Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML.

Autor:	de Botton S; Institut Gustave Roussy, Paris, France., Cluzeau T; Côte d'Azur Université, Centre Hospitalier Universitaire de Nice Hôpital, Nice, France., Vigil C; Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL., Cook RJ; Knight Cancer Institute, Oregon Health & Science University, Portland, OR., Rousselot P; Hôpital André Mignot, Centre Hospitalier de Versailles, Le Chesnay, France., Rizzieri DA; Novant Health Cancer Institute, Winston-Salem, NC., Liesveld JL; University of Rochester Medical Center, Rochester, NY., Fenaux P; Hôpital Saint-Louis, Paris, France., Braun T; Centre Hospitalier Universitaire Hôpital Avicenne, Bobigny, France., Banos A; Centre Hospitalier de la Côte Basque, Bayonne, France., Jurcic JG; Columbia University Irving Medical Center, New York, NY., Sekeres MA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL., Savona MR; Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN., Roboz GJ; Weill Cornell Medicine, New York, NY., Bixby D; Rogel Cancer Center, University of Michigan, Ann Arbor, MI., Madigan K; Syros Pharmaceuticals, Inc, Cambridge, MA., Volkert A; Syros Pharmaceuticals, Inc, Cambridge, MA., Stephens K; Syros Pharmaceuticals, Inc, Cambridge, MA., Kang-Fortner Q; Syros Pharmaceuticals, Inc, Cambridge, MA., Baker K; Syros Pharmaceuticals, Inc, Cambridge, MA., Paul S; Syros Pharmaceuticals, Inc, Cambridge, MA., McKeown M; Syros Pharmaceuticals, Inc, Cambridge, MA., Carulli J; Syros Pharmaceuticals, Inc, Cambridge, MA., Eaton M; Syros Pharmaceuticals, Inc, Cambridge, MA., Hodgson G; Syros Pharmaceuticals, Inc, Cambridge, MA., Fiore C; Syros Pharmaceuticals, Inc, Cambridge, MA., Kelly MJ; Syros Pharmaceuticals, Inc, Cambridge, MA., Roth DA; Syros Pharmaceuticals, Inc, Cambridge, MA., Stein EM; Memorial Sloan Kettering Cancer Center, New York, NY.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2023 May 09; Vol. 7 (9), pp. 1858-1870.
DOI:	10.1182/bloodadvances.2022008806
Abstrakt:	A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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