ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis

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.

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Journal
Blood Advances
Published
2025-05-07
DOI
https://doi.org/10.1182/bloodadvances.2025015860
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
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article

ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis

Jean‐Jacques Kiladjian, Heiko Becker, Andreas Reiter, Carl C. Crodel et al.
Blood Advances
Myeloproliferative Neoplasms: Diagnosis and Treatment
article

ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis

Jean‐Jacques Kiladjian, Heiko Becker, Andreas Reiter, Carl C. Crodel, Thomas Lehmann, Angela Zhang, Olga Vinogradova, Caroline Hasselbalch Riley, Kate Burbury, Alessandro Maria Vannucchi, Claire N. Harrison, Andrew C. Perkins, Monika Wroclawska, David M. Ross, Anirudh Prahallad, Jagannath Kota, Vikas K Gupta, István Takács, María Teresa Gómez‐Casares, Grace Cleary, Min Lü, Florian Heinrich Heidel, Mariëlle J. Wondergem
article en

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.

Blood AdvancesVol. 9(16)
Semmelweis University (HU), South Australia Pathology (AU), Novartis (Switzerland) (CH), Royal Adelaide Hospital (AU), University of Freiburg (DE), Guy's and St Thomas' NHS Foundation Trust (GB), University of St.Gallen (CH), Université Paris Cité (FR), Heidelberg University (DE), Universitätsmedizin Greifswald (DE), Kantonsspital St. Gallen (CH), Peter MacCallum Cancer Centre (AU), University Medical Center Freiburg (DE), The Alfred Hospital (AU), University Hospital Heidelberg (DE), Copenhagen University Hospital (DK), Princess Margaret Cancer Centre (CA), Rigshospitalet (DK), Pirogov Russian National Research Medical University (RU), Medizinische Hochschule Hannover (DE), Novartis (India) (IN), Monash Alfred Psychiatry Research centre (AU), Assistance Publique – Hôpitaux de Paris (FR), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Azienda Ospedaliero-Universitaria Careggi (IT), Botkin Hospital (RU), Tisch Hospital (US), Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (RU), Jena University Hospital (DE), Hôpital Saint-Louis (FR), Centrum für Integrierte Onkologie (DE), Amsterdam University Medical Centers (NL), Novartis (Ireland) (IE), University Medical Centre Mannheim (DE), University of Florence (IT), Monash University (AU), Icahn School of Medicine at Mount Sinai (US)
Pfizer, AstraZeneca, Celgene, Incyte, Galecto, Astellas Pharma, Servier, Swedish Orphan Biovitrum, AOP Orphan, Blood Cancer UK, Novartis Pharma, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 86%
Myeloproliferative Neoplasms: Diagnosis and Treatment
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