66 (80.5%) pts. Thrombotic events occurred in 4 (4.9%) pts, 2 of whom had prior history of thrombosis. No pts progressed to MF, but one pt progressed to acute myeloid leukemia (NPM1 mutated/JAK2 wildtype) 10 mos after achieving undetectable JAK2 and proceeding with TFR.
Median VAF at baseline was 28%, with pts achieving a median nadir of 4.2% at a median of 41.5 mos. The median absolute change in VAF was -18.7; median percent change was -81.6%. Complete molecular response (undetectable JAK2) occurred in 4 (4.9%) pts, and 65 (79.2%) achieved ³50% reduction. A VAF nadir <1% was achieved in 16 (19.5%) pts and nadir <5% in 42 (53.2%) pts. Decreasing VAF was observed with ongoing therapy, with median VAF of 9.9% at 12-24 mos, 3.7% at 24-36 mos, and 2.2% at 36-48 mos, with relative stability to month 72 and then increasing to 9.7% beyond 72 mos. The later increase in part reflects pts who discontinued therapy. No baseline characteristics were predictive of VAF reduction. TFR was pursued in 7 pts after a median of 45 mos of therapy; median VAF was 0.52%. Median duration of TFR was 39 mos, with 3 pts resuming therapy (2 for loss of CHR, 1 for increased symptoms).Conclusions: This real-world analysis demonstrates the feasibility and efficacy of IFN therapy in clinical practice. Most pts achieved sustained CHR with low treatment discontinuation rate; thrombotic and disease progression events were rare. Importantly, we demonstrate the substantial impact of IFN on reducing JAK2 allele burden. While largely unexplored in the real-world setting, this data supports observations from prospective clinical trials and highlights the potential of VAF assessment to monitor treatment efficacy and guide treatment cessation.
