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Clonal expansion of JAK2V617F-mutated hematopoietic stem cells underlies almost all cases of PV, a rare myeloproliferative neoplasm.1 Nevertheless, the clinical relevance of reducing the variant allele frequency (VAF) (i.e., achieving molecular response [MR] to treatment) has been disputed. Prospective trials in PV are challenging given the latent onset and low penetrance of major outcomes such as thrombotic events and progression to myelofibrosis or acute myeloid leukemia.2 Therefore, recent analyses demonstrating a correlation of MR with prolonged EFS in high-risk PV patients resistant/intolerant to hydroxyurea generated strong interest.3, 4 If confirmed in a wider PV population, these findings suggest MR could be a major treatment aim. We examined the relationship between MR and EFS in the PROUD-PV/CONTINUATION-PV studies (#NCT01949805; #NCT02218047) in an early-stage PV population and explored the clinical relevance of further depleting the JAK2V617F clone. The phase 3 randomized PROUD-PV study and its extension CONTINUATION-PV enrolled low- and high-risk PV patients requiring cytoreduction who were treatment-naïve or hydroxyurea pre-treated for ≤3 years without resistance/intolerance. Design and methods have been published previously.5, 6 Patients were randomized 1:1 to receive ropeginterferon alfa-2b or hydroxyurea for 12 months. Ropeginterferon alfa-2b (BESREMi®) was started at a dose of 50–100 μg every 2 weeks and escalated until blood counts normalized, with a maximum dose of 500 μg. Hydroxyurea was administered at 500–3000 mg daily. Patients who enrolled in CONTINUATION-PV remained in their allocated treatment arm. Control arm patients could switch from hydroxyurea to any standard treatment (i.e., best available therapy [BAT]); those receiving ropeginterferon alfa-2b could extend the administration interval to every 3 or 4 weeks. The primary endpoint of both PROUD-PV and CONTINUATION-PV was the disease response rate; sample size calculations have been reported. Change in JAK2V617F VAF was a secondary endpoint assessed every 6 months; imputation of the last observation carried forward was utilized for missing values using an assay with a detection limit of 0.014% as previously described.6 Adverse events were recorded at every visit. Clinical outcomes (events defined as thromboembolic events, progression to myelofibrosis or acute myeloid leukemia, or death, derived from safety data) were assessed over ≥6 years. EFS by treatment arm (intent-to-treat analysis) was assessed using Kaplan–Meier analysis of time to first event. The analysis was repeated whereby patients switching to any interferon therapy as BAT for ≥12 months were included in the experimental arm. EFS was assessed by Kaplan–Meier analysis by JAK2V617F MR (defined by European LeukemiaNet criteria7) at the last available assessment. An extended Cox proportional hazard model was utilized to analyze the association between JAK2V617F VAF or MR (considering changing values over time) and the hazard of events. The analysis was repeated including age as a covariate. All analyses were performed on the CONTINUATION-PV full analysis set. The CONTINUATION-PV full analysis set comprised 95 patients allocated to ropeginterferon alfa-2b and 74 to hydroxyurea/BAT (Figure S1). Although patients with more advanced disease were not excluded from the studies,5, 7 baseline characteristics indicated an early-stage PV population: in both arms, the median age was ≤60 years and median duration since PV diagnosis was <2 months (Table 1). Disease-related symptoms and clinically significant splenomegaly were present in only 15.8% and 7.4% of patients respectively (ropeginterferon alfa-2b arm), and 23.0% and 10.8% respectively (control arm). Median treatment duration was 6.3 years (ropeginterferon alfa-2b arm) and 6.0 years (control arm). Patients in the control arm largely remained on hydroxyurea throughout the trial (88% of patients at month 72).8 Median JAK2V617F VAF declined from 37.3% at baseline to 8.5% after 6 years of ropeginterferon alfa-2b treatment; at the same time points, median VAF in the control arm increased from 39.4% to 50.4% (comparison of arms at Month 72: p < 0.0001).8 MR at 6 years was achieved in 66.0% of patients in the ropeginterferon alfa-2b arm and 19.4% in the control arm (RR; 3.23 [2.01–5.19]; p < 0.0001).8 Furthermore, ropeginterferon alfa-2b treated patients spent significantly more time in MR than those in the control arm (median cumulative proportion of time in MR: 66.7% vs. 8.4%; p = 0.01). EFS was significantly higher in the ropeginterferon alfa-2b arm; events occurred in 5/95 patients versus 12/74 patients allocated to hydroxyurea/BAT (p = 0.04 [log-rank test]).8 Seven patients switched from hydroxyurea to interferon as BAT for ≥12 months, three of whom subsequently achieved an MR. Kaplan–Meier analysis including these seven switched patients in the experimental arm rendered similar results to the intent-to-treat analysis, with significantly improved EFS among interferon-treated patients versus the control group (events in 6/102 vs. 11/67, respectively; p = 0.04 [log-rank test]). Analysis of the entire cohort regardless of treatment showed EFS was significantly improved among patients who had an MR at the last available assessment (events in 3/78 vs. 14/89 patients; HR: 0.24 [95% CI: 0.07–0.83], p = 0.002 [Cox PH model]; p = 0.001 [log-rank]; Figure 1). Events occurred in 3.8% of patients who achieved MR versus 15.7% in those with no MR (p = 0.02 [Fisher's exact test]). The same trend was observed within each treatment arm (ropeginterferon alfa-2b arm: events in 3.3% with MR vs. 8.8% with no MR; control arm: 5.9% versus 20.0%, respectively). Applying an extended model incorporating changes in MR during treatment, the HR for responders versus non-responders was 0.185 (95% CI: 0.040, 0.866; p = 0.03), indicating that responders had an approximately 80% lower risk of events than patients without MR. Regarding quantitative JAK2V617F VAF over time, the HR for events was 1.042 (95% CI: 1.023–1.062; p = 0.0001), translating to a 4.2% increase for each percentage point increase in absolute VAF. Figure 2 depicts the relationship between HR and JAK2V617F VAF for a reference VAF of 50%. The association between JAK2V617F VAF and EFS remained statistically significant when age was included as a covariate (HR for JAK2V617F VAF: 1.039; p < 0.0001). Safety findings over the entire PROUD-PV and CONTINUATION-PV study duration have been published previously.8 The present analysis shows for the first time that MR correlates with improved EFS in patients with early-stage PV. Our findings expand on results from the MAJIC-PV study reporting the same correlation in patients with more advanced disease.3 In both these studies, patients who achieved MR had prolonged EFS independently of the treatment administered. Ropeginterferon alfa-2b, an agent that preferentially targets JAK2V617F-mutated hematopoietic stem cells,9 induced a significantly higher MR rate than hydroxyurea/BAT over a 6-year period in PROUD-PV/CONTINUATION-PV.8 Prolonged EFS seen in the ropeginterferon alfa-2b arm corroborates the relationship between MR and the risk of events in PV.8 Overall, these results imply that the anti-clonal capability of alfa interferon may underpin improved long-term outcomes in PV patients treated with alfa interferons versus other cytoreductive therapies as reported in retrospective studies.10, 11 The degree of JAK2V617F VAF reduction achieved may be clinically important beyond the threshold of MR, reflecting the known gene dosage effect on phenotype and prognosis.1, 12-15 Modelling of changes in mutational burden over time showed a significant change in the risk of events for each percentage point change of JAK2V617F VAF, suggesting that PV treatment should aim to diminish JAK2V617F clones. A limitation of this analysis is that the PROUD-PV/CONTINUATION-PV studies, such as the MAJIC-PV study, were originally designed to evaluate disease response and were not powered to analyze EFS.3, 5 The first randomized clinical study in PV to evaluate EFS as a primary outcome, MITHRIDATE (#NCT04116502) may provide further answers on the potential of current treatments to alter the natural history of PV. In conclusion, in line with the MAJIC-PV study, these data suggest that the aims of PV treatment should be reconsidered to include depletion of JAK2V617F mutated cells to modify the course of the disease, an endpoint that can be effectively achieved with ropeginterferon alfa-2b. The studies were funded by AOP Health. The authors would like to thank the patients and their families, and the study support staff. Jean-Jacques Kiladjian: Investigation; writing—review and editing; conceptualization. Christoph Klade: Writing—review and editing; conceptualization; methodology. Pencho Georgiev: Investigation; writing—review and editing. Dorota Krochmalczyk: Investigation; writing—review and editing. Liana Gercheva-Kyuchukova: Investigation; writing—review and editing. Miklos Egyed: Investigation; writing—review and editing. Petr Dulicek: Investigation; writing—review and editing. Arpad Illes: Investigation; writing—review and editing. Halyna Pylypenko: Investigation; writing—review and editing. Lylia Sivcheva: Investigation; writing—review and editing. Jiří Mayer: Investigation; writing—review and editing. Vera Yablokova: Investigation; writing—review and editing. Kurt Krejcy: Writing—review and editing; conceptualization; methodology. Victoria Empson: Conceptualization; writing—original draft; writing—review and editing; supervision. Hans C. Hasselbalch: Writing—review and editing; methodology. Robert Kralovics: Writing—review and editing; methodology. Heinz Gisslinger: Investigation; writing—review and editing; methodology. J. J. K. reports grants and personal fees from AOP Health, and personal fees from Novartis, BMS/Celgene, AbbVie, and PharmaEssentia. J. M. reports grants from AOP Health. R. K. reports personal fees from AOP Health, PharmaEssentia, Qiagen, and Novartis, and stock ownership in MyeloPro Diagnostics and Research. H. H. reports Data Monitoring Board honoraria from AOP Health and grants from Novartis. C. K., K. K., and V. E. report that they are employees of AOP Health. H. G. reports grants and personal fees from AOP Health and Novartis, and personal fees from BMS-Pharma. The remaining authors have no conflicts of interest to disclose. The PROUD-PV/CONTINUATION-PV studies were funded by AOP Health. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. 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