Key Points:
- The PHOENIX trial was a phase 3 clinical study to assess the efficacy of adding ibrutinib to R-CHOP in untreated non-GCB DLBCL.
- RNA sequencing demonstrated decreased event-free survival (EFS) and overall survival (OS) in patients with high BCL2/MYC co-expression.
- Adding ibrutinib to R-CHOP improved EFS and OS in patients younger than 60 with high BCL2/MYC co-expression.
- High BCL2/MYC co-expression was associated with B-cell-like and MYD88L265P/CD79B-mutation DLBCL subtypes.
- High BCL2/MYC co-expression may indicate a subset of non-GCB DLBCL that may be responsive to ibrutinib therapy.
High levels of BCL2 and MYC protein co-expression in diffuse large B-cell lymphoma (DLBCL) (double-expressor [DE] lymphoma) were associated with a poor prognosis, especially in cases of non-germinal centre B-cell-like (non-GCB) DLBCL. Overexpression of BCL2/MYC was linked to activation of the B-cell receptor (BCR) pathway, suggesting that BCR inhibitors may be effective against DE DLBCL.
Baseline biopsies from the PHOENIX trial (NCT01855750) were used to test the hypothesis that high BCL2/MYC co-expression by RNA sequencing could identify a patient subset responding to ibrutinib in previously untreated non-GCB DLBCL. Kaplan-Meier estimates, Cox regression, and log-rank testing indicated that higher levels of BCL2/MYC RNA expression were associated with shorter event-free survival (EFS) and overall survival (OS).
High BCL2/MYC co-expression was found in 234/766 patients (30.5%), of whom 123/386 (31.9%) were treated with ibrutinib with R-CHOP, and 111/380 (29.2%) were treated with R-CHOP alone. In patients with strong BCL2/MYC co-expression, the combination of ibrutinib and R-CHOP improved event-free survival compared to R-CHOP alone (HR, 0.646; 95% CI, 0.424-0.984; P=.0403), but it did not affect overall survival (P=.1574). For patients aged <60 years with strong BCL2/MYC co-expression, however, ibrutinib with R-CHOP exhibited clinically substantial improvement over R-CHOP alone in terms of both 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).
Significant correlations between high BCL2/MYC co-expression and activated B-cell-like (P<.0001) and MYD88L265P/CD79B-mutated (P=.0016) subtypes of DLBCL were found by the research team. Therefore, further exploration is warranted into the fraction of non-GCB DLBCL that has significant BCL2/MYC co-expression and may be selectively sensitive to ibrutinib.
Source:https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2022009389/494222/Clinical-impact-of-ibrutinib-plus-R-CHOP-in
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT01855750
Johnson P, Balasubramanian S, Hodkinson B, Shreeve S, Sun S, Srinivasan S, Steele A, Vermeulen J, Sehn L, Wilson W. Clinical impact of ibrutinib plus R-CHOP in untreated DLBCL co-expressing BCL2 and MYC in the phase 3 PHOENIX trial. Blood Adv. 2023 Jan 25:bloodadvances.2022009389. doi: 10.1182/bloodadvances.2022009389. Epub ahead of print. PMID: 36696540.
