Authors: David P. Steensma, Martin Wermke, Virginia M. Klimek, Peter L. Greenberg, Patricia Font, Rami S. Komrokji, Jay Yang, Andrew M. Brunner, Hetty E. Carraway, Lionel Ades, Aref Al-Kali, Juan M. Alonso-Dominguez, Ana Alfonso-Piérola, Catherine C. Coombs, H. Joachim Deeg, Ian Flinn, James M. Foran, Guillermo Garcia-Manero, Michael B. Maris, Malgorzata McMasters, Jean-Baptiste Micol, Jaime Perez De Oteyza, Felicitas Thol, Eunice S. Wang, Justin M. Watts, Justin Taylor, Richard Stone, Vikram Gourineni, Alyssa J. Marino, Huilan Yao, Benoit Destenaves, Xiaobin Yuan, Kun Yu, Sara Dar, Lernik Ohanjanian, Keisuke Kuida, Jianjun Xiao, Catherine Scholz, Antonio Gualberto, Uwe Platzbecker
Published: 2021-06-25
DOI: 10.1038/s41375-021-01328-9
Source: Full article
AbstractWe conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.