Impact of MYC Alterations in De Novo and Transformed Large B-Cell Lymphoma: An Italian Single Center Experience

Introduction: Large B-cell lymphoma (LBCL) transformed from follicular lymphoma (FL) has traditionally been associated with poor prognosis but their outcome has improved in the immuno-chemotherapy era, with a reported median survival of about 5 years (Wagner-Johnston ND et al, 2015). A more favorable prognosis is observed in patients (pts) with evidence of transformation at the time of diagnosis (Rusconi et al. 2019). Moreover, many studies have shown a negative prognostic impact of translocation involving MYC gene, but there are few data about these alterations in transformed LBCL (tLBCL) where genetic rearrangement of MYC with translocation involving BCL2 and/or BCL6 (DHL/THL) occurs even more frequently than in de novo large B cell lymphoma (dLBCL) (20-34% vs. 6-14%, Behdad A et al, 2019).

Aim: To evaluate the impact of MYC alterations on clinical features and outcome of tLBCL compared to dLBCL.

Method: This is a retrospective observational study of all consecutive pts with dLBCL and tLBCL (diffuse large B cell or high grade B cell lymphoma) and alterations of MYC+/- BCL2+/-BCL6 detected by FISH (fuorescent in situ hybridation), diagnosed in a single Hematology Unit and classified according to the onset time of FL: trasformed at diagnosis (group1) or after diagnosis of FL (group 2). According to genetic alterations LBCLs are categorized as single hit lymphoma (SHL), DHL/THL and lymhoma with MYC gain copy number [atypical SHL (aSH) and atypical DHL-THL (aDHL/THL)].

Results: From January 2011 to December 2022, we identified 174 pts with LBCL and MYC alterations: 128 pts had dLBCL and 46 tLBCL (17 in group 1, 29 in group 2).

The median age of the whole group was 68 years (range 31- 88). The clinical characteristics were comparable in the two groups other than a significantly higher bone marrow involvement in tLBCL [30% vs 19% in dLBCL (p 0,013)]. Most pts had advanced stage disease (76%) and IPI≥3 (67%) .

SHL were significantly more frequent in dLBCL than in tLBCL [19% vs 6% (p 0,049)], while DHL/THL in tLBCL [61% vs 30% (p 0,0001)], aDHL/THL were similar in the two groups [(45% and 33% in dLBCL and tLBCL respectively; p not significant (ns)]. Most pts had germinal center B phenotype (GCB) (according to Hans algorithm): 79% in dLBCL and 89% in tLBCL. Ki67 proliferative index was significantly higher in dLBCL [median 90% vs 80% in tLBCL (p 0,003)].

Treatment offered to dLBCL and tLBCL pts was respectively: R-CHOP or R-CHOP-like (33% and 24%), R-DAEPOCH (31% and 39%), intensive chemotherapy (iCT) such as GMALL or other regimens containing HD MTX and ARA-C (31% and 28%), palliative therapy (2% and 9%). Three pts died before to receive any treatment. Upfront autologous stem-cell transplantation (ASCT) as consolidative treatment was performed in 27% dLBCL and 30% tLBCL (p ns). In tLBCL group rituximab maintenance was performed in 54% of responsive pts.

With a median follow up of 69 months (ms) (range 11-159), 3-years overall (OS) and progression free survival (PFS) were significantly better in dLBCL than tLBCL (OS 65% and 43% and PFS 60% and 39% in dLBCL and tLBCL respectively, both p 0,005). According to the onset of LBCL, there wasn’t significant difference in OS and PFS between dLBCL and group1. In DHL/THL the significantly better OS and PFS in dLBCL were confirmed [3-years OS 65% vs 43% (p 0,025), 3-years PFS 65% and 35% (p 0,007) in dLBCL and tLBCL respectively]; conversely, in SHL and aDHL/THL there wasn’t significant difference in OS and PFS between the two groups.

In univariate analysis for the whole population IPI≥3, ECOG≥2, tLBCL, stage III-IV, age>60 years and extranodal involvement were related to a worse OS and PFS, while iCT, GCB phenotype, SHL and ASCT to a better OS and PFS; increased LDH correlated with shorter OS alone and kidney/adrenal gland involvement with shorter PFS alone.

In multivariate analysis tLBCL, ECOG≥2 and IPI≥3 maintained their negative prognostic impact and ASCT and SHL their favorable prognostic impact on OS and PFS.

Conclusions: In this retrospective analysis dLBCL and tLBCL with MYC alterations showed similar clinical characteristics other than higher bone marrow involvement in tLBCL. However, in this last group PFS and OS were significantly worse except in pts with transformation concomitant with the FL diagnosis. The prognosis was particularly poor in DHL/THL group where an early use of new therapeutic approaches (i.e. CAR-T or bispecific antibodies) should be evaluated in prospective studies.