Clinical significance of co-expression of MYC and BCL2 protein in aggressive B-cell lymphomas treated with a second line immunochemotherapy

Abstract

The clinical significance of concurrent expression of MYC and BCL2 protein, known as "double-expressor lymphoma" (DEL), among patients with relapsed or refractory aggressive B-cell lymphomas, remains unclear. A retrospective analysis was performed of 38 patients treated with a salvage treatment consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone followed by consolidative high-dose chemotherapies. A total of 17 cases (45%) were categorized as DEL using immunohistochemical assay with a cut-off value of positivity of 40% for MYC and 50% for BCL2, respectively. DEL was associated with a lower overall response rate (35% vs 71%, p = 0.0481), worse 2-year progression-free survival (9% vs 67%, p = 0.001) and overall survival (35% vs 71%, p = 0.037). This analysis suggests that DEL is common among patients with relapsed/refractory aggressive B-cell lymphomas and that such patients require novel treatment strategies.

Diffuse large B‐cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment

“…Patients with DLBCL and overexpression of the c‐MYC oncogene and BCL2 (≥40% and >50% by IHC, respectively) have double expressor lymphoma (DEL), which is associated with an intermediate prognosis to up‐front R‐CHOP. DELs account for approximately one‐third of de novo disease and up to 50% of relapsed/refractory (RR) DLBCL . Patients with genetic rearrangements in c‐MYC in addition to BCL2 and/or BCL6 have high‐grade B‐cell lymphoma with MYC and BCL2 and/or BCL6 according to the WHO 2016 classification of hematologic malignancies, and are also called double‐hit or triple‐hit lymphomas (DH/THLs).…”

MYC protein expression scoring and its impact on the prognosis of aggressive B-cell lymphoma patients

“…In fact, it allows recognition of a poor-response subset of patients who may benefit from alternate Therefore, evaluation of MYC and BCL-2 protein expression by IHC is an important tool in prognostic stratification of patients 2 . Although expression of MYC-IHC in >40% neoplastic cells and the BCL-2 in >50% have been indicated as prognostically significant cut-offs in many reports, the degree of agreement among haematopathologists for these thresholds has only moderate concordance 3,4 .…”

“…Although expression of MYC-IHC in >40% neoplastic cells and the BCL-2 in >50% have been indicated as prognostically significant cut-offs in many reports, the degree of agreement among haematopathologists for these thresholds has only moderate concordance 3,4 . Standardizing cut-offs to define positivity for MYC-IHC and BCL-2-IHC with higher reproducibility and prognostic impact is thus highly desirable for optimizing patients' management 5,6 .…”

“…However, it has been recently reported that the adverse prognosis may be mitigated by other factors such as that lack of BCL-2 protein, and absence/low MYC protein expression 5 . The clinical significance of MYC-IHC and BCL-2-IHC expression has been extensively studied but the results have not been consistent; hence, a clinical utility of protein expression evaluation is still unclear [13][14] .…”

Increased glutaminolytic flux and activation of mitochondrial metabolism by BCL2 hyperactivity in lymphoma

“…Further, multi-omics integration reveals that BCL2 activation is often observed at multiple different levels including copy number, gene expression, and/or protein expression ( Figure 1C). Elevated BCL2 activity has a negative effect on overall decreased patient survival ( Figure 1C-D) [38][39][40][41][42] .…”