EHA Library - The official digital education library of European Hematology Association (EHA)

BET INHIBITOR PELABRESIB (CPI-0610) COMBINED WITH RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS — JAK INHIBITOR-NAÏVE OR WITH SUBOPTIMAL RESPONSE TO RUXOLITINIB — PRELIMINARY DATA FROM THE MANIFEST STUDY
Author(s): ,
John Mascarenhas
Affiliations:
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,États-unis;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Vereinigte Staaten;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Stati Uniti;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,United States;Tisch Cancer Institute, Icahn School
,
Marina Kremyanskaya
Affiliations:
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,États-unis;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Vereinigte Staaten;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Stati Uniti;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,United States;Tisch Cancer Institute, Icahn School
,
Andrea Patriarca
Affiliations:
Hematology Unit, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità,Novara,Italie;Hematology Unit, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità,Novara,Italien;Hematology Unit, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità,Novara,Italia;Hematolog
,
Claire Harrison
Affiliations:
Guy's and St Thomas' NHS Foundation Trust,London,Royaume-uni;Guy's and St Thomas' NHS Foundation Trust,London,Vereinigtes Königreich;Guy's and St Thomas' NHS Foundation Trust,London,Regno Unito;Guy's and St Thomas' NHS Foundation Trust,London,United Kingdom;Guy's and St Thomas' NHS Foundation Trust,London,Reino Unido;Guy's and St Thomas' NHS Foundation Trust,London,Verenigd Koninkrijk;Guy's and St
,
Prithviraj Bose
Affiliations:
MD Anderson Cancer Center,Houston, TX,États-unis;MD Anderson Cancer Center,Houston, TX,Vereinigte Staaten;MD Anderson Cancer Center,Houston, TX,Stati Uniti;MD Anderson Cancer Center,Houston, TX,United States;MD Anderson Cancer Center,Houston, TX,Estados Unidos;MD Anderson Cancer Center,Houston, TX,Verenigde Staten;MD Anderson Cancer Center,Houston, TX,Estados Unidos;MD Anderson Cancer Center,Houst
,
Raajit K Rampal
Affiliations:
Memorial Sloan-Kettering Cancer Center,New York, NY,États-unis;Memorial Sloan-Kettering Cancer Center,New York, NY,Vereinigte Staaten;Memorial Sloan-Kettering Cancer Center,New York, NY,Stati Uniti;Memorial Sloan-Kettering Cancer Center,New York, NY,United States;Memorial Sloan-Kettering Cancer Center,New York, NY,Estados Unidos;Memorial Sloan-Kettering Cancer Center,New York, NY,Verenigde Staten;
,
Francesca Palandri
Affiliations:
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologna,Italie;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologna,Italien;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologna,Italia;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologn
,
Timothy Devos
Affiliations:
University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven,Leuven,Belgique;University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven,Leuven,Belgien;University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven,Leuven,Belgio;University Hospitals Leuven and Laboratory of Molecular Immunology (Re
,
Francesco Passamonti
Affiliations:
University of Insubria,Varese,Italie;University of Insubria,Varese,Italien;University of Insubria,Varese,Italia;University of Insubria,Varese,Italy;University of Insubria,Varese,Italia;University of Insubria,Varese,Italië;University of Insubria,Varese,Itália;University of Insubria,Varese,Италия;University of Insubria,Varese,Italien
,
Gabriela Hobbs
Affiliations:
Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School,Boston, MA,États-unis;Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School,Boston, MA,Vereinigte Staaten;Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School,Boston, MA,Stati Uniti;Division of Hematology/Oncology, Massachusetts General Hospit
,
Moshe Talpaz
Affiliations:
University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,États-unis;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Vereinigte Staaten;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Stati Uniti;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,United States;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Estados Unidos;Univ
,
Alessandro Vannucchi
Affiliations:
Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italie;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italien;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italia;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italy;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Floren
,
Jean-Jacques Kiladjian
Affiliations:
Hôpital Saint-Louis, Université de Paris,Paris,France;Hôpital Saint-Louis, Université de Paris,Paris,Frankreich;Hôpital Saint-Louis, Université de Paris,Paris,Francia;Hôpital Saint-Louis, Université de Paris,Paris,France;Hôpital Saint-Louis, Université de Paris,Paris,Francia;Hôpital Saint-Louis, Université de Paris,Paris,Frankrijk;Hôpital Saint-Louis, Université de Paris,Paris,França;Hôpital Saint
,
Srdan Verstovsek
Affiliations:
Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,États-unis;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,Vereinigte Staaten;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,Stati Uniti;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,United States;Leukemia Department, Univers
,
Ron Hoffman
Affiliations:
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,États-unis;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Vereinigte Staaten;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Stati Uniti;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,United States;Tisch Cancer Institute, Icahn School
,
Mohamed E Salama
Affiliations:
Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,États-unis;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,Vereinigte Staaten;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,Stati Uniti;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,United States;Leukemia Department, Univers
,
Dong Chen
Affiliations:
Mayo Clinic,Rochester, MN,États-unis;Mayo Clinic,Rochester, MN,Vereinigte Staaten;Mayo Clinic,Rochester, MN,Stati Uniti;Mayo Clinic,Rochester, MN,United States;Mayo Clinic,Rochester, MN,Estados Unidos;Mayo Clinic,Rochester, MN,Verenigde Staten;Mayo Clinic,Rochester, MN,Estados Unidos;Mayo Clinic,Rochester, MN,United States;Mayo Clinic,Rochester, MN,USA
,
Pietro Taverna
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Alex Chang
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Gozde Colak
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Sandra Klein
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
Vikas Gupta
Affiliations:
Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Kanada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canadá;Princess Margaret Cancer Centre, University of Tor
(Abstract release date: 05/12/22) EHA Library. Mascarenhas J. 06/11/22; 357062; S198
Dr. John Mascarenhas
Dr. John Mascarenhas
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S198

Type: Oral Presentation

Session title: Treatments and complications in MPN

Background
Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (e.g. NF-κB, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. While many MF patients (pts) receive the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) as the current standard of care, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction from BL (TSS50) are limited; thus, a significant unmet medical need exists. Pelabresib (CPI-0610) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB gene expression and other relevant genes involved in MF disease pathways.  

 

Aims
Data (Sep 2021 data cut) on the safety and efficacy of pelabresib in combination with RUX in pts with MF from Arms 2 and 3 of the ongoing, open-label Phase 2 MANIFEST study (NCT02158858). In Arm 2, MF pts with suboptimal response to RUX are treated with pelabresib as ‘add-on’ to RUX (Arm 2A: transfusion dependent [TD]; Arm 2B: non-TD). In Arm 3, JAKi-naïve MF pts are treated with pelabresib in combination with RUX.

Methods
The primary endpoints are SVR35 at Week (Wk) 24 for Arm 3 and Arm 2B (non-TD cohort) and TD to transfusion independence (TI) in Arm 2A (TD cohort). The key secondary endpoint is TSS50 per Myelofibrosis Symptom Assessment Form v4.0 at Wk 24; in Arm 2A (TD cohort), SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated.

Results
At Wk 24 in Arm 3 (N=84), 68% (57/84) pts achieved SVR35 (median change: –50%; Figure), and 56% (46/82) pts achieved TSS50 (median change: –59%). Twenty-four percent of pts had a mean hemoglobin increase ≥1.5 g/dL from BL over 12 weeks without transfusions. At Wk 24 in Arm 2 (N=86), 20% (16/81) pts achieved SVR35 (median change: –18%; Figure), and 37% (30/81) pts achieved TSS50 (median change: –47%). In Arm 2A, the TD to TI rate was 16% (6/38).

BM fibrosis improvement by ≥1 grade was achieved in 31% (16/52) and 25% (9/36) pts in Arm 3 and 2, respectively. Further central review and exploratory analyses of BM pathology from a more mature data set, including clinical correlations, will be presented.

The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) pts in Arm 3 and 2, respectively. Anemia was reported in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) pts in Arm 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections in Arm 3 and 2 were observed but rarely a reason for treatment discontinuation.

Conclusion
Based on these interim Phase 2 data, pelabresib in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in splenic and symptom responses and BM fibrosis improvement, and appeared to be well tolerated. Based on data from MANIFEST Arm 3, the randomized, double-blind, active-control Phase 3 MANIFEST-2 study was initiated to further evaluate the safety and efficacy of pelabresib in combination with ruxolitinib in JAKi treatment-naïve pts with MF (NCT04603495).

Keyword(s): Bone Marrow Fibrosis, Clinical trial, Janus Kinase inhibitor, Myelofibrosis

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S198

Type: Oral Presentation

Session title: Treatments and complications in MPN

Background
Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (e.g. NF-κB, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. While many MF patients (pts) receive the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) as the current standard of care, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction from BL (TSS50) are limited; thus, a significant unmet medical need exists. Pelabresib (CPI-0610) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB gene expression and other relevant genes involved in MF disease pathways.  

 

Aims
Data (Sep 2021 data cut) on the safety and efficacy of pelabresib in combination with RUX in pts with MF from Arms 2 and 3 of the ongoing, open-label Phase 2 MANIFEST study (NCT02158858). In Arm 2, MF pts with suboptimal response to RUX are treated with pelabresib as ‘add-on’ to RUX (Arm 2A: transfusion dependent [TD]; Arm 2B: non-TD). In Arm 3, JAKi-naïve MF pts are treated with pelabresib in combination with RUX.

Methods
The primary endpoints are SVR35 at Week (Wk) 24 for Arm 3 and Arm 2B (non-TD cohort) and TD to transfusion independence (TI) in Arm 2A (TD cohort). The key secondary endpoint is TSS50 per Myelofibrosis Symptom Assessment Form v4.0 at Wk 24; in Arm 2A (TD cohort), SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated.

Results
At Wk 24 in Arm 3 (N=84), 68% (57/84) pts achieved SVR35 (median change: –50%; Figure), and 56% (46/82) pts achieved TSS50 (median change: –59%). Twenty-four percent of pts had a mean hemoglobin increase ≥1.5 g/dL from BL over 12 weeks without transfusions. At Wk 24 in Arm 2 (N=86), 20% (16/81) pts achieved SVR35 (median change: –18%; Figure), and 37% (30/81) pts achieved TSS50 (median change: –47%). In Arm 2A, the TD to TI rate was 16% (6/38).

BM fibrosis improvement by ≥1 grade was achieved in 31% (16/52) and 25% (9/36) pts in Arm 3 and 2, respectively. Further central review and exploratory analyses of BM pathology from a more mature data set, including clinical correlations, will be presented.

The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) pts in Arm 3 and 2, respectively. Anemia was reported in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) pts in Arm 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections in Arm 3 and 2 were observed but rarely a reason for treatment discontinuation.

Conclusion
Based on these interim Phase 2 data, pelabresib in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in splenic and symptom responses and BM fibrosis improvement, and appeared to be well tolerated. Based on data from MANIFEST Arm 3, the randomized, double-blind, active-control Phase 3 MANIFEST-2 study was initiated to further evaluate the safety and efficacy of pelabresib in combination with ruxolitinib in JAKi treatment-naïve pts with MF (NCT04603495).

Keyword(s): Bone Marrow Fibrosis, Clinical trial, Janus Kinase inhibitor, Myelofibrosis

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies