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The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.
Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).
The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.
The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.
This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.
The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.
Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).
The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.
The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.
This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.
The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.
Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).
The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.
The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.
This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: The combination of dasatinib and venetoclax shows promise for the treatment of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) samples in xenografted immunodeficient mice and should be further evaluated for patient care.
Major finding: A stepwise reduction in median inhibitory concentration of dasatinib was seen with increasing doses of venetoclax.
Data source: In vitro and in vivo evaluation of BCL-2 inhibition in combination with kinase inhibition in a murine model of Ph+ALL.
Disclosures: This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.