Impact of MYC alterations in de novo large B-cell lymphoma: An italian single center experience

Abstract

Abstract Introduction: Large B-cell lymphoma (LBCL) with translocations involving MYC (MYC-T) and BCL2 (BCL2-T) +/- BCL6 (BCL6-T) (DHL-THL) comprises 10% of cases of LBCL and carries a poor prognosis. Also MYC increased copy number (MYC-ICN) seems to influence the outcome, but there is no consensus on their frequency and prognostic significance. In 2019 Schieppati et al. reported a single center experience on patients (pts) with MYC-ICN and MYC-T and showed that MYC-ICN was significantly associated with worse prognosis only with >4 MYC extra copies. We present an update of this study, including pts with subsequent diagnosis and reclassifyng pathologic entities according to the 2022 WHO Classification. Aim: To evaluate the clinical impact of MYC-ICN and to compare clinical characteristics and treatment outcomes in pts with MYC-ICN and MYC-T. Method: This is a retrospective observational study of all consecutive pts with LBCL (diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBCL)) and alterations of MYC detected by FISH (fluorescent in situ hybridation), diagnosed in a single Hematology Unit. According to genetic alterations LBCLs were categorized as single hit lymphoma (SHL), DHL-THL and MYC-ICN. MYC-ICN was defined when ≥3 copies were identified, amplification was defined as countless copies of MYC (MYC-AMP). In MYC-ICN group pts were classified as MYC-ICN ≤4 (3-4 copies of MYC) and MYC-ICN >4 (>4 copies orMYC-AMP). Results: From 2011 to 2024, we identified 259 pts with LBCL and MYC alterations: 148 (57%) had MYC-T, 111 (43%) MYC-ICN (of these 46 pts had MYC-ICN ≤4, 56 pts MYC-ICN >4 and 9 pts MYC-AMP). MYC-T included 47% SHL, 53% DHL-THL. The median age was 67 years (y) (range 22-88 y). Most pts had advanced stage (76%) and IPI≥3 (66%). The clinical and histological characteristics were comparable between MYC-T and MYC-ICN other than a significantly higher involvement of ≥2 extranodal sites, a more frequent germinal center B immunophenotype (GCB) and transformation from indolent lymphoma (tLBCL) in MYC-T. In MYC-T group pts with DHL-THL had significantly more frequently stage III-IV, bulky disease, IPI≥3, higher ki67%, GCB phenotype and tLBCL than SHL. In MYC-ICN group the clinical and histological characteristics were comparable between MYC-ICN ≤4 and MYC-ICN>4. other than a significantly higher ki67% in MYC-ICN>4. In MYC-ICN group 95% pts had a diagnosis of DLBCL and 5% of HGBCL NOS, in MYC-T group 53% pts had DHL-THL, 39% DLBCL and 8% HGBCL NOS. MYC-T compared to MYC-ICN pts received significantly less frequently standard chemotherapy (sCT) as R-CHOP R-CHOP-like than intensive chemotherapy (iCT) as R-DAEPOCH, Burkitt-like therapy or regimens containing HD MTX/ARA-C, sCT followed by autologous stem cell transplantation (ASCT) as consolidation (24% sCT and 69% iCT in MYC-T, 58% sCT and 35% iCT in MYC-ICN (p 0,001)); 7% of pts in both group received palliative therapy. Upfront consolidative ASCT was performed in 30% of pts in MYC-T group and 21% in MYC-ICN group (p ns). With a median follow up of 59 months (range 41-76), 3-y overall (OS) and progression free survival (PFS) of treated pts, were similar in MYC-T and MYC-ICN (OS 67% and 63% and PFS 59% and 55% in MYC-T and MYC-ICN respectively). In MYC-T group there weren't significative differences in OS and PFS between SHL and DHL-THL while in MYC-ICN group OS was significantly better in MYC-ICN ≤4 [3-y OS 75% vs 54% (p 0,028)] and there was a trend of better PFS in MYC-ICN ≤4. According to the treatment received, there weren't significant difference in OS and PFS between sCT and iCT in MYC-ICN group (both MYC-ICN ≤4 and MYC-ICN>4) while in MYC-T group OS and PFS were better in pts treated with iCT [3-y OS 50% vs 71% (p 0,023), 3-y PFS 39% and 66% (p 0,012) with sCT and iCT respectively]. In the whole series in univariate analysis age>60y, ECOG≥2, tLBCL, stage III-IV, extranodal involvement and increased LDH were related to worse OS and PFS, ASCT consolidation to better OS and PFS. In multivariate analysis tLBCL, ECOG≥2 and stage III-IV and ASCT maintained their prognostic impact on OS and PFS. Conclusions: In this study numerical aberrations of MYC have significantly impact on prognosis, especially in MYC-ICN>4. There are no differences in outcome between pts with MYC-ICN and MYC-T but the former received less often iCT. Further studies are warranted to clarify the biological implications of numerical aberrations of MYC and the possible benefit of iCT.