• Clinical benefit of pelabresib (Cpi-0610) in combination with ruxolitinib in JAK inhibitor treatment-naive myelofibrosis patients: interim efficacy subgroup analysis from Arm 3 of the MANIFEST Phase 2 Study

      Gupta, V.; Kremyanskaya, M.; Mascarenhas, J.; Palandri, F.; Patriarca, A.; Devos, T.; Harrison, C.; Passamonti, F.; Rampal, R.; Mead, A.; et al. (2021)
      Context: Pelabresib (CPI-0610), a fi rst-in-class, oral, small molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fi brotic, and infl ammatory factors in MF. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with approximately 30–40% splenic response (spleen volume reduction 35% [SVR35]) at 6 months. BETi pelabresib monotherapy demonstrated clinical activity in heavily pre-treated MF pts. Therefore, combination of pelabresib with rux is expected to achieve higher SVR35 response rate in JAKi treatment-naïve MF pts. Objective: Evaluation of pelabresib in combination with rux in JAKi treatment-naïve MF pts. Design: Pts with MF who were not previously treated with JAKi were enrolled in Arm 3 of MANIFEST. The primary endpoint is SVR35 response at wk 24. Pts were treated with pelabresib 125 mg daily on days 1–14 in a 21-day cycle in combination with rux, which was dosed based on the baseline platelet count. Results: As of 29 September 2020, 78 pts were treated, and 66 pts were ongoing. Baseline characteristics were mean age: 67 years; 72% male; primary MF: 54% pts; DIPSS Int-2: 76% pts; IPSS Int-2: 83%; Hgb <10g/dL: 65%; median platelet: 294 x 109 /L (range: 100, 1849); median spleen volume: 1719 cc (range: 451, 4782); median TSS: 16 (range: 0, 38); high molecular-risk mutations: 55%, JAK2 mutation: 72%. At wk 24, 67% (42/63) pts achieved SVR35 (median % change from baseline: -50%; range: -84.4%, 23.7%). Subgroup analysis showed that mean percentage change in spleen volume at wk 24 was consistent across subgroups based on gender, age, risk score, MF subtype, baseline platelet count, and baseline spleen size. Importantly, subgroup analysis based on molecular fi ndings showed a signifi cant benefi t regardless of the mutational status, including the presence of ASXL1 mutation, which generally carries a poor prognosis. Pelabresib was generally well tolerated. Conclusions: Pelabresib treatment in combination with rux in JAKi treatment-naïve MF pts resulted in spleen volume reduction that was greater than what would be expected with rux alone, regardless of baseline patient disease and demographic characteristics
    • Pelabresib (CPI-0610) improved anemia associated with myelofibrosis: interim results from the ongoing MANIFEST phase 2 study

      Bose, P.; Verstovsek, S.; Kremyanskaya, M.; Mascarenhas, J.; Talpaz, M.; Harrison, C.; Rampal, R.; Patriarca, A.; Gupta, V.; Granacher, N.; et al. (2021)
      Pelabresib (CPI-0610), a first-in-class, oral, small molecule inhibitor of BET proteins, has the potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fi brotic, and infl ammatory factors in MF. Many patients (pts) with MF treated with ruxolitinib (rux) develop worsening anemia and may become RBC transfusion-dependent (TD). Objective: Evaluation of pelabresib monotherapy or as add on to rux in advanced MF pts. Design: In Arm 1, pts refractory, intolerant, or ineligible for JAKi were treated with pelabresib monotherapy. In Arm 2, pts receiving rux but not deriving adequate benefi t were treated with add-on pelabresib. The primary endpoint was achievement of transfusion independence (TI) 12 wks in TD cohorts and 35% spleen volume reduction at wk 24 in non-TD cohorts. Results: As of 29 Sept. 2020, 19 TD pts and 27 non-TD pts were treated in Arm 1. Seventy-six percent of pts had baseline Hgb <10g/dL (median: 9, range: 6–15). In the TD cohort, 21% (3/14) of pts achieved TI (median duration: 44 wk, range: 32–50). In the non-TD cohort, a mean Hgb increase 1.5 g/dL sustained over a 12-wk transfusion-free period was achieved by 59.1% (13/22) of pts. In Arm 2, 52 TD pts and 26 non-TD pts were treated with pelabresib as add-on to rux. Seventy-six percent of pts had baseline Hgb <10g/dL (median: 9, range: 6–13). In the TD cohort, 36% (13/36) pts achieved TI (median duration: 39 wk, range: 18–148); 17.4% (4/23) of non-TD pts had mean Hgb increase 1.5 g/dL sustained over a 12-wk transfusion-free period. Hgb improvement/ achievement of TI has been associated with increased reticulocyte count and/or CD71+ progenitor cells in bone marrow, suggesting a positive effect on erythroid differentiation. Pelabresib was generally well tolerated. Conclusions: Pelabresib monotherapy was associated with a mean increase in Hgb 1.5 g/dL in majority of non-TD pts and conversion of one-fifth of TD pts to TI in Arm 1. Pelabresib add-on to rux in Arm 2 resulted in mean increase in Hgb 1.5 g/dL in 17% of non-TD pts and conversion to TI in more than one-third of TD pts.