TY - JOUR
T1 - Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies
AU - Senapati, Jayastu
AU - Fiskus, Warren C.
AU - Daver, Naval
AU - Wilson, Nathaniel R.
AU - Ravandi, Farhad
AU - Garcia-Manero, Guillermo
AU - Kadia, Tapan
AU - DiNardo, Courtney D.
AU - Jabbour, Elias
AU - Burger, Jan
AU - Short, Nicholas J.
AU - Alvarado, Yesid
AU - Jain, Nitin
AU - Masarova, Lucia
AU - Issa, Ghayas C.
AU - Qiao, Wei
AU - Khoury, Joseph D.
AU - Pierce, Sherry
AU - Miller, Darla
AU - Sasaki, Koji
AU - Konopleva, Marina
AU - Bhalla, Kapil N.
AU - Borthakur, Gautam
AU - Pemmaraju, Naveen
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Purpose: 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. Patients and Methods: 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. Results: 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. Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107þ azacitidine was well-tolerated and resulted in modest clinical benefit.
AB - Purpose: 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. Patients and Methods: 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. Results: 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. Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107þ azacitidine was well-tolerated and resulted in modest clinical benefit.
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U2 - 10.1158/1078-0432.CCR-23-1429
DO - 10.1158/1078-0432.CCR-23-1429
M3 - Article
C2 - 37585491
AN - SCOPUS:85175878128
SN - 1078-0432
VL - 29
SP - 4352
EP - 4360
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -