MYC‐associated and double‐hit lymphomas: A review of pathobiology, prognosis, and therapeutic approaches

Abstract

Aberrant expression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) proto-oncogene has known transformative potential in healthy human cells. Chromosomal MYC rearrangements and consequent MYC overexpression is the defining lesion in Burkitt lymphoma (BL), conferring a highly proliferative state. However, abnormalities of MYC are increasingly appreciated in non-BL histologies, including diffuse large B-cell lymphoma (DLBCL) and B-cell lymphomas intermediate between BL and DLBCL, with a particularly aggressive clinical phenotype. Although there are conflicting data regarding prognostic implications of isolated MYC aberrancy in these non-BLs, the co-occurrence of MYC rearrangements and either the antiapoptotic gene B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) or the transcriptional repressor BCL6 leads to an entity termed double-hit B-cell lymphoma (DHL) (or triple-hit if all 3 abnormalities are observed) with a particularly poor prognosis and no established treatment paradigms. Notably, a distinct pattern of gene expression profiling has been noted when MYC is overexpressed in BL compared with other lymphomas, supporting the notion that, although MYC promotes target gene transcription, the target genes vary by disease subtype. The frequency of MYC activity depends on the method of detection and ranges from 5% to 10% using fluorescence in situ hybridization but up to 30% of DLBCL using immunohistochemistry. Standard therapies developed for DLBCL are less effective when the disease is driven by MYC, leading to lower response rates and response durations. An important clinical challenge is to pre-emptively identify MYCassociated lymphomas and to subsequently develop trials specifically for this group of patients. However, the design of such studies is complicated by variable definitions of MYC-associated lymphoid malignancies and the lack of effective therapies to date. The objective if the current review was to evaluate the implications of MYC aberrancy with respect to the B-cell lymphoma double-hit and triple-hit phenotypes and to consider the available data for clinical and practical management. Cancer 2014;120:3884-95.

Validation of clinical prognostic indices for diffuse large B-cell lymphoma in the National Cancer Data Base

“…Recently, attention has been focused on the subset of DLBCL overexpressing the MYC gene in conjunction with BCL2 and/or BCL6 (referred to as doublehit or triple-hit lymphomas) [32]. This highly aggressive entity may have a particularly poor prognosis despite standard therapy [33,34]. Many other immunophenotypical, genetic, and laboratory biomarkers are actively investigated for further risk stratification, as recently reviewed elsewhere [35,36].…”

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis

“…5 DHL, as defined by cytogenetic criteria (karyotype or fluorescence in situ hybridization [FISH]), constitutes anywhere from 3% to 32% of cases of DLBCL in individual case series, 7,8 but its true frequency is likely 5% to 10% based on collective data. 9 Multiple retrospective series suggest that patients with DHL, as defined by FISH, face very poor prognoses when treated with R-CHOP, with a median overall survival (OS) of 12 months or less. [10][11][12][13][14] These studies furthermore suggest that, compared with patients with non-DHL DLBCL, DHL patients more frequently present with extranodal involvement, elevated lactate dehydrogenase (LDH) levels, central nervous system (CNS) involvement, and higher international prognostic index (IPI) scores.…”

De Novo Precursor B-Lymphoblastic Leukemia/Lymphoma With Double-Hit Gene Rearrangements (MYC/BCL-2) Presented With Spinal Cord Compression and Acquired Factor XIII Deficiency

“…MYC/BCL2 DHL is a rare entity; the incidence of genetic DHL varies among different studies, ranging from 3% to 13% of diffuse large B-cell lymphoma (DLBCL) [2]. These neoplasms usually have a mature germinal center B-cell immunophenotype, a complex karyotype and an extremely aggressive clinical course with poor response to Manuscript submitted June 7, 2017, accepted June 29, 2017 Soliman et al J Hematol.…”