Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1785147041492500480 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10642902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Wolters Kluwer Health |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mascarenhasjohn manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT kremyanskayamarina manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT patriarcaandrea manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT palandrifrancesca manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT devostimothy manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT passamontifrancesco manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT rampalraajitk manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT meadadamj manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT hobbsgabriella manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT scandurajosephm manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT talpazmoshe manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT granachernikki manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT somervailletimcp manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT hoffmanronald manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT wondergemmariellej manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT salamamohamede manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT colakgozde manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT cuijike manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT kiladjianjeanjacques manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT vannucchialessandrom manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT verstovseksrdan manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT curtogarcianatalia manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT harrisonclaire manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis AT guptavikas manifestpelabresibincombinationwithruxolitinibforjanuskinaseinhibitortreatmentnaivemyelofibrosis |