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Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study

2023; Elsevier BV; Volume: 401; Issue: 10373 Linguagem: Inglês

10.1016/s0140-6736(22)02036-0

1474-547X

Srđan Verstovšek, Aaron T. Gerds, Alessandro M. Vannucchi, Haifa Kathrin Al‐Ali, David Lavie, Andrew Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela Lazaroiu, Miklós Egyed, María Laura Fox, Donal P. McLornan, Andrew C. Perkins, Sung‐Soo Yoon, Vikas Gupta, Jean‐Jacques Kiladjian, Nikki Granacher, Sung‐Eun Lee, Luminita Ocroteala, Francesco Passamonti, Claire Harrison, Barbara Klencke, Sunhee Ro, Rafe Donahue, Jun Kawashima, Ruben A. Mesa, Adi Shacham Abulafia, Haifa Kathrin Al‐Ali, Björn Andréasson, Anna Angona, Rosa Ayala, Soo‐Mee Bang, Bruce Bank, Fiorenza Barraco, Eloise Beggiato, Fleur Samantha Benghiat, Massimiliano Bonifacio, Claire Bories, Gabriela Borsaru, Mette Brabrand, Andrei Braester, Andes Broliden, Veronika Buxhofer‐Ausch, Nathalie Cambier, Marianna Caramella, Benjamin Carpentier, Nicola Cascavilla, Maria Giraldo Castellano, Chang Hung Kiang, Chih‐Cheng Chen, June‐Won Cheong, Yunsuk Choi, Philip Choi, Maria Teresa Corsetti, Isabel Montero Cuadrado, Julia Cunningham, Gandhi Damaj, Valerio De Stefano, Robert Delage, Regina Garcĺa Delgado, José Miguel Torregrosa Diaz, Péter Dombi, Viviane Dubruille, Miklós Egyed, Daniel El Fassi, Anna Elinder-Camburn, Elena Maria Elli, Martin Ellis, Carmen Fava, Salman Fazal, Angela Fleischman, Lynda Foltz, María Laura Fox, Nashat Gabrail, Jose Valentĺn Garcĺa-Gutiérrez, Aaron T. Gerds, Stéphane Girault, Heinz Gisslinger, Alexandru Gluvacov, Yeow Tee Goh, Joachim R. Göthert, Nikki Granacher, Sebastian Grosicki, Vikas Gupta, Evgeni Hadjiev, Kaoutar Hafraoui, Aryan Hamed, Claire Harrison, Hans Carl Hasselbalch, Hanns Hauser, Mark Heaney, Holger Hebart, Jesús María Hernández‐Rivas, Victor Higuero Saavedra, Christopher Hillis, Hsin‐An Hou, Jonathan P. How, Daniel Huang, Marek Hus, Árpád Illés, Alessandro Isidori, Alessandra Iurlo, Vadim T. Ivanov, Peter Johansson, Chul Won Jung, Jean‐Jacques Kiladjian, Ilya Kirgner, Maya Koren‐Michowitz, Steffen Koschmieder, Szabolcs Ors Kosztolanyi, Natalia Kreiniz, Andrew Kuykendall, Jonathan Lambert, Kamel Laribi, Axelle Lascaux, Noa Lavie, David Lavie, Mihaela Lazaroiu, Michael F. Leahy, Ewa Lech‐Marańda, Sung‐Eun Lee, Won Sik Lee, Ollivier Legrand, Roberto M. Lemoli, James Liang, Sung-Nam Lim, Michaël Loschi, Alessandro Lucchesi, Ioan Macarie, Jean‐Pierre Marolleau, Maurizio Martelli, Jiřı́ Mayer, James A. McCloskey, Christopher McDermott, Donal P. McLornan, Brandon McMahon, Priyanka Mehta, Ruben A. Mesa, Gábor Mikala, Dragana Milojković, Philippe Mineur, Elena Mishchenko, Joon Ho Moon, Z.P. Nagy, Srinivasan Narayanan, Casey L. O’Connell, Luminita Ocroteala, Stephen T. Oh, Mario Ojeda‐Uribe, Kiat Hoe Ong, Folashade Otegbeye, Jeanne Palmer, Fabrizio Pane, Francesco Passamonti, Andrea Patriarca, Andrew C. Perkins, Giuseppe Pietrantuono, Márk Plander, Uwe Platzbecker, Ritam Prasad, Witold Prejzner, Tobias Rachow, Atanas Radinoff, László Rejtő, Ciro R. Rinaldi, Tadeusz Robak, Angeles Fernández‐Rodríguez, Aaron Ronson, David M. Ross, Tomasz Sacha, Parvis Sadjadian, Antonio Salar, Guillermo Sanz Santillana, Christof Scheid, Aline Schmidt, Marianne Tang Severinsen, Vera Stoeva, Paweł Szwedyk, Mario Tiribelli, Karolin Trautmann‐Grill, Amy M. Trottier, Nikolay Tzvetkov, Janusz van Droogenbroeck, Alessandro M. Vannucchi, Srđan Verstovšek, Nicola Vianelli, Nikolas von Bubnoff, Dominik Wolf‎, Dariusz Woszczyk, T Woźny, Tomasz Wróbel, Blanca Xicoy, Su‐Peng Yeh, Sung‐Soo Yoon,

Chronic Myeloid Leukemia Treatments

Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.Sierra Oncology.