PELABRESIB (CPI-0610) IMPROVED ANEMIA ASSOCIATED WITH MYELOFIBROSIS: INTERIM RESULTS FROM MANIFEST PHASE 2 STUDY
Author(s): ,
Srdan Verstovsek
Affiliations:
The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Marina Kremyanskaya
Affiliations:
Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute,New York,United States
,
John Mascarenhas
Affiliations:
Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute,New York,United States
,
Moshe Talpaz
Affiliations:
The University of Michigan, Rogel Cancer Center,Ann Arbor,United States
,
Claire Harrison
Affiliations:
Guy's and St Thomas' Hospital,London,United Kingdom
,
Raajit Rampal
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Andrea Patriarca
Affiliations:
Azienda Ospedaliero Universitaria Maggiore della Carità di Novara SCDU Ematologia,Novara,Italy
,
Vikas Gupta
Affiliations:
Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada
,
Nikki Granacher
Affiliations:
Ziekenhuis Netwerk Antwerpen,Antwerp,Belgium
,
Tim Somervaille
Affiliations:
Manchester Institute, The University of Manchester,Manchester,United Kingdom
,
Gary Schiller
Affiliations:
David Geffen School of Medicine at UCLA,Los Angeles,United States
,
Mark Drummond
Affiliations:
Beatson West of Scotland Cancer Centre,Glasgow,United Kingdom
,
Linda Foltz
Affiliations:
University of British Columbia, St. Paul’s Hospital,Vancouver,Canada
,
Jonathan Lambert
Affiliations:
University College London Hospitals NHS Foundation Trust,London,United Kingdom
,
Witold Prejzner
Affiliations:
Department of Hematology and Transplantology Medical University of Gdansk,Gdansk,Poland
,
Gozde Colak
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Patricia Keller
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
James Shao
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Katarina Luptakova
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Ronald Hoffman
Affiliations:
Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute,New York,United States
,
Prithviraj Bose
Affiliations:
The University of Texas, MD Anderson Cancer Center,Houston,United States
Alessandro Vannucchi
Affiliations:
Azienda Ospedaliero Universitaria Careggi,Firenze,Italy
EHA Library. Verstovsek S. 06/09/21; 324800; EP1077
Dr. Srdan Verstovsek
Dr. Srdan Verstovsek
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1077

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, has the potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in the clonal disease cells of origin in myelofibrosis (MF). Furthermore, pelabresib promotes maturation and ex vivo differentiation of erythroid progenitors (Mertz, ASH 2020). Many MF patients (pts) treated with ruxolitinib (rux) develop worsening anemia and may become red blood cell (RBC) transfusion-dependent (TD) which represents a significant unmet medical need. Here we report improvement of anemia in advanced MF pts as evidenced by achievement of RBC-transfusion independence (TI) in TD pts or sustained mean hemoglobin (Hgb) increase of ≥1.5g/dL for 12 wks in non-transfusion dependent (non-TD) pts. 

Aims
Evaluation of pelabresib monotherapy or as add-on to rux in advanced MF pts.

Methods
MANIFEST is an ongoing, open-label Phase 2 study. In Arm 1, pts that were refractory, intolerant or ineligible for JAKi were treated with pelabresib monotherapy. A washout of ≥2 wks since last systemic MF therapy was required. In Arm 2, pts receiving rux but not deriving adequate benefit were treated with pelabresib add-on to rux. Pts are stratified to cohorts 1A and 2A if they were TD (receiving ≥6U RBCs/12 wks) and into cohorts 1B and 2B as non-TD if they did not meet TD criteria.  Primary endpoint was achievement of TI ≥12 wks in TD cohorts; ≥35% spleen volume reduction at wk 24 in non-TD cohorts.

Results
As of 29 Sep 2020, 19 TD pts and 27 non-TD pts were treated in Arm 1 (monotherapy). 76% of pts had baseline Hgb <10g/dL (Median: 9, range: 6-15). Median number of prior therapies was 2 (1-6). Median time since last rux dose in non-TD cohort was 9.2 mo (range 0.5-46 mo). In TD cohort, 21% (3/14) of pts achieved TI (median duration of transfusion-free period: 44 wk, range 32-50). In non-TD cohort, mean Hgb increase ≥ 1.5 g/dL sustained over a 12-wk transfusion-free period was achieved by 59.1% (13/22) of pts among which only 1 pt received rux within 4 months of study entry, suggesting the increase in Hgb was not a consequence of rebound due to rux discontinuation.

In Arm 2, 52 TD pts and 26 non-TD pts were treated with pelabresib as add-on to rux. 76% of pts had baseline Hgb <10g/dL (median: 9, range: 6-13). In TD cohort, 36% (13/36) of pts achieved TI (median duration of transfusion-free period: 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-wks transfusion-free period.


In pts with an anemia response, the observed Hgb improvement or achievement of TI has been generally associated with an increase in reticulocyte count and/or increased CD71+ progenitor cells in the bone marrow, suggesting a positive pelabresib effect on erythroid differentiation.


Pelabresib was generally well tolerated. The most common treatment emergent adverse events include diarrhea (46%, ≥Gr3: 4%), thrombocytopenia (40%, ≥Gr3: 22%), nausea (36%, ≥Gr3: 2%), asthenic conditions (32%, ≥Gr3: 2%), respiratory tract infections (32%, ≥Gr3: 4% ), dysgeusia (26%, ≥Gr3: 1%) and cough (25%, no ≥Gr3).

Conclusion
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 heavily pretreated MF pts in Arm 1. Addition of pelabresib to rux in Arm 2 pts with suboptimal response on stable doses of rux 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.

Keyword(s): Anemia, Hemoglobin, Myelofibrosis, Ruxolitinib

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1077

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, has the potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in the clonal disease cells of origin in myelofibrosis (MF). Furthermore, pelabresib promotes maturation and ex vivo differentiation of erythroid progenitors (Mertz, ASH 2020). Many MF patients (pts) treated with ruxolitinib (rux) develop worsening anemia and may become red blood cell (RBC) transfusion-dependent (TD) which represents a significant unmet medical need. Here we report improvement of anemia in advanced MF pts as evidenced by achievement of RBC-transfusion independence (TI) in TD pts or sustained mean hemoglobin (Hgb) increase of ≥1.5g/dL for 12 wks in non-transfusion dependent (non-TD) pts. 

Aims
Evaluation of pelabresib monotherapy or as add-on to rux in advanced MF pts.

Methods
MANIFEST is an ongoing, open-label Phase 2 study. In Arm 1, pts that were refractory, intolerant or ineligible for JAKi were treated with pelabresib monotherapy. A washout of ≥2 wks since last systemic MF therapy was required. In Arm 2, pts receiving rux but not deriving adequate benefit were treated with pelabresib add-on to rux. Pts are stratified to cohorts 1A and 2A if they were TD (receiving ≥6U RBCs/12 wks) and into cohorts 1B and 2B as non-TD if they did not meet TD criteria.  Primary endpoint was achievement of TI ≥12 wks in TD cohorts; ≥35% spleen volume reduction at wk 24 in non-TD cohorts.

Results
As of 29 Sep 2020, 19 TD pts and 27 non-TD pts were treated in Arm 1 (monotherapy). 76% of pts had baseline Hgb <10g/dL (Median: 9, range: 6-15). Median number of prior therapies was 2 (1-6). Median time since last rux dose in non-TD cohort was 9.2 mo (range 0.5-46 mo). In TD cohort, 21% (3/14) of pts achieved TI (median duration of transfusion-free period: 44 wk, range 32-50). In non-TD cohort, mean Hgb increase ≥ 1.5 g/dL sustained over a 12-wk transfusion-free period was achieved by 59.1% (13/22) of pts among which only 1 pt received rux within 4 months of study entry, suggesting the increase in Hgb was not a consequence of rebound due to rux discontinuation.

In Arm 2, 52 TD pts and 26 non-TD pts were treated with pelabresib as add-on to rux. 76% of pts had baseline Hgb <10g/dL (median: 9, range: 6-13). In TD cohort, 36% (13/36) of pts achieved TI (median duration of transfusion-free period: 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-wks transfusion-free period.


In pts with an anemia response, the observed Hgb improvement or achievement of TI has been generally associated with an increase in reticulocyte count and/or increased CD71+ progenitor cells in the bone marrow, suggesting a positive pelabresib effect on erythroid differentiation.


Pelabresib was generally well tolerated. The most common treatment emergent adverse events include diarrhea (46%, ≥Gr3: 4%), thrombocytopenia (40%, ≥Gr3: 22%), nausea (36%, ≥Gr3: 2%), asthenic conditions (32%, ≥Gr3: 2%), respiratory tract infections (32%, ≥Gr3: 4% ), dysgeusia (26%, ≥Gr3: 1%) and cough (25%, no ≥Gr3).

Conclusion
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 heavily pretreated MF pts in Arm 1. Addition of pelabresib to rux in Arm 2 pts with suboptimal response on stable doses of rux 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.

Keyword(s): Anemia, Hemoglobin, Myelofibrosis, Ruxolitinib

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