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
PY - 2023/11/10
Y1 - 2023/11/10
N2 - 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.
AB - 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.
KW - Humans
KW - Aged
KW - Janus Kinase Inhibitors/adverse effects
KW - Primary Myelofibrosis/drug therapy
KW - Protein Kinase Inhibitors/adverse effects
KW - Nitriles/therapeutic use
KW - Hemoglobins/therapeutic use
KW - Janus Kinase 2/genetics
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85159629620&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/8ccda1c7-4b7f-33ff-9e25-9d814acd3d8a/
U2 - 10.1200/JCO.22.01972
DO - 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 -