Francesco Passamonti1, Martin Griesshammer2, Francesca Palandri3, Miklos Egyed4, Giulia Benevolo5, Timothy Devos6, Jeannie Callum7, Alessandro M Vannucchi8, Serdar Sivgin9, Caroline Bensasson10, Mahmudul Khan11, Nadjat Mounedji12, Guray Saydam13. 1. Department of Hematology, University of Insubria, Varese, Italy. Electronic address: francesco.passamonti@asst-settelaghi.it. 2. Department of Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Clinic, Minden, Germany. 3. Department of Hematology/Oncology, Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy. 4. Hematology Department of Somogy County, Kaposi Mor Teaching Hospital, Kaposvar, Hungary. 5. Department of Hematology, Città della Salute e della Scienza di Torino, Turin, Italy. 6. Laboratory of Experimental Transplantation, Department of Microbiology and Immunology and Department of Hematology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 7. Department of Transfusion Medicine and Tissue Banks, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. 8. Department of Experimental and Clinical Medicine, Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, University of Florence, Florence, Italy. 9. Department of Hematology, Dedeman Stem Cell Transplantation Hospital, Erciyes University, Kayseri, Turkey. 10. Department of Clinical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 11. Department of Biostatistics, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 12. Department of Oncology, Novartis Pharma S.A.S., Rueil-Malmaison, France. 13. Department of Hematology, Ege University Medical Faculty, Izmir, Turkey.
Abstract
BACKGROUND: In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled withhydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. METHODS: RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by aninteractive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. FINDINGS:Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43-15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3-4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3-4 anaemia and three patients (4%) reported grade 3-4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3-4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. INTERPRETATION: RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. FUNDING: Novartis.
RCT Entities:
BACKGROUND: In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. METHODS: RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. FINDINGS: Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43-15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3-4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3-4 anaemia and three patients (4%) reported grade 3-4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3-4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. INTERPRETATION: RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyureapatient population. FUNDING: Novartis.
Authors: Tiziano Barbui; Ayalew Tefferi; Alessandro M Vannucchi; Francesco Passamonti; Richard T Silver; Ronald Hoffman; Srdan Verstovsek; Ruben Mesa; Jean-Jacques Kiladjian; Rȕdiger Hehlmann; Andreas Reiter; Francisco Cervantes; Claire Harrison; Mary Frances Mc Mullin; Hans Carl Hasselbalch; Steffen Koschmieder; Monia Marchetti; Andrea Bacigalupo; Guido Finazzi; Nicolaus Kroeger; Martin Griesshammer; Gunnar Birgegard; Giovanni Barosi Journal: Leukemia Date: 2018-02-27 Impact factor: 11.528