American Association for Cancer Research
ccr-23-1429_supplementary_table_s2_suppts2.docx (119.81 kB)

Supplementary Table S2 from Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies

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journal contribution
posted on 2023-11-01, 07:40 authored by Jayastu Senapati, Warren C. Fiskus, Naval Daver, Nathaniel R. Wilson, Farhad Ravandi, Guillermo Garcia-Manero, Tapan Kadia, Courtney D. DiNardo, Elias Jabbour, Jan Burger, Nicholas J. Short, Yesid Alvarado, Nitin Jain, Lucia Masarova, Ghayas C. Issa, Wei Qiao, Joseph D. Khoury, Sherry Pierce, Darla Miller, Koji Sasaki, Marina Konopleva, Kapil N. Bhalla, Gautam Borthakur, Naveen Pemmaraju

Hepatic adverse events


University of Texas MD Anderson Cancer Center (MD Anderson)



Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies. We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy. Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1–9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders. In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.

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