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

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.