Pelabresib (CPI-0610) monotherapy in high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: Preliminary results from MANIFEST study.

person Francesco Passamonti University of Insubria, Varese, Italy info_outline Francesco Passamonti, Andrea Patriarca, Steven Knapper, Candido Rivera, Joseph Scandura, Timothy Devos, Nikki Granacher, Adam J. Mead, Stephen Oh, Jeanne M. Palmer, Raajit Rampal, Lino Teichmann, Jie Cui, Sandra Klein, Gozde Colak, Claire Harrison

Authors person Francesco Passamonti University of Insubria, Varese, Italy info_outline Francesco Passamonti, Andrea Patriarca, Steven Knapper, Candido Rivera, Joseph Scandura, Timothy Devos, Nikki Granacher, Adam J. Mead, Stephen Oh, Jeanne M. Palmer, Raajit Rampal, Lino Teichmann, Jie Cui, Sandra Klein, Gozde Colak, Claire Harrison Organizations University of Insubria, Varese, Italy, Hematology Unit, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità, Novara, Italy, Department of Haematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom, Mayo Clinic Florida, Jacksonville, FL, The Richard T. Silver, M.D. Myeloproliferative Neoplasms Center, Division of Hematology and Oncology, Cornell Medicine, New York, NY, Department of Hematology, University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium, Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium, MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom, Washington University School of Medicine in St. Louis, St. Louis, MO, Mayo Clinic, Phoenix, AZ, Memorial Sloan Kettering Cancer Center, New York, NY, Universitätsklinikum Bonn, Bonn, Germany, Constellation Pharmaceuticals, Inc., a MorphoSys Company, Boston, MA, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Constellation Pharmaceuticals, Inc., a MorphoSys Company Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets > 600 x 10 9 /L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 10 9 /L), WBC count (≤10 x 10 9 /L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 10 9 /L and WBC ≤10 x 10 9 /L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 10 9 /L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x10 9 /L and 8.2 x 10 9 /L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858. CHR, n (%) [Primary endpoint] Best Response (N=20) Confirmed* Unconfirmed † - WBC Count ≤10 x 10 9 /L - Platelet Count ≤400 x 10 9 /L PHR, n (%) Confirmed* Unconfirmed † 8 (40) 12 (60) 19 (95) 12 (60) 4 (20) 6 (30) Symptom improvement (N=14) TSS50 Median TSS reduction, Wk 12, % 7 (50) –31% *Confirmed CHR/PHR: conditions met in two consecutive cycles. † Unconfirmed CHR/PHR: conditions met in one cycle but not the next.

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