The genetic classification of DLBCL identified subgroups that benefit from addition of ibrutinib and its underlying mechanism.

  • Major Finding: The genetic classification of DLBCL identified subgroups that benefit from addition of ibrutinib and its underlying mechanism.

  • Concept: Dependency on B-cell receptor–dependent NFκB activity underlies the survival advantage induced by ibrutinib addition.

  • Impact: These results suggest survival benefit of ibrutinib plus R-CHOP in younger patients with MCD and N1 DLBCL.

In a phase III clinical trial (“Phoenix”), the ABC subgroup of diffuse large B-cell lymphoma (DLBCL), which is based on gene expression profiling, specifically showed survival benefit of ibrutinib in combination with R-CHOP in younger patients. However, how ibrutinib affects survival in this patient population is unclear. To address this question, Wilson and colleagues performed RNA and DNA sequencing on DLBCL tumors from patients of the Phoenix trial to identify mutations, translocations, and gene expression phenotypes. While the old classification divides DLBCL into three subgroups—ABC, GBC, and unclassified—newer classification methods subdivide the 3 groups into additional genetic subtypes based on patterns of co-occuring genetic alterations, thus splitting the ABC subgroup into four genetic subtypes: MCD, BN2, N1, and A53, with the MCD type characterized by MYD88/CD79B mutations, the BN2 type by BCL6 translocations or NOTCH2 mutations, and the N1 subtype characterized by NOTCH1 mutations. Using the LymphGen algorithm, each tumor was assigned to a genetic subtype. The distribution of MCD, BN2, and N1 cases in the Phoenix clinical trial cohort was comparable to the National Cancer Institute cohort, and tumor phenotypes followed expected patterns, with MCD cases being primarily ABC DLBCL and N1 and BN2 cases being most often classified as GCB or unclassified. To investigate ibrutinib effects, patients were stratified based on age due to toxicities observed in patients over 60 years of age. Younger patients with MCD or N1 DLBCL who received both ibrutinib and R-CHOP demonstrated a 3-year event-free survival and overall survival of 100%, which was significantly higher than R-CHOP alone. Mechanistically, MCD DLBCL is highly dependent on B-cell receptor (BCR)–dependent NFκB activity, and as ibrutinib specifically targets this dependency, the observed survival benefit of ibrutinib for MCD DLBCL was expected; however, in contrast, the survival benefit for N1 DLBCL was not. N1 tumors were enriched in recurrent mutations in regulators of NOTCH1, B-cell differentiation, and tumor surveillance, but, notably, N1 tumors also had recurrent mutations in the BCR-dependent NFκB pathway, suggesting this dependency as the underlying mechanism of ibrutinib in mitigating N1 DLBCL. In summary, this study reveals the effects of ibrutinib in different subtypes of DLBCL, and describes the usefulness of implementing the genetic classification of DLBCL in future clinical trials.

Wilson WH, Wright GW, Huang DW, Hodkinson B, Balasubramanian S, Fan Y, et al. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell 2021 Nov 3 [Epub ahead of print].

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