Abstract
The BTK inhibitor ibrutinib is preferentially effective in patients with the ABC subtype of DLBCL.
Major finding: The BTK inhibitor ibrutinib is preferentially effective in patients with the ABC subtype of DLBCL.
Clinical relevance: Chronic active BCR signaling confers sensitivity to ibrutinib even in the absence of BCR mutations.
Impact: The ABC DLBCL gene expression signature may select patients most likely to respond to ibrutinib.
Diffuse large B-cell lymphoma (DLBCL) is categorized into two distinct molecular subtypes, activated B cell-like (ABC) and germinal center B cell–like (GCB). The ABC subtype is characterized by chronic active B-cell receptor (BCR) signaling, which stimulates NF-κB activity via Bruton tyrosine kinase (BTK), suggesting that inhibition of BTK may be preferentially effective in ABC DLBCL. To test this hypothesis, Wilson and colleagues assessed the activity of the selective covalent BTK inhibitor ibrutinib in 80 patients with relapsed or refractory de novo DLBCL in a phase I/II clinical trial. Indeed, the response rate to ibrutinib was greater in patients with ABC DLBCL (14 of 38; 37%), including a 16% rate of complete responses, than in patients with GCB DLBCL (1 of 20; 5%). The response rate was high among patients with a mutation in the BCR subunit gene CD79B (5 of 9; 55.5%), and was even higher among patients with both CD79B and myeloid differentiation primary response 88 (MYD88) mutations (4 of 5; 80%), consistent with in vitro evidence of cooperation between the BCR and MYD88 pathways. Importantly, the majority of ibrutinib responders (67%) had wild-type CD79A and CD79B, providing evidence that nongenetic influences may also drive chronic active BCR signaling in DLBCL. In contrast, tumors with MYD88 mutations but wild-type CD79B did not respond to treatment, suggesting that MYD88 can promote ABC DLBCL independent of BCR signaling. In addition, ibrutinib was ineffective in tumors with mutations that activated CARD11, which acts downstream of BTK, and in tumors with mutations that inactivated TNFAIP3, which negatively regulates NF-κB. Together, these findings suggest that ABC DLBCL may arise via BCR-dependent and BCR-independent mechanisms and support the use of the ABC DLBCL gene expression signature to select patients likely to respond to ibrutinib in ongoing phase III DLBCL clinical trials.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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