Clinical impact of ibrutinib plus R-CHOP in untreated DLBCL coexpressing BCL2 and MYC in the phase 3 PHOENIX trial

Abstract

Diffuse large B-cell lymphoma (DLBCL) with high co-expression of BCL2 and MYC proteins (double-expressor [DE] lymphoma), is considered an adverse prognostic indicator associated mostly with non-germinal center B-cell-like (non-GCB) DLBCL. BCL2/MYC overexpression is associated with B-cell receptor (BCR) pathway activation and, consequently, DE DLBCL may be sensitive to BCR inhibitors. We assessed whether high BCL2/MYC co-expression by RNA sequencing could identify a patient subset responsive to ibrutinib using baseline biopsies from the PHOENIX trial (NCT01855750), which evaluated the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-GCB DLBCL. BCL2/MYC RNA expression was correlated with lower event-free survival (EFS) and overall survival (OS) using Kaplan-Meier estimates with Cox regression and log-rank testing. In total, 234/766 (30.5%) patients had high BCL2/MYC co-expression: 123/386 (31.9%) received ibrutinib plus R-CHOP and 111/380 (29.2%) received R-CHOP. EFS was superior with ibrutinib plus R-CHOP vs R-CHOP alone in patients with high BCL2/MYC co-expression (HR, 0.646; 95% CI, 0.424-0.984; P=.0403), but there was no significant impact on OS (P=.1574). However, EFS (HR, 0.381; 95% CI, 0.193-0.752; P=.0039) and OS (HR, 0.234; 95% CI, 0.078-0.707; P=.0050) showed clinically meaningful improvement with ibrutinib plus R-CHOP over R-CHOP alone in patients aged <60 years with high BCL2/MYC co-expression. We observed a significant association between high BCL2/MYC co-expression and activated B-cell-like (P<.0001) and MYD88L265P/CD79B-mutated (P=.0016) subtypes of DLBCL. Consequently, high BCL2/MYC co-expression identifies a subset of non-GCB DLBCL that may be preferentially responsive to ibrutinib and warrants further investigation. ClinicalTrials.gov NCT01855750.

CD5 Gene Signature Identifies Diffuse Large B-Cell Lymphomas Sensitive to Brutonʼs Tyrosine Kinase Inhibition

“…An easy-to-use IHC biomarker or gene expression signature could allow for widespread adoption in the clinic, particularly within the community setting. Moreover, a recent retrospective analysis has also demonstrated that non-GCB DLBCLs with high MYC and BCL2 mRNA expression also benefit from the addition of ibrutinib to R-CHOP, 39 which further supports the notion that transcriptional profiling can effectively enrich for responsiveness to BTKi-based regimens in DLBCL.…”

Efficacy and safety of Orelabrutinib-based regimens in diffuse large B-cell lymphoma: a single-center retrospective analysis

“…In the Phoenix clinical trial, the 3-year OS and PFS in the intent-to-treat population treated with ibrutinib plus R-CHOP were 85.8% and 70.8%, respectively [ 21 ]. Compared to the Phoenix study, the performance status of the patients in this study was worse (ECOG = 2, 42.1% vs. 9.1%), with an increase in the proportion of patients with BM involvement (21.1% vs. 11.9%), DEL involvement (57.9% vs. 43.6%) [ 37 ], extranodal involvement ≥ 2 (47.4% vs. 31%), and IPI 3–5 (57.9% vs. 43.6%). Due to the limited number and the heterogeneity of patients in this research, the OS and PFS of the non-GCB group were lower than in the Phoenix study.…”

“…In the phase 3 PHOENIX trial, DEL patients receiving ibrutinib plus R-CHOP had comparable OS (HR: 1.042, 95%CI: [1.708–1.534], P = 0.8338) and EFS (HR: 0.987, 95%CI: [0.608–1.601], P = 0.9573) to non-DEL patients. Moreover, ibrutinib plus R-CHOP increased EFS and OS in patients younger than 60 years old with DEL compared to R-CHOP, but there was no significant difference in older patients [ 37 ]. BTKi have shown potential benefits in the treatment of DEL patients, but further research is needed to discover its specific mechanism toward DEL, and whether they might aid older DEL patients.…”

2024 Update: Advances in the risk stratification and management of large B‐cell lymphoma

“…It was also associated with more frequent adverse events (e.g., febrile neutropenia) 58 . Post‐hoc gene expression analysis of tumor samples revealed superior EFS and OS in patients <60‐years‐of‐age with DEL, MCD and N1 non‐GCB disease 59 . Similarly, in the single‐arm phase II IVORY trial of 24 patients with EBV+ DLBCL, I‐RCHOP yielded a more favorable CR in patients <65‐years‐old relative to matched cases treated with R‐CHOP (87% vs. 69%) 60 .…”