Improved Ibrutinib Response in Select DLBCL Subtype

Sensitivity to ibrutinib in patients with activated B cell-like diffuse large B cell lymphoma subtypes suggests potential for personalised treatment

medwireNews: Research published in Nature Medicine suggests that patients with activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL), but not those with germinal centre B cell-like (GCB) DLBCL, could benefit from ibrutinib therapy.

“On the basis of the observed selectivity of ibrutinib for ABC DLBCL cases in the present trial, a randomized phase 3 study of ibrutinib with R-CHOP treatment has begun, and is enrolling only newly diagnosed subjects with non-GCB DLBCL”, say the authors.

They explain that of the two major DLBCL subtypes – ABC and GCB – only the former arises by acquiring mutations that target the B cell receptor resulting in chronic activation of the signalling pathway. As the Bruton’s Tyrosine kinase inhibitor blocks B-cell Receptor signalling, the researchers hypothesise that ibrutinib treatment would be active in the ABC but not the GCB subtype. This is of particular interest as ABC DLBCL has fewer effective treatments than GCB, they add.

After a median follow-up of 11.53 months, treatment with ibrutinib at a dose of 560 mg/day led to responses in 25% of 80 patients with refractory or relapsed de novo DLBCL, with 12 partial and eight complete responses. Median progression-free survival (PFS) was 1.64 months and median overall survival (OS) was 6.41 months.

When patients were classified into subtypes on the basis of tumour Gene expression profiling, the response rate was significantly higher in the 38 patients in the ABC subgroup than in the 20 patients in the GCB subgroup, at 37% and 5%, respectively. And 16% of ABC cases achieved a complete response while no GCB cases did so.

Both PFS and OS were longer in the ABC than in the GCB subgroup, at a median of 2.02 versus 1.31 months and 10.32 versus 3.35 months, respectively. But the difference in PFS was statistically significant while the OS difference only tended towards significance.

Further analysis of biopsy samples showed that approximately half of the participants in the ABC DLBCL subgroup had tumours harbouring mutations in CD79B while none had CD79A mutations, where both genes encode B-cell receptor subunits. Responses were observed not only in 55.5% of nine patients with CD79B mutations, but also in 31% of 29 patients with Wild-type CD79B.

“Although there could be some…undefined genetic lesions that activate [B-cell receptor] signaling in these tumors, this finding raises the possibility of a non-genetic mechanism of [B-cell receptor] pathway addiction”, say Louis Staudt, from the National Cancer Institute in Bethesda, Maryland, USA, and co-workers.

They add: “Taken together, these observations suggest that future DLBCL trials involving ibrutinib should not restrict enrollment to subjects with CD79A- or CD79B-mutated tumors, as this approach would probably overlook a large subset of ibrutinib-responsive tumors.”

Reference

Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015; Advance online publication 20 July. doi:10.1038/nm.3884

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