Abstract
Simple SummaryDiffuse large B-cell lymphoma (DLBCL) with co-expression of MYC and BCL2 proteins is referred to as double expressor lymphoma. Multiple studies have identified double expressor status to be an adverse predictive factor for response to standard chemotherapy regimens. The revised 2016 WHO classification recommends cutoff values of 40% for MYC and 50% for BCL2 protein expression; however, actual cutoff values have varied widely among published studies. Increasing recognition of the potential prognostic value of double expressor status prompted this systematic review and meta-analysis of the worldwide literature. Our findings indicate that approximately 23% of de novo DLBCL tumors express both MYC and BCL2 proteins above the indicated thresholds. Remarkably, different immunohistochemical cutoff values did not significantly affect the proportion of tumors attaining double expressor status. Cases lacking MYC/BCL2 co-expression were associated with a significantly higher probability of complete remission, thereby reaffirming the value of this predictive biomarker.MYC/BCL2 protein co-expression (i.e., double expressor) has been shown to be a negative predictor of outcome in diffuse large B-cell lymphoma (DLBCL). We aimed to establish the incidence of double expressor status in patients with de novo DLBCL and identify the predictive value of this biomarker on treatment response through systematic review and meta-analysis. PubMed and Embase were searched for studies published through December 2019 that reported proportions of double expressor DLBCL. The pooled proportions of MYC and BCL2 expression, both alone and in combination, were computed using the inverse variance method for calculating weights and by the DerSimonian–Laird method. The pooled odds ratios (ORs) of complete remission (CR) rate were calculated, and meta-regression analysis was conducted to explore heterogeneity. Forty-one studies (7054 patients) were included. The pooled incidence of double expressor status in DLBCL was 23% (95% confidence interval [CI], 20–26%), with an adjusted estimate of 31% (95% CI, 27–36%). Neither MYC/BCL2 protein cutoff values, race, mean, or median age of included patients, or overall study quality was a significant factor of heterogeneity (p ≥ 0.20). Cases without double expressor status demonstrated a higher probability of CR to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment (OR, 2.69; 95% CI, 1.55–4.67). Our results reaffirm the predictive power of this important biomarker.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma [1]
Recent evidence shows that MYC and BCL2 copy number variations do not produce the high-risk gene expression signature seen in most true double-hit and triple-hit (DH/TH) lymphomas harboring MYC and BCL2 rearrangements, suggesting that copy number variations should not be used to expand the definition of DH/TH lymphomas [9]
In this systematic review and meta-analysis, we established the incidence of MYC/BCL2 co-expression in all de novo DLBCL studies published to date and calculated pooled estimates of double expressor status according to different IHC cutoff values
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma [1]. A vigorous search has been made for biomarkers that can predict patients at high risk for treatment failure. Clinical and molecular factors including age, International Prognostic Index (IPI) score, molecular cell-of-origin (COO), chromosomal rearrangements, and protein expression have been identified as potential prognostic factors [3,4,5,6]. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, so called double-hit and triple-hit (DH/TH) lymphomas, are defined in the 2016 World Health Organization (WHO) classification as a new diagnostic category and includes a subset of tumors with DLBCL morphology [7]. Recent evidence shows that MYC and BCL2 copy number variations do not produce the high-risk gene expression signature seen in most true DH/TH lymphomas harboring MYC and BCL2 rearrangements, suggesting that copy number variations should not be used to expand the definition of DH/TH lymphomas [9]
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