TY - JOUR
T1 - MANIFEST
T2 - Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis
AU - Mascarenhas, John
AU - Kremyanskaya, Marina
AU - Patriarca, Andrea
AU - Palandri, Francesca
AU - Devos, Timothy
AU - Passamonti, Francesco
AU - Rampal, Raajit K.
AU - Mead, Adam J.
AU - Hobbs, Gabriella
AU - Scandura, Joseph M.
AU - Talpaz, Moshe
AU - Granacher, Nikki
AU - Somervaille, Tim C. P.
AU - Hoffman, Ronald
AU - Wondergem, Marielle J.
AU - Salama, Mohamed E.
AU - Colak, Gozde
AU - Cui, Jike
AU - Kiladjian, Jean-Jacques
AU - Vannucchi, Alessandro M.
AU - Verstovsek, Srdan
AU - Curto-García, Natalia
AU - Harrison, Claire
AU - Gupta, Vikas
N1 - Funding Information: Supported by Constellation Pharmaceuticals Inc, a MorphoSys Company (Boston, MA). Medical writing support for this publication was provided by Torsten Gerike, Mark Winderlich, Pietro Taverna (MorphoSys Inc), and Ramya Kollipara (LiNK Medical). T.C.P.S. was supported by Cancer Research UK grant No. C5759/A20971. Publisher Copyright: © American Society of Clinical Oncology.
PY - 2023/11/10
Y1 - 2023/11/10
N2 - PURPOSEStandard 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).METHODSMANIFEST (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 â ‰¥ 35% (SVR35) at 24 weeks.RESULTSEighty-four patients received â ‰¥ 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 â ‰¥ 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 â ‰¥ 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 â ‰¥ 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.CONCLUSIONThe 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.
AB - PURPOSEStandard 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).METHODSMANIFEST (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 â ‰¥ 35% (SVR35) at 24 weeks.RESULTSEighty-four patients received â ‰¥ 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 â ‰¥ 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 â ‰¥ 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 â ‰¥ 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.CONCLUSIONThe 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.
UR - http://www.scopus.com/inward/record.url?scp=85159629620&partnerID=8YFLogxK
U2 - https://doi.org/10.1200/JCO.22.01972
DO - https://doi.org/10.1200/JCO.22.01972
M3 - Article
C2 - 36881782
SN - 0732-183X
VL - 41
SP - 4993
EP - 5004
JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
IS - 32
ER -