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

Stéphane de Botton, Thomas Cluzeau, Carlos Vigil, Rachel J. Cook, Philippe Rousselot, David A. Rizzieri, Jane L. Liesveld, Pierre Fenaux, Thorsten Braun, Anne Banos, Joseph G. Jurcic, Mikkael A. Sekeres, Michael R. Savona, Gail J. Roboz, Dale Bixby, Kate Madigan, Angela Volkert, Kristin Stephens, Qing Kang-Fortner, Kristen BakerSofia Paul, Michael McKeown, John Carulli, Matthew Eaton, Graeme Hodgson, Christopher Fiore, Michael J. Kelly, David A. Roth, Eytan M. Stein

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    18 Citations (Scopus)

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)1858-1870
    Nombre de pages13
    journalBlood Advances
    Volume7
    Numéro de publication9
    Les DOIs
    étatPublié - 9 mai 2023

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