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Ibrutinib promising in subtype of DLBCL
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Ibrutinib promising in subtype of DLBCL Patients with the activated B-celllike (ABC) subtype of diffuse large B-cell lymphoma were more likely to respond to ibrutinib than were those with the germinal centre B-celllike (GCB) subtype of the disease, according to results of a phase 2 study. Of 80 patients who had relapsed or had not responded to previous treatment, 37% of those with ABC diffuse large B-cell lymphoma had a complete or partial response to the drug, compared with only 5% of those with the germinal GCB subtype. Ibrutinib is an inhibitor of a key enzyme in B-cell receptor (BCR) signalling, Bruton’s tyrosine kinase, which is essential for the survival of ABC lymphoma cells by reducing NFκB pathway activity. “This is the first clinical study to demonstrate the importance of precision medicine in lymphoma”, said the first author, Wyndham Wilson
(National Cancer Institute, Bethesda, MD, USA). “It represents the first effort to really understand that specific mutations respond to targeted agents in lymphoma”, he added. Diffuse large B-cell lymphomas account for about 30% of all lymphomas in the USA. Patients with the ABC subtype have poorer overall survival than do those with the GCB subtype. The two molecularly distinct subtypes were discovered in 2000 by Louis Staudt (National Institutes of Health, Bethesda, MD, USA), a co-author of the new study. “These results confirmed our hypothesis that ibrutinib would be active in the ABC subtype but not in the GCB [subtype], based on genetic evidence that B-cell receptor signalling is critical to the development of this [subtype of the] disease”, said Staudt. The ABC gene signature has been used to select patients to be treated with ibrutinib plus R-CHOP
in a 900-patient phase 3 study that is nearly accrued and will investigate whether ibrutinib can increase the proportion of cured patients. According to study author John Gerecitano (Memorial Sloan-Kettering Cancer Center, New York, NY, USA), the researchers found unexpectedly that most responses to ibrutinib occurred in ABC lymphomas that lacked BCR mutations, suggesting that BCR oncogenic signalling in these tumours does not require BCR mutations. “The future impact of this discovery is enormous, as the use of ibrutinib can be focused on patients with ABC diffuse large B-cell lymphoma, who are genetically wired to respond to ibrutinib while sparing other patients unnecessary exposure to the drug”, said Asher Chanan-Khan (Mayo Clinic, Jacksonville, FL, USA).
Lancet Oncol 2015 Published Online July 24, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00192-8 For the study by Wilson and colleagues see Nat Med 2015; published online July 20. DOI:10.1038/nm.3884
Vicki Brower
www.thelancet.com/oncology Published online July 24, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00192-8
1
Ibrutinib promising in subtype of DLBCL Patients with the activated B-celllike (ABC) subtype of diffuse large B-cell lymphoma were more likely to respond to ibrutinib than were those with the germinal centre B-celllike (GCB) subtype of the disease, according to results of a phase 2 study. Of 80 patients who had relapsed or had not responded to previous treatment, 37% of those with ABC diffuse large B-cell lymphoma had a complete or partial response to the drug, compared with only 5% of those with the germinal GCB subtype. Ibrutinib is an inhibitor of a key enzyme in B-cell receptor (BCR) signalling, Bruton’s tyrosine kinase, which is essential for the survival of ABC lymphoma cells by reducing NFκB pathway activity. “This is the first clinical study to demonstrate the importance of precision medicine in lymphoma”, said the first author, Wyndham Wilson
(National Cancer Institute, Bethesda, MD, USA). “It represents the first effort to really understand that specific mutations respond to targeted agents in lymphoma”, he added. Diffuse large B-cell lymphomas account for about 30% of all lymphomas in the USA. Patients with the ABC subtype have poorer overall survival than do those with the GCB subtype. The two molecularly distinct subtypes were discovered in 2000 by Louis Staudt (National Institutes of Health, Bethesda, MD, USA), a co-author of the new study. “These results confirmed our hypothesis that ibrutinib would be active in the ABC subtype but not in the GCB [subtype], based on genetic evidence that B-cell receptor signalling is critical to the development of this [subtype of the] disease”, said Staudt. The ABC gene signature has been used to select patients to be treated with ibrutinib plus R-CHOP
in a 900-patient phase 3 study that is nearly accrued and will investigate whether ibrutinib can increase the proportion of cured patients. According to study author John Gerecitano (Memorial Sloan-Kettering Cancer Center, New York, NY, USA), the researchers found unexpectedly that most responses to ibrutinib occurred in ABC lymphomas that lacked BCR mutations, suggesting that BCR oncogenic signalling in these tumours does not require BCR mutations. “The future impact of this discovery is enormous, as the use of ibrutinib can be focused on patients with ABC diffuse large B-cell lymphoma, who are genetically wired to respond to ibrutinib while sparing other patients unnecessary exposure to the drug”, said Asher Chanan-Khan (Mayo Clinic, Jacksonville, FL, USA).
Lancet Oncol 2015 Published Online July 24, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00192-8 For the study by Wilson and colleagues see Nat Med 2015; published online July 20. DOI:10.1038/nm.3884
Vicki Brower
www.thelancet.com/oncology Published online July 24, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00192-8
1