Population Pharmacokinetics‐Pharmacodynamics and Exposure‐Response of Ropeginterferon Alfa‐2b in Chinese and Japanese Patients With Polycythemia Vera DOI Creative Commons
Albert Qin, Kazuya Shimoda,

Shanshan Suo

et al.

Pharmacology Research & Perspectives, Journal Year: 2025, Volume and Issue: 13(3)

Published: May 1, 2025

ABSTRACT Ropeginterferon alfa‐2b (ropeg) represents a new‐generation interferon‐based therapy approved for polycythaemia vera (PV) treatment. This study aimed to elucidate its population pharmacokinetics‐pharmacodynamics (PopPK‐PD) and exposure‐response (E‐R) relationships. A PopPK model was developed using pooled data from four clinical studies, including two Phase I studies in healthy volunteers ( n = 48) II Chinese or Japanese patients with PV 78). Sequential modeling used analyze (PK‐PD) regarding hematological parameters, hematocrit, platelet, white blood cell counts. Hematological changes were simulated fast‐ slow‐dose titration regimens. Individual exposure values the E‐R relationships complete hematologic response (CHR), driver mutation, JAK2 V617F allele burden, safety. In this study, we target‐mediated drug disposition model. Sigmoid indirect effects elucidated PK‐PD terms of changes. Simulations showed that fast‐titration regimen significantly accelerated hematocrit reduction. Logistic regression models probability achieving CHR increased at Week 24 but not 52. contrast, reductions correlated both Weeks Exposure‐safety analysis revealed manageable risk adverse events associated transaminase increases. established robust framework ropeg PK‐PD, providing insights into disease‐modifying action. Trial Registration: A17‐102, A19‐201, A20‐202 are registered ClinicalTrials.gov . The registration numbers as follows: NCT03546465; NCT04182100; A20‐202, NCT05485948. A17‐101 is www.chinadrugtrials.org.cn number CTR20190451

Language: Английский

Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment DOI Creative Commons
Heinz Gisslinger,

Christoph Klade,

Pencho Georgiev

et al.

Leukemia, Journal Year: 2023, Volume and Issue: 37(10), P. 2129 - 2132

Published: Aug. 26, 2023

Language: Английский

Citations

40
Clinical impact of mutated JAK2 allele burden reduction in polycythemia vera and essential thrombocythemia DOI
Paola Guglielmelli, Barbara Mora,

Francesca Gesullo

et al.

American Journal of Hematology, Journal Year: 2024, Volume and Issue: 99(8), P. 1550 - 1559

Published: June 6, 2024

Abstract The variant allele frequency (VAF) of driver mutations ( JAK2, CALR ) in myeloproliferative neoplasms is associated with features advanced disease and complications. Ruxolitinib interferon were reported to variably reduce the mutant VAF, but long‐term impact molecular responses (MR) remains debated. We prospectively measured changes JAK2 VAF 77 patients polycythemia vera essential thrombocythemia, treated ruxolitinib for a median 8 years, assessed correlation complete clinical hematological response (CCHR) outcomes. At last observation time, reduced overall from 68% (range, 20%–99%) 3.5% (0%–98%). A profound durable MR (DMR; defined as stably ≤2%), including 8%, was achieved 20% patients, partial (PMR; reduction >50% baseline level) 25%, 56% had no (NMR). CCHR reached by 69% overall, independently any degree achieved; conversely, DMR correlated longer duration and, most importantly, rate progression myelofibrosis myelofibrosis‐free, event‐free progression‐free survival. Achievement PMR also some favorable on outcomes, compared NMR. <50%, ≥35% after 2 years treatment, predicted achievement myelofibrosis. Overall, these findings support value achieving profound, its consideration surrogate endpoint future trials.

Language: Английский

Citations

16
Mechanism of Action of Ropeginterferon Alfa-2b in Polycythemia Vera Treatment DOI
Albert Qin

Clinical Therapeutics, Journal Year: 2024, Volume and Issue: 46(5), P. 439 - 440

Published: May 1, 2024

Language: Английский

Citations

11
Effective Management of Polycythemia Vera With Ropeginterferon Alfa-2b Treatment DOI Creative Commons

S. Suo,

Rong Feng Fu,

Albert Qin

et al.

Journal of Hematology, Journal Year: 2024, Volume and Issue: 13(1-2), P. 12 - 22

Published: April 1, 2024

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm. Ropeginterferon alfa-2b new-generation polyethylene glycol-conjugated proline-interferon. It approved for the treatment of PV at starting dose 100 µg (50 patients receiving hydroxyurea (HU)) and titrations up to 500 by 50 increments. The study was aimed assessing its efficacy safety higher simpler intra-patient escalation. Methods: Forty-nine with having HU intolerance from major hospitals in China were treated biweekly an initial 250 µg, followed 350 thereafter if tolerated. Complete hematological response (CHR) assessed every 12 weeks based on European LeukemiaNet criteria. primary endpoint CHR rate week 24. secondary endpoints included rates 12, 36 52, changes JAK2 V617F allelic burden, time first CHR, assessments. Results: 61.2%, 69.4% 71.4% 24, 36, respectively. Mean allele burden driver mutation declined 58.5% baseline 30.1% 52 weeks. Both reduction showed consistent increases over treatment. Twenty-nine (63.0%) achieved partial molecular (PMR) two complete (CMR). rapid median 5.6 months according central lab results. CHRs durable duration not reached 52. spleen index reduced 55.6 cm 2 50.2 Adverse events (AEs) mostly mild or moderate. Most common AEs reversible alanine aminotransferase aspartate increases, which associated significant elevations bilirubin levels jaundice. There no grade 4 5 AEs. Grade 3 manageable. Only one AE led discontinuation. No incidence thromboembolic observed. Conclusion: 250-350-500 dosing regimen well tolerated effectively induced MR managed size increase. Our findings demonstrate that ropeginterferon this can provide effective management support using as option. J Hematol. 2024;13(1-2):12-22 doi: https://doi.org/10.14740/jh1245

Language: Английский

Citations

10
Clearance of Driver Mutations after Transplantation for Myelofibrosis DOI
Nico Gagelmann,

Marie Quarder,

Anita Badbaran

et al.

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: 392(2), P. 150 - 160

Published: Jan. 8, 2025

Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for myelofibrosis. Driver mutations are pathophysiological hallmark of disease, but role mutation clearance after unclear. We used highly sensitive polymerase-chain-reaction technology to analyze dynamics driver in peripheral-blood samples from 324 patients with myelofibrosis (73% JAK2 mutations, 23% CALR and 4% MPL mutations) who were undergoing reduced-intensity conditioning. Mutations detected before at 30, 100, 180 days measure its effect on relapse cure. The two primary end points disease-free survival. At day 30 transplantation, was found 42% had 73% those 54% mutations; corresponding percentages 100 63%, 82%, 100%. cumulative incidence 1 year 6% (95% confidence interval [CI], 2 10) among 21% CI, 15 27) without 30. Disease-free overall survival 6 years 61% 74%, respectively, 41% 60%, Mutation appeared outperform traditional donor chimerism as a response; it independently associated reduced risk or progression (hazard ratio, 0.36; 95% 0.21 0.61) overcome differences prognosis based type (JAK2 vs. CALR). In myelofibrosis, influence survival, irrespective underlying mutation.

Language: Английский

Citations

2
Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL DOI Creative Commons
Aaron T. Gerds, Ruben A. Mesa, John M. Burke

et al.

Blood, Journal Year: 2023, Volume and Issue: 143(16), P. 1646 - 1655

Published: Dec. 24, 2023

Abstract Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and associated with an increased risk thrombotic events (TEs). Established factors for TEs in patients PV include advanced age, TE history, elevated hematocrit. Although association white blood cell (WBC) counts has been suggested retrospective studies, this relationship needs further validation. The prospective observational study polycythemia US clinical practices (REVEAL) collected data from 2510 median follow-up 44.7 months (range, 2-59 months) enrollment. Using time-dependent covariate Cox proportional hazards models, were individually modeled sex, disease duration, history at enrollment (baseline covariates), treatment (time-dependent covariate). Analysis 2271 participants identified 142 106 patients. Significant associations initial occurrence during the period observed hematocrit level &gt;45% (hazard ratio [HR], 1.84; 95% confidence interval [95% CI], 1.234-2.749; P = .0028) WBCs &gt;11 × 109/L (HR, 2.35; CI, 1.598-3.465; &lt; .0001). Elevated WBC count was significantly both low-risk high-risk PV. When controlled ≤45%, &gt;12 1.95; 1.066-3.554; .0300). results support incorporation into stratification studies strategies, indicate importance controlling management. This trial registered www.clinicaltrials.gov as #NCT02252159.

Language: Английский

Citations

22
JAK2V617Fmutation is highly prevalent in patients with ischemic stroke: a case-control study DOI Creative Commons
Marie Hvelplund Kristiansen, Lasse Kjær, Vibe Skov

et al.

Blood Advances, Journal Year: 2023, Volume and Issue: 7(19), P. 5825 - 5834

Published: July 31, 2023

Abstract Ischemic stroke has a high recurrence rate despite treatment. This underlines the significance of investigating new possible cerebrovascular risk factors, such as acquired gene mutation JAK2V617F found in 3.1% general population. We aimed to investigate prevalence population with ischemic compared that matched controls. enrolled 538 consecutive Danish patients (mean age, 69.5 ± 10.9 years; 39.2% female) within 7 days symptom onset. Using multiple-adjusted conditional logistic regression analysis, we age- and sex-matched controls free disease (ICVD) from General Suburban Population Study. DNA was analyzed for using sensitive droplet digital polymerase chain reaction Of stroke, 61 (11.3%) had mutation. There were no differences patient demographics or comorbidities between without mutations. Patients more likely have than controls, whom 4.4% (odds ratio, 2.37; 95% confidence interval, 1.57-3.58; P &lt; .001). A subanalysis stratified by smoking history revealed association strongest current smokers 4.78; 2.22-10.28; 2.4 times ICVD when adjusting other factors. finding supports novel factor.

Language: Английский

Citations

19
Hematologic and molecular responses to ropeginterferon alfa‐2b therapy of polycythemia vera: 48‐week results from a prospective study DOI Creative Commons
Seug Yun Yoon,

Sung‐Soo Yoon,

Deok‐Hwan Yang

et al.

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 15, 2025

Abstract To prevent thrombosis in patients with polycythemia vera (PV), achieving a complete hematologic response (CHR) is highly recommended practice. In addition, reduced JAK2 V617F mutation burden expected to have disease‐modifying effect, and its molecular (MR) currently of significant interest. This study aimed assess the association between CHR MR PV following treatment ropeginterferon alfa‐2b. phase 2, single‐arm, open‐label, investigator‐initiated trial was conducted at 16 sites South Korea. Ninety‐nine were treated alfa‐2b subcutaneously every 2 weeks, doses 250 μg (week 1), 350 3), 500 5), until week 48. CHRs 27% (25/94), 46% (40/87), 56% (47/84), 63% (51/81) 12, 24, 36, 48 respectively. The rates 32% (28/88), 36% (29/81), 49% (38/77), 57% (42/74) Phi Coefficient for 0.6146 ( p < .0001) weeks. subgroup analysis, hydroxyurea resistance or intolerance, those who hydroxyurea‐naïve, had similar results terms CHR. conclusion, observed be associated ropeginterferon.

Language: Английский

Citations

1
Moving toward disease modification in polycythemia vera DOI
Jan Philipp Bewersdorf, Joan How, Lucia Masarová

et al.

Blood, Journal Year: 2023, Volume and Issue: 142(22), P. 1859 - 1870

Published: Sept. 20, 2023

Language: Английский

Citations

16
Exposure–efficacy and exposure–safety analyses of ropeginterferon alfa‐2b treatment in patients with polycythaemia vera DOI
Albert Qin,

Daoxiang Wu,

Yaning Li

et al.

British Journal of Clinical Pharmacology, Journal Year: 2024, Volume and Issue: 90(6), P. 1493 - 1502

Published: March 19, 2024

To investigate the exposure-response (E-R) relationship, including exposure-efficacy and exposure-safety, of ropeginterferon alfa-2b treatment in patients with polycythaemia vera (PV).

Language: Английский

Citations

6