ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis
Abstract: Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative...
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Elsevier
2025-08-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925002794 |
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| author | David M. Ross Florian H. Heidel Andrew Charles Perkins Andreas Reiter Carl Crodel Caroline Riley María Teresa Gómez-Casares Istvan Takacs Heiko Becker Thomas Lehmann Olga Vinogradova Kate Burbury Alessandro M. Vannucchi Vikas Gupta Marielle Wondergem Jean-Jacques Kiladjian Grace Cleary Angela Zhang Jagannath Kota Anirudh Prahallad Monika Wroclawska Min Lu Claire N. Harrison |
| author_facet | David M. Ross Florian H. Heidel Andrew Charles Perkins Andreas Reiter Carl Crodel Caroline Riley María Teresa Gómez-Casares Istvan Takacs Heiko Becker Thomas Lehmann Olga Vinogradova Kate Burbury Alessandro M. Vannucchi Vikas Gupta Marielle Wondergem Jean-Jacques Kiladjian Grace Cleary Angela Zhang Jagannath Kota Anirudh Prahallad Monika Wroclawska Min Lu Claire N. Harrison |
| author_sort | David M. Ross |
| collection | DOAJ |
| description | Abstract: Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821. |
| format | Article |
| id | doaj-art-ede6de5863b5493fadd83cbeeb33264e |
| institution | DOAJ |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-ede6de5863b5493fadd83cbeeb33264e2025-08-20T03:05:52ZengElsevierBlood Advances2473-95292025-08-019164195420510.1182/bloodadvances.2025015860ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosisDavid M. Ross0Florian H. Heidel1Andrew Charles Perkins2Andreas Reiter3Carl Crodel4Caroline Riley5María Teresa Gómez-Casares6Istvan Takacs7Heiko Becker8Thomas Lehmann9Olga Vinogradova10Kate Burbury11Alessandro M. Vannucchi12Vikas Gupta13Marielle Wondergem14Jean-Jacques Kiladjian15Grace Cleary16Angela Zhang17Jagannath Kota18Anirudh Prahallad19Monika Wroclawska20Min Lu21Claire N. Harrison22Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, AustraliaHematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; Klinik und Poliklinik für Innere Medizin C, Universitätsklinikum Greifswald, Greifswald, GermanyAustralian Centre for Blood Diseases, Monash University and Alfred Hospital, Melbourne, VIC, AustraliaDepartment of Hematology and Oncology, University Hospital Mannheim, Mannheim, GermanyKlinik für Innere Medizin II Abt. Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, GermanyDepartment of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkHospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria, SpainClinic of Internal Medicine and Oncology, Semmelweis University, Budapest, HungaryDepartment of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyClinic for Medical Oncology and Hematology, Cantonal Hospital St Gallen, St Gallen, SwitzerlandMoscow City Hematology Centre, Botkin Hospital, Moscow, Russia; Dmitry Rogachev National Research Center of Pediatric Hematology/Oncology and Immunology, Moscow, Russia; Pirogov Russian National Research Medical University, Moscow, RussiaDepartment of Haematology, Peter MacCallum Cancer Centre, Melbourne, AustraliaCenter for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, ItalyDepartment of Medicine, Princess Margaret Cancer Centre, Toronto, ON, CanadaDepartment of Hematology, Amsterdam University Medical Centers, Amsterdam, The NetherlandsDepartment of Hematology, Hôpital Saint-Louis and Université de Paris, Paris, FranceNovartis Ireland Limited, Dublin, IrelandNovartis Pharma AG, Basel, SwitzerlandNovartis Healthcare Pvt Ltd, Hyderabad, IndiaNovartis Pharma AG, Basel, SwitzerlandNovartis Pharma AG, Basel, SwitzerlandDivision of Hematology/Medical Oncology/Pathology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NYGuy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom; Correspondence: Claire N. Harrison, Haematology, Guy's and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, United Kingdom SE1 9RT;Abstract: Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.http://www.sciencedirect.com/science/article/pii/S2473952925002794 |
| spellingShingle | David M. Ross Florian H. Heidel Andrew Charles Perkins Andreas Reiter Carl Crodel Caroline Riley María Teresa Gómez-Casares Istvan Takacs Heiko Becker Thomas Lehmann Olga Vinogradova Kate Burbury Alessandro M. Vannucchi Vikas Gupta Marielle Wondergem Jean-Jacques Kiladjian Grace Cleary Angela Zhang Jagannath Kota Anirudh Prahallad Monika Wroclawska Min Lu Claire N. Harrison ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis Blood Advances |
| title | ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis |
| title_full | ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis |
| title_fullStr | ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis |
| title_full_unstemmed | ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis |
| title_short | ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis |
| title_sort | adore an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925002794 |
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