Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor–Naïve Myelofibrosis: Phase III SENTRY Trial
Abstract
PURPOSE Ruxolitinib improves splenomegaly and symptoms in myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in Janus kinase inhibitor–naïve MF. METHODS In this double-blind, phase III trial, patients were randomly assigned (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Coprimary end points were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to week 24. RESULTS A total of 353 patients were randomly assigned. At week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolitinib group versus 28.0% of the placebo plus ruxolitinib group (difference, 21.8 percentage points; odds ratio, 2.58 [95% CI, 1.60 to 4.17]; P < .0001). Differences were evident by week 12 and through week 36. The AbsTSS coprimary end point was not met; however, symptom scores improved from baseline in both groups (−9.9 selinexor plus ruxolitinib, −10.9 placebo plus ruxolitinib), with no significant between-group difference. At a median follow-up of approximately 12 months, the overall survival (OS) hazard ratio was 0.43 ([95% CI, 0.19 to 1.00]; nominal P = .022). Grade ≥3 adverse events (AEs) occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib or placebo plus ruxolitinib groups, respectively, most commonly anemia, thrombocytopenia, and neutropenia. Nausea was more frequent with selinexor but predominantly low-grade and early. CONCLUSION In patients with JAK inhibitor–naïve MF, selinexor plus ruxolitinib met its coprimary end point of improved SVR35 but did not meet the AbsTSS coprimary end point, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known AE profiles of the individual agents.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (162)
Valentin Garcia-Gutierrez
Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
Yi Chai
Pietro Taverna
18Karyopharm Therapeutics, Newton, United States
Tomer Mark
4Karyopharm Therapeutics, Newton, United States
Amama Sadiq
Karyopharm Therapeutics, Newton, MA
Reshma Rangwala
Karyopharm Therapeutics, Newton, MA
Aitor Abuin Blanco
61Hospital Clínico de Santiago de Compostela, SANTIAGO DE COMPOSTELA, Spain
Haris Ali
Seo-Yeon Ahn
1Chonnam National University Hwasun Hospital, Hwasun-gun, Korea, Rep. of South
Haifa Kathrin Al-Ali
3Krukenberg Cancer-Center, University Hospital Halle (Saale), Halle, Germany
alberto Alvarez-Larran
3Hospital Clínic, Barcelona, Barcelona, Spain
Anna Angona
12Hospital Universitario Doctor Josep Trueta - ICO, Barcelona, Spain
Emanuele Ammatuna
Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Rosa Ayala
HOSPITAL 12 DE OCTUBRE, MADRID, Spain
Soo-Mee Bang
Fiorenza Barraco
10Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Service d'Hématologie Clinique, Pierre-Bénite, France
Sabrina Barriere
3CHU de Clermont-Ferrand, Service d'hématologie clinique, Clermont-Ferrand, France
Aart Beeker
Eloise Beggiato
10University Hospital City of Health and Science of Turin - Hospital Molinette, Complex Structure of Hematology, Torino, Italy
Petra Belohlavkova
104th Department of Internal Medicine – Haematology, Charles University Hospital, Hradec Kralove, Czech Republic
Christopher Benton
Bhavana Bhatnagar
16Ohio State University Comprehensive Cancer Center, Columbus, United States
Massimiliano Bonifacio
1University of Verona, Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Verona, Italy
Gabriela Borsaru
Prithviraj Bose
5University of Texas MD Anderson Cancer Center, Houston, United States
Françoise Boyer-Perrard
Joseph Brandwein
13University of Alberta, Edmonton, Canada
Massimo Breccia
25Hematology, Department of Translational and Precision Medicine, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy
Celeste Bremer
Aleksandra Butrym
17Wroclaw Medical University, Walbrzych, Poland
Nauman Butt
4ClatterbridgeCancer Centre, Haematology, Liverpool, United Kingdom
Marianna Caramella
17Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
Yariv Carasso
Hung Chang
20Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan
June-won Cheong
11Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
Ling-Jung Chiu
Dominik Chraniuk
11Hematology Ward, Wojewodzki Szpital Zespolony im. L. Rydygiera, Torun, Poland
Daniela Cilloni
24Hematology Division, Mauriziano Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
Blanca Xicoy Cirici
Carl Crodel
6Hematology/Oncology, Jena University Hospital, Jena, Germany
Julia Cunningham
Catalin Doru Danaila
Ruchi Desai
12Virginia Commonwealth University, Richmond, United States
Valerio De Stefano
6Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Timothy Devos
8Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium
Martin Donchev
Jan Van Droogenbroeck
Jarosław Dybko
Gabriel Etienne
9Hematology Department, Institut Bergonié, Bordeaux, France
Maria Angeles Fernandez Rodriguez
Fiona Fernando
2Imperial College Healthcare NHS Trust, Clinical Haematology, London, United Kingdom
Maria Laura Fox
6Hospital Universitario Vall d'Hebron, Barcelona, Spain
Mitul Gandhi
10Virginia Cancer Specialists, US Oncology Research, Gainesville, VA
Regina Garcia Delgado
15Hospital Universitario Virgen de la Victoria, Malaga, Spain
Elena Maria Elli
4Fondazione IRCCS San Gerardo dei Tintori, Divisione di ematologia e unità trapianto di midollo, Monza, Italy
José Valentín García-Gutiérrez
Nicolas Gauthier
Daniela Georgescu
Bartlomiej Getta
11Department of Haematology, Liverpool Hospital, Liverpool, Australia
Federica Gigli
14Divisione di Oncoematologia, IRCCS Istituto Europeo di Oncologia., Milano, Italy
Maria Pilar Giraldo Castellano
Krzysztof Giannopoulos
14Medical University of Lublin, Department of Experimental Hematooncology, Lublin, Poland
Nikki Granacher
15ZAS CADIX, Antwerp, Belgium
Stefanie Gröpper
Zhanet Grudeva-Popova
8Medical University of Plovdiv, Plovdiv, Bulgaria
Sebastian Grosicki
Department of Cancer Prevention, Medical University of Silesia, Katowice, Poland
Evgueniy Hadjiev
Anna Halpern
1University of Washington, Medicine (Hematology/Oncology), Seattle, United States
Claire Harrison
11Department of Haematology, Guy’s and St Thomas’ National Health Service Foundation Trust, London, United Kingdom
Eleftheria Hatzimichael
24Department of Haematology, Faculty of Medicine, University of Ioannina,Greece, Ioannina, Greece
Victor Higuero Saavedra
Holger Hebart
2Kliniken Ostalb, Mutlangen, Germany
Jesus Maria Hernandez Rivas
8Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain., Hematology Department, Salamanca, Spain
Antonin Hlusi
9Palacky University and University Hospital Olomouc, Olomouc, Czech Republic
Junshik Hong
Hsin-An Hou
10National Taiwan University Hospital, Taipei, Taiwan
Jonathan How
2Royal Victoria Hospital, McGill University, Division Oof Hematology, Montreal, Canada
Hui-Hua Hsiao
4Kaohsiung Medical University, Kaohsiung, Korea
Jean-Christophe Ianotto
14CHU de Brest, Brest, France
Ian Irving
Alessandra Iurlo
1Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Tania Jain
1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Anna Jonasova
91st Medical Department – Hematology, General Hospital, Prague, Czech Republic
Chul Won Jung
Jean-Jacques Kiladjian
Ilya Kirgner
21Department of Hematology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Maya Koren-Michowitz
6Asaf Haroffe Medical Center, Hematology, Holon, Israel
Jacek Krzanowski
7Specialist Hospital in Brzozow, Podkarpackie Oncology Center, Brzozow, Poland
Michal Kwiatek
2AIDPORT Clinical Trials Hospital, Skorzewo, Poland
David Lavie
2Hadassah Medical Center, Jerusalem, Israel
Sung-Eun Lee
11Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
Roberto Lemoli
Moshe Levy
4Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, United States
Elena Liew
1University of Alberta, Medicine, Edmonton, Canada
Michael Loschi
12Centre Hospitalier Universitaire de Nice, Nice, France
Alessandro Lucchesi
3IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Hematology Unit, Meldola, Italy
Ioan Macarie
Antoine Machet
22CHU de Tours, Hematology, Tours, France
John Mascarenhas
4Icahn School of Medicine at Mount Sinai, New York, United States
Dominiek Mazure
11Universitair Ziekenhuis Gent, Gent, Belgium
James McCloskey
John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, United States
Andrew McGregor
11Newcastle upon Tyne Hospitals NHS Foundation Trust, Haematology, Newcastle upon Tyne, United Kingdom
Adam Mead
1University of Oxford, Radcliffe Department of Medicine, Oxford, United Kingdom
Elena Mishchenko
Sanjay Mohan
3Vanderbilt University Medical Center, Department of Medicine, Division of Hematology and Medical Oncology, Nashville, United States
Anthony Naassan
Kalyan Nadiminti
3University of Wisconsin-Madison - Carbone Cancer Center, Division of Hematology, Oncology, Palliative Care, Madison, United States
Zsolt Nagy
32Semmelweis University, Department of Internal Medicine and Hematology, Division of Hematology, Budapest, Hungary
Mohit Narang
Luminita Ocroteala
7Filantropia Municipal Clinical Hospital, Craiova, Romania
Mario Ojeda-Uribe
16Mulhouse Hospital, Clinical Hematology, Mulhouse, France
Santiago Osorio Prendes
7Hospital Universitario Gregorio Marañón, Hematology and Hemotherapy, Madrid, Spain
Jennifer O'Sullivan
8Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Francesca Palandri
2Seragnoli Hematology Institute, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Giuseppe Palumbo
6Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, University of Catania, Catania, Italy
Panayiotis Panayiotidis
National and Kapodistrian University of Athens, Athens, Greece
Francesco Passamonti
University of Milan, Milan
Irene Pastor
Kruti Patel
2Oncology Hematology Care, Inc., Cincinnati, United States
Andrea Patriarca
Therapeutic Innovation in Hematology, Hematology Unit, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy
Raul Perez Lopez
14Hospital Clínico Universitario Virgen de la Arrixaca, Murcia. Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB., Murcia, Spain
Erin Pettijohn
5The Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI
Giuseppe Pietrantuono
32IRCCS CROB, Referral Cancer Center of Basilicata, Rionero In Vulture, Italy
Nikolai Podoltsev
15Yale University, New Haven, United States
Witold Prejzner
7Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii, Gdańsk, Poland
Atanas Radinoff
Department of Clinical Hematology, University Hospital St. Ivan Rilski, Sofia, Bulgaria
Raajit Rampal
15Memorial Sloan Kettering Cancer Center, New York, United States
Lindsay Rein
10Duke University School of Medicine, Durham, United States
Philippe Renaudier
Roland Repp
Luigi Rigacci
21Department of Hematology, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Ciro Rinaldi
1United Lincolnshire Hospitals NHS Trust – Pilgrim Hospital, Boston, United Kingdom
David Ross
1Royal Adelaide Hospital and SA Pathology, Adelaide, Australia
Elisa Rumi
19Department of Molecular Medicine, University of Pavia, Pavia, Italy
Eszter Sári
Gary Schiller
7David Geffen School of Medicine at UCLA, Los Angeles, United States
Adrian Segura Diaz
1H. U. Dr. Negrin de Gran Canaria, Las Palmas, Spain
Marianne Tang Severinsen
HoJin Shin
Sang Kyun Sohn
6Department of Hematology/Oncology, Kyungpook National University Hospital, Daegu, Korea
Damianos Sotiropoulos
1G. Papanicolaou Hospital, BMT Unit - Department of Hematology, Thessaloniki, Greece
Galia Stemer
4The Galilee Medical Center, Hematology, Naharia, Israel
Srinivas Tantravahi
16Huntsman Cancer Institute, Salt Lake City, United States
Andrew Srisuwananukorn
10Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
Don Stevens
3Norton Cancer Institute, Louisville, United States
Peter Tan
10One Clinical Research Pty Ltd, Nedlands, Australia
Evangelos Terpos
Maria D. Todorova
Panagiotis Tsirigotis
6Attikon University Hospital, National and Kapodistrian University of Athens, 2nd Department of Internal Medicine and Research Institute, Hematology Unit, Athens, Greece
Inna Tsoran-Rosenthal
Laura Gabriela Urian
6Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
Pankit Vachhani
25University of Alabama at Birmingham Cancer Center, Birmingham, United States
Peter Buur van Kooten Niekerk
Alessandro Vannucchi
5Center Research and Innovation of Myeloproliferative Neoplasms, Dipartimento di Medicina Sperimentale e Clinica, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy
Georgios Vasilopoulos
Yulia Volchek
1Chaim Sheba Medical Center, Tel-Hashomer, Israel
Mathieu Wemeau
1CHU LILLE, Department of Hematolgy, LILLE, France
Stefan Wickenhauser
15Centre Hospitalier Nîmes, Department of Hematology, Nîmes, France
Lindsay Wilde
1Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Department of Medical Oncology, Philadelphia, United States
Lise Willems
20CHU Cochin, Hematology, Paris, France
Basem William
1OhioHealth Marion General Hospital, Columbus, United States
Su-Peng Yeh
China Medical University Hospital, Taichung, Taiwan