Contributions
Abstract: EP327
Type: E-Poster Presentation
Session title: Acute lymphoblastic leukemia - Biology & Translational Research
Background
Outcomes in patients with T-cell Acute Lymphoblastic Leukaemia (T-ALL) have improved markedly over the recent decades, with intensive glucocorticoid-based chemotherapy accounting for 5-year event free survival (EFS) rates of over 80% in paediatric cases. [Patrick, et al, British Journal Haematology, 2014] Outcomes for patients refractory to or relapsing after treatment remain extremely poor. Overcoming glucocorticoid resistance is central to improving outcomes in these patients.
Physiological T-lymphocyte development is directed by pre T Cell Receptor (pTCR) signalling and expression of pro-survival factors, such as BCL2 and BCL2L1. We have shown that pTCR signalling activity is relevant in T-ALL. Dasatinib (DAS) effectively blocks the kinase LCK, which is an instrumental signalling molecule in the pTCR pathway. Combination of DAS with dexamethasone (DEX) impairs in vivo T-ALL expansion and results in cell death. [Shi, et al, Haematologica, 2020] Potent inhibitors of the BCL2 family have entered the clinical arena, and demonstrated single drug activity against T-ALL.
Aims
Establish efficacy of DEX+DAS and a BCL2 family inhibitor in T-ALL cell lines and patient-derived samples.
Methods
Cell viability assays combining DEX+DAS at a fixed ratio and BCL2 family inhibitors Venetoclax (ABT-199) or Navitoclax (ABT-263) were performed. Cell viability was determined by resazurin assay.
T-ALL PDX, in OP9-DL1 co-culture, were exposed to DEX+DAS and BCL2 inhibitors. Cell viability was assessed by resazurin assay, CytoQuant analysis and quantitative imaging.
Results
Both Venetoclax and Navitoclax act in an additive manner when combined with DEX+DAS in T-ALL cell lines and primary samples. In PDX samples sensitive to DAS, we observed superior cell kill with the addition of Navitoclax when compared to Venetoclax. Conversely, we observed that PDX samples resistant to dasatinib are more likely to respond to Venetoclax. The latter group is particularly enriched for Early T-cell Precursor ALLs, which rely on BCL2 for cell survival.
Conclusion
Based on these preliminary data, we suggest that T-ALL patients with activation of pTCR signalling, as exemplified by LCK status, benefit from DEX+DAS + Navitoclax treatment to overcome GC resistance. Other subgroups, including ETP ALL, may benefit from Venetoclax-based treatment. We will test this treatment recommendation in preclinical models to inform future patient management.
Keyword(s): Dexamethasone, Resistance, T cell acute lymphoblastic leukemia, Tyrosine kinase inhibitor
Abstract: EP327
Type: E-Poster Presentation
Session title: Acute lymphoblastic leukemia - Biology & Translational Research
Background
Outcomes in patients with T-cell Acute Lymphoblastic Leukaemia (T-ALL) have improved markedly over the recent decades, with intensive glucocorticoid-based chemotherapy accounting for 5-year event free survival (EFS) rates of over 80% in paediatric cases. [Patrick, et al, British Journal Haematology, 2014] Outcomes for patients refractory to or relapsing after treatment remain extremely poor. Overcoming glucocorticoid resistance is central to improving outcomes in these patients.
Physiological T-lymphocyte development is directed by pre T Cell Receptor (pTCR) signalling and expression of pro-survival factors, such as BCL2 and BCL2L1. We have shown that pTCR signalling activity is relevant in T-ALL. Dasatinib (DAS) effectively blocks the kinase LCK, which is an instrumental signalling molecule in the pTCR pathway. Combination of DAS with dexamethasone (DEX) impairs in vivo T-ALL expansion and results in cell death. [Shi, et al, Haematologica, 2020] Potent inhibitors of the BCL2 family have entered the clinical arena, and demonstrated single drug activity against T-ALL.
Aims
Establish efficacy of DEX+DAS and a BCL2 family inhibitor in T-ALL cell lines and patient-derived samples.
Methods
Cell viability assays combining DEX+DAS at a fixed ratio and BCL2 family inhibitors Venetoclax (ABT-199) or Navitoclax (ABT-263) were performed. Cell viability was determined by resazurin assay.
T-ALL PDX, in OP9-DL1 co-culture, were exposed to DEX+DAS and BCL2 inhibitors. Cell viability was assessed by resazurin assay, CytoQuant analysis and quantitative imaging.
Results
Both Venetoclax and Navitoclax act in an additive manner when combined with DEX+DAS in T-ALL cell lines and primary samples. In PDX samples sensitive to DAS, we observed superior cell kill with the addition of Navitoclax when compared to Venetoclax. Conversely, we observed that PDX samples resistant to dasatinib are more likely to respond to Venetoclax. The latter group is particularly enriched for Early T-cell Precursor ALLs, which rely on BCL2 for cell survival.
Conclusion
Based on these preliminary data, we suggest that T-ALL patients with activation of pTCR signalling, as exemplified by LCK status, benefit from DEX+DAS + Navitoclax treatment to overcome GC resistance. Other subgroups, including ETP ALL, may benefit from Venetoclax-based treatment. We will test this treatment recommendation in preclinical models to inform future patient management.
Keyword(s): Dexamethasone, Resistance, T cell acute lymphoblastic leukemia, Tyrosine kinase inhibitor