Contributions
Abstract: S829
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 11:45 - 12:00
Location: Room A7
Background
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies or complicated by relapse and associated with short overall survival.
Aims
We set out to identify novel effective treatments for T-PLL patients, especially new combinatorial treatment strategies.
Methods
We applied next-generation functional testing of primary patient-derived leukemia cells using a library 106 FDA approved anticancer drugs or compounds currently in clinical development. Combinatorial functional testing of T-PLL patient samples with venetoclax in combination with 14 other agents such as ibrutinib, idelalisib, 5-azacytidine, 6-mercaptopurin, alitretinoin, bendamustine, bortezomib, and cisplatin was performed. Bliss’ independence was used to assess synergistic or antagonistic effects of the respective combination partners ex vivo.
Results
We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response ex vivo when comparing individual drug response in 86 patients with refractory hematologic malignancies. Based on these results, off-label venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in striking clinical responses (Boidol et al., Blood 2017). The most promising candidates for combination were the Bruton tyrosine kinase inhibitor ibrutinib, the PI3K-inhibitor idelalisib, and the DNA methyltransferase inhibitor 5-azacytidine, whereas cisplatin antagonized the effect of venetoclax across all patient samples tested (Figure 1A). Off-label co-treatment of venetoclax and 5-azacytidine was commenced in a T-PLL patient at third relapse after a failed re-treatment attempt with alemtuzumab presenting with dyspnea, leukocytosis, splenomegaly and reduced clinical condition. Combination of 5-azatiidine and venetoclax demonstrated modest clinical and laboratory improvement. In contrast, after initiating co-treatment with ibrutinib and venetoclax a dramatic response was observed as evidenced in significant clinical improvement, significant decrease in spleen size and disease related laboratory values such as leukocytosis, LDH, and B2-MiG (Figure 1B). At time of report the response is ongoing.
Conclusion
Our findings demonstrate first evidence of single-agent activity of venetoclax. Furthermore, we identify ibrutinib as an effective combination partner both ex vivo and in patients, offering a novel treatment concept in T-PLL.
Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research
Keyword(s): Drug sensitivity, T cell leukemia, Therapy
Abstract: S829
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 11:45 - 12:00
Location: Room A7
Background
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies or complicated by relapse and associated with short overall survival.
Aims
We set out to identify novel effective treatments for T-PLL patients, especially new combinatorial treatment strategies.
Methods
We applied next-generation functional testing of primary patient-derived leukemia cells using a library 106 FDA approved anticancer drugs or compounds currently in clinical development. Combinatorial functional testing of T-PLL patient samples with venetoclax in combination with 14 other agents such as ibrutinib, idelalisib, 5-azacytidine, 6-mercaptopurin, alitretinoin, bendamustine, bortezomib, and cisplatin was performed. Bliss’ independence was used to assess synergistic or antagonistic effects of the respective combination partners ex vivo.
Results
We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response ex vivo when comparing individual drug response in 86 patients with refractory hematologic malignancies. Based on these results, off-label venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in striking clinical responses (Boidol et al., Blood 2017). The most promising candidates for combination were the Bruton tyrosine kinase inhibitor ibrutinib, the PI3K-inhibitor idelalisib, and the DNA methyltransferase inhibitor 5-azacytidine, whereas cisplatin antagonized the effect of venetoclax across all patient samples tested (Figure 1A). Off-label co-treatment of venetoclax and 5-azacytidine was commenced in a T-PLL patient at third relapse after a failed re-treatment attempt with alemtuzumab presenting with dyspnea, leukocytosis, splenomegaly and reduced clinical condition. Combination of 5-azatiidine and venetoclax demonstrated modest clinical and laboratory improvement. In contrast, after initiating co-treatment with ibrutinib and venetoclax a dramatic response was observed as evidenced in significant clinical improvement, significant decrease in spleen size and disease related laboratory values such as leukocytosis, LDH, and B2-MiG (Figure 1B). At time of report the response is ongoing.
Conclusion
Our findings demonstrate first evidence of single-agent activity of venetoclax. Furthermore, we identify ibrutinib as an effective combination partner both ex vivo and in patients, offering a novel treatment concept in T-PLL.
Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research
Keyword(s): Drug sensitivity, T cell leukemia, Therapy