THE PROGNOSTIC SIGNIFICANCE OF MYC AND BCL2 PROTEIN DOUBLE EXPRESSION IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA, NOS, IN THE ABSENCE OF MYC REARRANGEMENT

he revised 2016 WHO Classification distinguishes diffuse large B- cell lymphoma, not otherwise specified (DLBCL, NOS) from high grade B-cell Lymphomas (HG with MYCand BLC2or BCL6gene rearrange- ment, or NOS) and other entities. DLBCLs NOS with MYC and BCL2 protein double-expression by immunohistochemistry, also known as dou- ble expressor lymphomas (DEL), have been associated with a worse out- come in all categories. However, unlike MYC rearranged cases, DEL have been managed with standard R-CHOP when not associated with HG features or gene rearrangements. In this retrospective observational study we enrolled all consecutive patients with a diagnosis of DLBCL, NOS, between 2013 and 2019 treated and followed-up at University of Verona. Exclusion criteria were age >80, different treatment than R- CHOP, transformation from indolent lymphoma, HG histology, and pres- ence of MYC rearrangement. Expression of MYC and BCL2 proteins was defined with standard cut-offs (MYC ≥ 40% and BCL2 ≥ 50%). One hundred and ninety seven patients were included in the study. Median age was 63 (22-80), 117 were males, and median follow up was 24 months (4-94). Progression free survival (PFS) at 2 years was 68% ± 4% and overall survival was 77% ± 3%. Forty-nine patients (25%) were DEL, and 86 (44%) had international prognostic index (IPI) 3 to 5. Mul- tivariate analysis showed that the IPI of 3-5 (HR 2.56; 4.34-1.53), and DEL (HR 2.77; 4.76-1.66) were the only independent significant vari- ables associated with adverse PFS. Considering these two factors, a three-risk group model was built, recognizing a low-risk group (43% of all patients analyzed, no risk factors), an intermediate-risk group (45%, one risk factor), and a high-risk group (12%, both risk factors) with highly significantly different 2-year rates of PFS of 85%, 62%, and 33%, respectively as illustrated in Figure 1. Our analysis showed that DEL, together with IPI, can easily recognize patients with DLBCL, NOS, in the absence of MYC rearrangements, who do not benefit of R-CHOP. This score should be tested in prospective settings, in order to early iden- tify patients that may be candidate to alternative therapies.