Contributions
Abstract: EP444
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
Venetoclax (VEN) is an orally bioavailable selective BCL-2 inhibitor that promotes apoptosis in cancer cells. VIALE-A, a placebo-controlled randomized Phase 3 trial comparing VEN in combination with azacitidine (VEN+AZA) to placebo in combination with azacitidine (PBO+AZA), showed superior efficacy with VEN combination on key endpoints such as overall survival and overall response rates in subjects with treatment-naïve acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. Hematologic adverse events including anemia, neutropenia, febrile neutropenia, and thrombocytopenia are common in AML patients due to their underlying disease. In VIALE-A, subjects taking VEN+AZA had higher rates of neutropenia and febrile neutropenia than subjects taking PBO+AZA (DiNardo et al. N Engl J Med. 2020).
Aims
Here, we aimed to describe the relationship between VEN exposure, overall survival, and post-remission cytopenias, as defined by Grade 4 neutropenia or thrombocytopenia lasting ≥7 days, in subjects who achieved complete remission (CR) or complete remission with partial hematological recovery (CRh) in the VIALE-A study.
Methods
Data from 185 subjects treated with VEN+AZA and 33 subjects treated with PBO + AZA who achieved CR or CRh (blast clearance with neutrophil count > 0.5 × 103/µL and platelet count > 0.5 × 105/µL) in the VIALE-A study were included in the analysis. The VIALE-A protocol recommended dose interruptions and reduced VEN dosing duration per cycle for management of cytopenias following blast clearance. Therefore, VEN exposure was calculated as the average plasma concentration (Cavg) from blast clearance to the event of interest to account for these dosing modifications. Logistic regression and Cox proportional-hazards models were used to characterize the relationships between venetoclax exposure (Cavg) and frequency or timing of cytopenias. Cox proportional-hazards models were also used to characterize the relationships between venetoclax exposure (Cavg) and overall survival in subgroups based on dosing duration.
Results
Subjects taking VEN+AZA had a range of 0 to 15 post-remission cytopenias lasting ≥7 days in VIALE-A. Within subjects experiencing post-remission cytopenias on VEN+AZA, there was no apparent relationship between VEN exposure and frequency of post-remission cytopenias. However, subjects with no post-remission cytopenias on VEN+AZA had significantly (p < 0.01) lower VEN exposure than those with one or more post-remission cytopenias. Consistently, higher VEN exposure was associated (p < 0.01) with a shorter time to first episode of post-remission cytopenia. There were no apparent relationships between VEN exposure and overall survival in VEN+AZA subjects who achieved CR/CRh and experienced post-remission cytopenias, including in a subset of subjects who switched to 21-day dosing in 28-day cycles following the first episode of post-remission cytopenia. These results indicate that lower exposures associated with VEN dose reductions to manage cytopenias in patients who achieved a CR/CRh did not affect OS.
Conclusion
For treatment-naïve AML patients who achieve CR/CRh on VEN+AZA, VEN exposure may be a contributing factor to post-remission cytopenias.
Keyword(s): AML, Myelosuppression, Pharmacokinetic
Abstract: EP444
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
Venetoclax (VEN) is an orally bioavailable selective BCL-2 inhibitor that promotes apoptosis in cancer cells. VIALE-A, a placebo-controlled randomized Phase 3 trial comparing VEN in combination with azacitidine (VEN+AZA) to placebo in combination with azacitidine (PBO+AZA), showed superior efficacy with VEN combination on key endpoints such as overall survival and overall response rates in subjects with treatment-naïve acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. Hematologic adverse events including anemia, neutropenia, febrile neutropenia, and thrombocytopenia are common in AML patients due to their underlying disease. In VIALE-A, subjects taking VEN+AZA had higher rates of neutropenia and febrile neutropenia than subjects taking PBO+AZA (DiNardo et al. N Engl J Med. 2020).
Aims
Here, we aimed to describe the relationship between VEN exposure, overall survival, and post-remission cytopenias, as defined by Grade 4 neutropenia or thrombocytopenia lasting ≥7 days, in subjects who achieved complete remission (CR) or complete remission with partial hematological recovery (CRh) in the VIALE-A study.
Methods
Data from 185 subjects treated with VEN+AZA and 33 subjects treated with PBO + AZA who achieved CR or CRh (blast clearance with neutrophil count > 0.5 × 103/µL and platelet count > 0.5 × 105/µL) in the VIALE-A study were included in the analysis. The VIALE-A protocol recommended dose interruptions and reduced VEN dosing duration per cycle for management of cytopenias following blast clearance. Therefore, VEN exposure was calculated as the average plasma concentration (Cavg) from blast clearance to the event of interest to account for these dosing modifications. Logistic regression and Cox proportional-hazards models were used to characterize the relationships between venetoclax exposure (Cavg) and frequency or timing of cytopenias. Cox proportional-hazards models were also used to characterize the relationships between venetoclax exposure (Cavg) and overall survival in subgroups based on dosing duration.
Results
Subjects taking VEN+AZA had a range of 0 to 15 post-remission cytopenias lasting ≥7 days in VIALE-A. Within subjects experiencing post-remission cytopenias on VEN+AZA, there was no apparent relationship between VEN exposure and frequency of post-remission cytopenias. However, subjects with no post-remission cytopenias on VEN+AZA had significantly (p < 0.01) lower VEN exposure than those with one or more post-remission cytopenias. Consistently, higher VEN exposure was associated (p < 0.01) with a shorter time to first episode of post-remission cytopenia. There were no apparent relationships between VEN exposure and overall survival in VEN+AZA subjects who achieved CR/CRh and experienced post-remission cytopenias, including in a subset of subjects who switched to 21-day dosing in 28-day cycles following the first episode of post-remission cytopenia. These results indicate that lower exposures associated with VEN dose reductions to manage cytopenias in patients who achieved a CR/CRh did not affect OS.
Conclusion
For treatment-naïve AML patients who achieve CR/CRh on VEN+AZA, VEN exposure may be a contributing factor to post-remission cytopenias.
Keyword(s): AML, Myelosuppression, Pharmacokinetic