Biomarker expression may predict CNS relapse risk in DLBCL

Dual MYC and BCL2 expression appeared associated with an increased risk for central nervous system relapse in patients with diffuse large B-cell lymphoma, according to the results of a retrospective study.

The increased risk seen in this patient subgroup appeared to be independent of central nervous system risk score (CNS-IPI) or cell of origin, results showed.

“CNS relapse is a devastating event in patients with diffuse large B-cell lymphoma [DLBCL],” Kerry J. Savage, MD, MSc, associate professor of medical oncology at University of British Columbia and clinical scientist at BC Cancer Agency, and colleagues wrote. “Despite the overall improvement in outcome of DLBCL in the rituximab [Rituxan; Genentech, Biogen Idec] treatment era, CNS relapse continues to occur.”

Dual expression of MYC and BCL2 often results in unfavorable outcomes for patients with DLBCL, with dual translocation of MYC and BCL2 associated with a high risk for CNS relapse, according to study background.

However, the effect of dual expression on the risk for CNS relapse is unknown.

Thus, Savage and colleagues studied tissue microarrays of 428 patients with DLBCL enrolled in two trials to determine the influence of dual expresser status on CNS relapse risk.

The researchers had access to pretreatment formalin-fixed paraffin biopsies, which they evaluated for MYC and BCL2 expression through immunohistochemistry. They further determined the cell of origin through immunohistochemistry.

All patients were subsequently treated with rituximab plus CHOP chemotherapy.

CNS-IPI indicated 45% of patient had an intermediate risk for CNS relapse, whereas 21% had a high risk and 34% had a low risk.

The researchers observed dual MYC and BCL2 expression in 30% of patients (n = 127). Dual expressers tended to be older (median age, 68 years vs. 62 years; P = .004) and have more advanced disease (61% vs. 51%).

Median follow-up was 6.8 years (range, 0.8-13.3).

The entire cohort had a 2-year cumulative risk for CNS relapse of 4.3%. Despite divergent relapse estimates based on CNS-IPI categorization, the researchers found a significantly higher risk for relapse among dual expressers when compared with nondual expressers, regardless of CNS-IPI risk category (2-year risk, 9.7% vs. 2.2%; P = .001).

Patients with activated B-cell (ABC) DLBCL (56% of dual expressers) and nongerminal center B-cell (non-GCB) DLBCL also appeared at an increased risk for CNS relapse. More ABC DLBCL cases defined by the Lymph2Cx gene expression profiling assay (NanoString) experienced 2-year CNS relapse than GCB cases (9.1% vs. 2.3%; P = .02), and more non-GCB cases defined by the immunohistochemistry-based Hans algorithm experienced 2-year CNS relapse (7.1% vs. 2.2%; P = .02).

However, multivariate analyses identified only dual expresser status (HR = 3.68; 95% CI, 1.27-10.64) and high CNS-IPI score (HR = 5.21; 95% CI, 1.03-26.3) as independent predictors for CNS relapse.

“Our data support that dual expresser MYC- and BCL2-positive DLBCL defines a group of patients at a higher risk for CNS relapse and this represents a major component of the poor outcome in ABC and non-GCB DLBCL,” Savage and colleagues wrote. “The combination of clinical, biological and, in the future, genetic factors may help to further define a high-risk group to focus aggressive directed staging procedures and select patients for prophylactic strategies.” – by Cameron Kelsall

Disclosure: Savage reports institutional research funding from Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.