TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis

The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.

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Journal
Blood
Published
2026-06-30
DOI
https://doi.org/10.1182/blood.2025032360
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
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article
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article

TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis

Francesca Palandri, Steffen Koschmieder, Jean‐Jacques Kiladjian, Francesco Passamonti et al.
Blood
Myeloproliferative Neoplasms: Diagnosis and Treatment
article

TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis

Francesca Palandri, Steffen Koschmieder, Jean‐Jacques Kiladjian, Francesco Passamonti, Qi Jiang, Adam J. Mead, Andrija Bogdanović, Elektra J. Papadopoulos, Su‐Peng Yeh, Jason G. Harb, Bryan C. Murray, Robert Delage, Andrew McDonald, Srinivas K. Tantravahi, Andrew C. Perkins, Ömür Gökmen Sevindik, Atanas Radinoff, Christopher B. Benton, Avijeet Chopra, Emanuele Ammatuna, María Teresa Gómez‐Casares, Naveen Pemmaraju, Tim C. P. Somervaille, Keita Kirito, Jalaja Potluri, Timothy Devos, Rastislav Moskal, Sung‐Soo Yoon, Noa Lavi
article en

Abstract

The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.

Blood
University Medical Center Groningen (NL), The University of Texas MD Anderson Cancer Center (US), Inserm (FR), Université du Québec à Montréal (CA), University of Groningen (NL), China Medical University (TW), Université Paris Cité (FR), University of Utah (US), Rega Institute for Medical Research (BE), Huntsman Cancer Institute (US), Churchill Hospital (GB), Rambam Health Care Campus (IL), The Alfred Hospital (AU), Seoul National University Hospital (KR), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), AbbVie (United States) (US), Istanbul Medipol University (TR), University of Belgrade (RS), Monash Alfred Psychiatry Research centre (AU), Assistance Publique – Hôpitaux de Paris (FR), Hospital Universitario de Gran Canaria Doctor Negrín (ES), University Hospital St. Ivan Rilski (BG), MRC Weatherall Institute of Molecular Medicine (GB), Centar za Promociju Nauke (RS), Istituto di Ematologia di Bologna (IT), China Medical University Hospital (TW), University Clinical Centre (PL), The Christie NHS Foundation Trust (GB), Rocky Mountain Cancer Centers (US), Netcare Unitas Hospital (ZA), Hôpital Saint-Louis (FR), Oxford BioMedica (United Kingdom) (GB), The US Oncology Network (US), ABB (Czechia) (CZ), Université Laval (CA), University of Yamanashi (JP), RWTH Aachen University (DE), KU Leuven (BE)
Openalex Percentile: Top 8%
Myeloproliferative Neoplasms: Diagnosis and Treatment
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