CPI-0610, A BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) INHIBITOR, REDUCES PRO-INFLAMMATORY CYTOKINES, BONE MARROW FIBROSIS AND THE NUMBER OF TRANSFUSIONS IN MYELOFIBROSIS PATIENTS
Author(s): ,
Ronald Hoffman
Affiliations:
Division of Hematology/Medical Oncology, The Tisch Cancer Institute,Icahn School of Medicine at Mount Sinai,New York,United States;Myeloproliferative Neoplasm Research Consortium (MPN-RC),New York,United States
,
John Mascarenhas
Affiliations:
Division of Hematology/Medical Oncology, The Tisch Cancer Institute,Icahn School of Medicine at Mount Sinai,New York,United States;Myeloproliferative Neoplasm Research Consortium (MPN-RC),New York,United States
,
Marina Kremyanskaya
Affiliations:
Division of Hematology/Medical Oncology, The Tisch Cancer Institute,Icahn School of Medicine at Mount Sinai,New York,United States;Myeloproliferative Neoplasm Research Consortium (MPN-RC),New York,United States
,
Prithviraj Bose
Affiliations:
Department of Leukemia,MD Anderson Cancer Center,Houston,United States
,
Vikas Gupta
Affiliations:
Princess Margaret Hospital,Toronto,Canada
,
Gary Schiller
Affiliations:
University of California,Los Angeles,United States
,
Elena Liew
Affiliations:
University of Alberta,Alberta,Canada
,
Anna Godfrey
Affiliations:
Cambridge University Hospitals NHS Foundation Trust,Cambridge,United Kingdom
,
Jennifer Mertz
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Jessica Piel
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Patrick Trojer
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Claudia Lebedinsky
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Adrian Senderowicz
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Sujan Kabir
Affiliations:
Constellation Pharmaceuticals,Cambridge,United States
,
Jeffrey Supko
Affiliations:
Massachusetts General Hospital,Boston,United States
Srdan Verstovsek
Affiliations:
Department of Leukemia,MD Anderson Cancer Center,Houston,United States
EHA Library. Hoffman R. Jun 15, 2019; 267414; S831
Ronald Hoffman
Ronald Hoffman
Contributions
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Abstract

Abstract: S831

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 12:15 - 12:30

Location: Elicium 2

Background

Myelofibrosis (MF) is a myeloproliferative neoplasm associated with a cytokine (CK) milieu that leads to bone marrow (BM) fibrosis. Ruxolitinib (RUX) is the only approved therapy for MF, but patients (pts) can eventually relapse/have inadequate response. RUX can also worsen anemia and pts may require transfusions. BET proteins are transcriptional regulators that control key oncogenic pathways, including NF-κB, MYC, and BCL2 and TGFβ signaling, an important driver of fibrosis. Preclinical studies suggest that a combination of a BET inhibitor (BETi) and RUX results in a synergistic reduction of the hallmarks of MF: splenomegaly, BM fibrosis and the mutant (MUT) allele burden (Kleppe 2018). CPI-0610 is a selective and potent BETi that impacts megakaryocyte differentiation (unpublished data), cells responsible for pro-inflammatory CK production and is currently being evaluated in MF, alone or in combination with RUX in a clinical trial with 3 arms: CPI-0610 alone (Arm 1), CPI-0610+RUX in pts exposed to RUX/with an inadequate response to RUX (Arm 2), or CPI-0610+RUX in JAKi naïve pts with anemia (Arm 3). Arm 1 and 2 are stratified between transfusion dependence (TD) and splenomegaly at baseline. 

Aims

Phase 2 study to assess CPI-0610 alone or “add-on” to RUX in MF pts. Primary endpoints: conversion of TD to transfusion independence (TI), spleen volume response, patient reported outcomes, safety and PK. Additional endpoints include: changes in pro-inflammatory CK levels, BM fibrosis and MUT profiling.

Methods
Pt samples were used to analyze CK levels, MUT profiles and BM fibrosis. CK analyses utilized Myriad-RBM InflammationMAP and CustomMAP and MUT analysis utilized the Rapid Heme Panel (Kluk, 2016).

Results
23 pts were accrued to this multi-center study, with 18 pts analyzed: MUT profiles which revealed the following MUT: 11 ASXL1(61%), 10 JAK2(56%), 6 CALR (33%) and 2 MPL(11%). 10 pts (56%) had at least 3 MUTs and 17 pts (94%) had at least one driver MUT (JAK2, CALR or MPL). 1 pt (6%) was triple negative and 12 pts (67%) had a high MUT profile (HMR). Baseline CK levels were elevated, in pts who failed/inadequate response to RUX. CPI-0610 at a starting dose of 125 mg QD (days 1-14 of 21-day cycle) reduced CK levels in both monotherapy and combination arms. Suppression of IL-18 was observed in all pts analyzed (n=8) with >50% decrease in 4/8 pts. Trends were also observed for a number of other CK, including IL-8 and CRP. CK inhibition was sustained over multiple cycles of CPI-0610 (combination/monotherapy). Best spleen volume reduction ranged from 6-44% in 10 pts. Out of the 4 pts with BM assessments (pre and at least 1 post), 2 were TD at baseline. Three pts had one grade improvement in BM fibrosis (1 at 6 mth, 2 at 1 yr) and had Hgb increases of ≥1.5 g/dL for ≥12 weeks without transfusions. The other pt had a 1 grade improvement in the BM reticulin score (at 6 mth). Moreover, both of the TD pts became TI. Hepcidin levels and PK will be presented. The most common adverse events were Grade 1/2 diarrhea, nausea/vomiting and reversible and non-cumulative thrombocytopenia.

Conclusion
CPI-0610 alone or in combination with Rux demonstrates encouraging clinical activity (spleen responses, conversion to TI and improvement in BM fibrosis) with good tolerability. Assessment of CK levels suggest that CPI-0610 therapy durably reduces pro-inflammatory CK. Notably, levels of individual CK were reduced to levels observed in normal healthy donors and were maintained during treatment. Genomic profiling data shows that majority of pts had HMR MUT at baseline. Updated data will be presented.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Cytokine, Epigenetic, Myelofibrosis

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