Phase 1 Results of Bromodomain and Extraterminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies

by Selleckchem | Nov 25 2023

Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) MDS and AML remains dismal. Based on both extensive pre-clinical 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); morphological leukemia-free state (n=2); hematologic improvement (n=5). The most common non-hematological 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) vs pre-treatment 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 pre-treated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.

Comments:

The study you described reports the findings of a phase I clinical trial investigating the combination therapy of PLX51107 (a bromodomain and extra-terminal domain inhibitor, BETi) and azacitidine in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR MDS). The trial aimed to assess the safety and efficacy of this combination therapy in a cohort of heavily pre-treated patients. Here's a summary of the key points from the study:

### Study Overview:
- **Purpose:** To evaluate the potential of BETi in treating patients with high-risk myeloid malignancies, based on pre-clinical and emerging clinical data.

- **Patients:** The trial included 37 patients with HR R/R MDS (n=4) and R/R AML (n=33). Notably, a significant proportion of patients had genetic mutations, such as MECOM gene rearrangement and TP53 mutation. Patients had a median of three prior therapies, with almost all having received hypomethylating agents and a majority having received venetoclax previously.

### Treatment Outcomes:
- **Response Rate:** The overall response rate was 22%, with responses categorized as complete remission with incomplete platelet recovery, morphological leukemia-free state, and hematologic improvement.

- **Toxicities:** The most common non-hematological toxicities included febrile neutropenia and pneumonia in 32% of patients each. Severe hyperbilirubinemia was observed in 17% of patients.

### Mechanistic Insights:
- **Gene Expression Changes:** RNA-Sequencing analysis revealed significant changes in mRNA expressions in responders. There was a downregulation of genes associated with cancer (MYC, BCL2, CDK6) and upregulation of genes associated with cellular regulation (HEXIM1, CD93, DCXR, CDKN1A) in responders.

- **Protein Expression Changes:** Immunoblot analyses confirmed the reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and the induction of BRD4 and HEXIM1 protein levels in responders.

### Conclusions:
- **Safety:** The combination therapy of PLX51107 and azacitidine was well-tolerated in heavily pre-treated patients with R/R MDS and AML.

- **Efficacy:** The treatment resulted in modest clinical benefit, with an overall response rate of 22%.

- **Mechanistic Insights:** Responders showed significant changes in gene and protein expressions, indicating potential pathways affected by the combination therapy.

In summary, while the combination therapy showed some efficacy and promising mechanistic changes, further research and potentially larger clinical trials are needed to optimize the treatment regimen and improve outcomes for patients with high-risk myeloid malignancies.