Tiziano Barbui1, Alessandro Maria Vannucchi2, Valerio De Stefano3, Arianna Masciulli4, Alessandra Carobbio4, Alberto Ferrari4, Arianna Ghirardi4, Elena Rossi3, Fabio Ciceri5, Massimiliano Bonifacio6, Alessandra Iurlo7, Francesca Palandri8, Giulia Benevolo9, Fabrizio Pane10, Alessandra Ricco11, Giuseppe Carli12, Marianna Caramella13, Davide Rapezzi14, Caterina Musolino15, Sergio Siragusa16, Elisa Rumi17, Andrea Patriarca18, Nicola Cascavilla19, Barbara Mora20, Emma Cacciola21, Carmela Mannarelli2, Giuseppe Gaetano Loscocco2, Paola Guglielmelli2, Silvia Betti3, Francesca Lunghi5, Luigi Scaffidi6, Cristina Bucelli7, Nicola Vianelli8, Marta Bellini22, Maria Chiara Finazzi22, Gianni Tognoni23, Alessandro Rambaldi24. 1. FROM, Fondazione per la Ricerca Ospedale di Bergamo, Bergamo, Italy. Electronic address: tbarbui@fondazionefrom.it. 2. CRIMM, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Florence, Italy. 3. Dipartimento di Scienze Radiologiche ed Ematologiche, Sezione di Ematologia, Università Cattolica del Sacro Cuore-Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. 4. FROM, Fondazione per la Ricerca Ospedale di Bergamo, Bergamo, Italy. 5. Unità Operativa di Ematologia e Trapianto Midollo Osseo, IRCCS Ospedale San Raffaele, Milan, Italy. 6. Department of Medicine, Section of Hematology, University of Verona, Policlinico Giambattista Rossi, Verona, Italy. 7. UOC Ematologia, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. 8. Institute of Hematology "L & A Seràgnoli", Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. 9. SC Ematologia, AOU Città della Salute e della Scienza di Torino-Presidio Ospedaliero Molinette, Turin, Italy. 10. UOC di Ematologia e Trapianti di Midollo, Azienda Ospedaliera Universitaria Federico II di Napoli, Napoli, Italy; Dipartimento di Medicina clinica e Chirurgia, Università di Napoli Federico II, Napoli, Italy. 11. U.O. Ematologia con Trapianto Azienda Ospedaliera Universitaria "Consorziale Policlinico" di Bari, Bari, Italy. 12. UOC Ematologia, Azienda ULSS 8 Berica Ospedale San Bortolo di Vicenza, Vicenza, Italy. 13. Divisione Ematologia, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy. 14. Divisione di Ematologia, Azienda Ospedaliera S. Croce e Carle di Cuneo, Cuneo, Italy. 15. UOC Ematologia, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy. 16. Divisione Ematologia, Azienda Ospedaliera Universitaria Policlinico "P. Giaccone", Palermo, Italy. 17. Divisione di Ematologia, Fondazione IRCCS Policlinico San Matteo Pavia, Pavia, Italy. 18. SCDU Ematologia, Azienda Ospedaliero Universitaria Maggiore della Carità, Novara, Italy. 19. UO Ematologia IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, San Giovanni Rotondo, Italy. 20. Divisione UO Ematologia, ASST dei Sette Laghi, Varese, Italy. 21. UOC di Emostasi Centro Federato FCSA, Azienda Ospedaliera Universitaria "Policlinico Vittorio Emanuele" PO Gaspare Rodolico, Catania, Italy. 22. UOC Ematologia, ASST Papa Giovanni XXIII, Bergamo, Italy. 23. IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. 24. UOC Ematologia, ASST Papa Giovanni XXIII, Bergamo, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
Abstract
BACKGROUND: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone. METHODS: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325. FINDINGS:Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. INTERPRETATION:Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. FUNDING: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.
RCT Entities:
BACKGROUND: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone. METHODS: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325. FINDINGS: Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. INTERPRETATION: Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. FUNDING: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.
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