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MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis

PURPOSE: Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extratermin...

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Autores principales: Mascarenhas, John, Kremyanskaya, Marina, Patriarca, Andrea, Palandri, Francesca, Devos, Timothy, Passamonti, Francesco, Rampal, Raajit K., Mead, Adam J., Hobbs, Gabriella, Scandura, Joseph M., Talpaz, Moshe, Granacher, Nikki, Somervaille, Tim C. P., Hoffman, Ronald, Wondergem, Marielle J., Salama, Mohamed E., Colak, Gozde, Cui, Jike, Kiladjian, Jean-Jacques, Vannucchi, Alessandro M., Verstovsek, Srdan, Curto-García, Natalia, Harrison, Claire, Gupta, Vikas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer Health 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642902/
https://www.ncbi.nlm.nih.gov/pubmed/36881782
http://dx.doi.org/10.1200/JCO.22.01972
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author Mascarenhas, John
Kremyanskaya, Marina
Patriarca, Andrea
Palandri, Francesca
Devos, Timothy
Passamonti, Francesco
Rampal, Raajit K.
Mead, Adam J.
Hobbs, Gabriella
Scandura, Joseph M.
Talpaz, Moshe
Granacher, Nikki
Somervaille, Tim C. P.
Hoffman, Ronald
Wondergem, Marielle J.
Salama, Mohamed E.
Colak, Gozde
Cui, Jike
Kiladjian, Jean-Jacques
Vannucchi, Alessandro M.
Verstovsek, Srdan
Curto-García, Natalia
Harrison, Claire
Gupta, Vikas
author_facet Mascarenhas, John
Kremyanskaya, Marina
Patriarca, Andrea
Palandri, Francesca
Devos, Timothy
Passamonti, Francesco
Rampal, Raajit K.
Mead, Adam J.
Hobbs, Gabriella
Scandura, Joseph M.
Talpaz, Moshe
Granacher, Nikki
Somervaille, Tim C. P.
Hoffman, Ronald
Wondergem, Marielle J.
Salama, Mohamed E.
Colak, Gozde
Cui, Jike
Kiladjian, Jean-Jacques
Vannucchi, Alessandro M.
Verstovsek, Srdan
Curto-García, Natalia
Harrison, Claire
Gupta, Vikas
author_sort Mascarenhas, John
collection PubMed
description PURPOSE: Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). METHODS: MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks. RESULTS: Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response (P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks. CONCLUSION: The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.
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spelling pubmed-106429022023-11-15 MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis Mascarenhas, John Kremyanskaya, Marina Patriarca, Andrea Palandri, Francesca Devos, Timothy Passamonti, Francesco Rampal, Raajit K. Mead, Adam J. Hobbs, Gabriella Scandura, Joseph M. Talpaz, Moshe Granacher, Nikki Somervaille, Tim C. P. Hoffman, Ronald Wondergem, Marielle J. Salama, Mohamed E. Colak, Gozde Cui, Jike Kiladjian, Jean-Jacques Vannucchi, Alessandro M. Verstovsek, Srdan Curto-García, Natalia Harrison, Claire Gupta, Vikas J Clin Oncol ORIGINAL REPORTS PURPOSE: Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). METHODS: MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks. RESULTS: Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response (P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks. CONCLUSION: The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity. Wolters Kluwer Health 2023-11-10 2023-03-07 /pmc/articles/PMC10642902/ /pubmed/36881782 http://dx.doi.org/10.1200/JCO.22.01972 Text en © 2023 by American Society of Clinical Oncology https://creativecommons.org/licenses/by-nc-nd/4.0/Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/)
spellingShingle ORIGINAL REPORTS
Mascarenhas, John
Kremyanskaya, Marina
Patriarca, Andrea
Palandri, Francesca
Devos, Timothy
Passamonti, Francesco
Rampal, Raajit K.
Mead, Adam J.
Hobbs, Gabriella
Scandura, Joseph M.
Talpaz, Moshe
Granacher, Nikki
Somervaille, Tim C. P.
Hoffman, Ronald
Wondergem, Marielle J.
Salama, Mohamed E.
Colak, Gozde
Cui, Jike
Kiladjian, Jean-Jacques
Vannucchi, Alessandro M.
Verstovsek, Srdan
Curto-García, Natalia
Harrison, Claire
Gupta, Vikas
MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
title MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
title_full MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
title_fullStr MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
title_full_unstemmed MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
title_short MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
title_sort manifest: pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve myelofibrosis
topic ORIGINAL REPORTS
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642902/
https://www.ncbi.nlm.nih.gov/pubmed/36881782
http://dx.doi.org/10.1200/JCO.22.01972
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