Jean-Jacques Kiladjian1, Pierre Zachee2, Masayuki Hino3, Fabrizio Pane4, Tamas Masszi5, Claire N Harrison6, Ruben Mesa7, Carole B Miller8, Francesco Passamonti9, Simon Durrant10, Martin Griesshammer11, Keita Kirito12, Carlos Besses13, Beatriz Moiraghi14, Elisa Rumi15, Vittorio Rosti16, Igor Wolfgang Blau17, Nathalie Francillard18, Tuochuan Dong19, Monika Wroclawska20, Alessandro M Vannucchi21, Srdan Verstovsek22. 1. Hôpital Saint-Louis, Assitance Publique - Hôpitaux de Paris, Université de Paris, Inserm, Paris, France. Electronic address: jean-jacques.kiladjian@aphp.fr. 2. Ziekenhuis Netwerk Antwerpen, Stuivenberg, Antwerp, Belgium. 3. Department of Clinical Hematology, Osaka City University Graduate School of Medicine, Osaka, Japan. 4. University of Naples Federico II, Naples, Italy. 5. 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. 6. Guy's and St Thomas' NHS Foundation Trust, London, UK. 7. UT Health San Antonio Cancer Center, San Antonio, TX, USA. 8. Saint Agnes Cancer Institute, Baltimore, MD, USA. 9. Ospedale di Circolo e Fondazione Macchi, Varese, Italy. 10. Royal Brisbane and Women's Hospital, Brisbane, Australia. 11. Johannes Wesling Clinic, University of Bochum, Minden, Germany. 12. Department of Hematology and Oncology, University of Yamanashi, Japan. 13. Haematology Department, Hospital del Mar-IMIM, Universidad Autónoma de Barcelona, Barcelona, Spain. 14. Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina. 15. Department of Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 16. Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 17. Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité Universitätsmedizin Berlin, Germany. 18. Novartis Pharma SAS, Rueil Malmaison, France. 19. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 20. Novartis Pharma AG, Basel, Switzerland. 21. University of Florence, Florence, Italy. 22. The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. METHODS: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944. FINDINGS: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. INTERPRETATION: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. FUNDING: Novartis Pharmaceuticals Corporation.
BACKGROUND: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. METHODS: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944. FINDINGS: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. INTERPRETATION: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. FUNDING: Novartis Pharmaceuticals Corporation.
Authors: Srdan Verstovsek; Alessandro M Vannucchi; Martin Griesshammer; Tamas Masszi; Simon Durrant; Francesco Passamonti; Claire N Harrison; Fabrizio Pane; Pierre Zachee; Keita Kirito; Carlos Besses; Masayuki Hino; Beatriz Moiraghi; Carole B Miller; Mario Cazzola; Vittorio Rosti; Igor Blau; Ruben Mesa; Mark M Jones; Huiling Zhen; Jingjin Li; Nathalie Francillard; Dany Habr; Jean-Jacques Kiladjian Journal: Haematologica Date: 2016-04-21 Impact factor: 9.941
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Authors: Holly Geyer; Robyn Scherber; Heidi Kosiorek; Amylou C Dueck; Jean-Jacques Kiladjian; Zhijian Xiao; Stefanie Slot; Sonja Zweegman; Federico Sackmann; Ana Kerguelen Fuentes; Dolores Hernández-Maraver; Konstanze Döhner; Claire N Harrison; Deepti Radia; Pablo Muxi; Carlos Besses; Francisco Cervantes; Peter L Johansson; Bjorn Andreasson; Alessandro Rambaldi; Tiziano Barbui; Karin Bonatz; Andreas Reiter; Francoise Boyer; Gabriel Etienne; Jean-Christophe Ianotto; Dana Ranta; Lydia Roy; Jean-Yves Cahn; Norman Maldonado; Giovanni Barosi; Maria L Ferrari; Robert Peter Gale; Gunnar Birgegard; Zefeng Xu; Yue Zhang; Xiujuan Sun; Junqing Xu; Peihong Zhang; Peter A W te Boekhorst; Suzan Commandeur; Harry Schouten; Heike L Pahl; Martin Griesshammer; Frank Stegelmann; Thomas Lehmann; Zhenya Senyak; Alessandro M Vannucchi; Francesco Passamonti; Jan Samuelsson; Ruben A Mesa Journal: J Clin Oncol Date: 2015-11-23 Impact factor: 44.544
Authors: Barbara Mora; Paola Guglielmelli; Andrew Kuykendall; Elisa Rumi; Margherita Maffioli; Francesca Palandri; Valerio De Stefano; Marianna Caramella; Silvia Salmoiraghi; Jean-Jacques Kiladjian; Jason Gotlib; Alessandra Iurlo; Francisco Cervantes; Marco Ruggeri; Richard T Silver; Francesco Albano; Giulia Benevolo; David M Ross; Matteo G Della Porta; Timothy Devos; Giada Rotunno; Rami S Komrokji; Ilaria C Casetti; Michele Merli; Marco Brociner; Domenica Caramazza; Giuseppe Auteri; Tiziano Barbui; Daniele Cattaneo; Lorenza Bertù; Luca Arcaini; Alessandro M Vannucchi; Francesco Passamonti Journal: Leukemia Date: 2022-08-30 Impact factor: 12.883