Oral presentation by Dr. Anas Younes
Standard treatment for advanced stage diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). It is well understood that DLBCL is a heterogeneous entity, with patients with activated B-cell (ABC; as classified by gene expression profiling) or non-germinal centre B-cell (non-GCB; as classified by immunohistochemistry) subtypes having a worse prognosis. Patients with ABC (or non-GCB) DLBCL have constitutive overactivation of the B-cell receptor pathway and may benefit from targeted agents exploiting this. The Bruton tyrosine kinase inhibitor, ibrutinib, has been previously evaluated in patients with relapsed/refractory DLBCL, demonstrating activity in the ABC subset and prompting further evaluation.
The Phoenix trial evaluated whether the addition of ibrutinib to R-CHOP would improve efficacy in previously untreated patients with non-GCB DLBCL or the ABC subtype. Patients with non-GCB DLBCL (as confirmed by centralized review) were randomized 1:1 to standard R-CHOP with either ibrutinib or placebo on a 21-day cycle for 6 or 8 cycles. ABC DLBCL was retrospectively identified using gene expression profiling. The primary endpoint was event-free survival (EFS) in the intent-to-treat or ABC population. Overall, 838 patients were randomized to ibrutinib with R-CHOP (n = 419) or placebo with R-CHOP (n = 419). The median age was 62 years and only 68% of patients had documented ABC subtype. In the ibrutinib plus R-CHOP arm, fewer patients received ≥6 cycles of R-CHOP (81% vs. 91%) with a higher number of patients discontinuing treatment (22.4% vs. 13.6%), respectively, primarily due to adverse events. This poor tolerance to therapy was mainly seen in patients >60 years of age. Ultimately, with a median follow-up of 35 months, ibrutinib plus R-CHOP did not improve EFS in patients with non-GCB or ABC DLBCL. However, multivariate analysis showed a significant interaction with age. Efficacy appeared improved in younger patients (<60 years) with 3-year EFS (75% vs. 65%) and overall survival (OS; 93% vs. 81%) favouring the addition of ibrutinib. However, in older patients (>60) the addition of ibrutinib led to worse outcomes (3-year EFS of 66% vs. 70% and OS of 77% vs. 82%). Increased toxicities with the addition of ibrutinib included neutropenia and infection, which were notably higher in older patients.
As the overall result of this trial was negative, the addition of ibrutinib to R-CHOP cannot be considered a standard of care. However, the intriguing signal of benefit in younger patients warrants further investigation. It is noteworthy that only 68% of this non-GCB population (as identified by immunohistochemistry) had ABC DLBCL, highlighting the need for more accurate molecular subtyping in clinical practice.