MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy

Abstract

Approximately 5% to 10% of diffuse large B-cell lymphomas (DLBCLs) harbor an MYC oncogene rearrangement (MYC ؉ ). The prognostic significance of MYC ؉ DLBCL was determined in an unselected population of patients with newly diagnosed DLBCL treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP). Using a Vysis break-apart fluorescence in situ hybridization probe, 12 of 135 (8.8%) cases of MYC ؉ DLBCL were identified that had no defining high-risk features. MYC ؉ DLBCL was associated with an inferior 5-year progression-free survival (66% vs 31%, P ‫؍‬ .006) and overall survival (72% vs 33%, P ‫؍‬ .016). Multivariate analysis confirmed the prognostic importance of MYC for both progression-free survival (hazard ratio ‫؍‬ 3.28; 95% confidence interval, 1.49-7.21, P ‫؍‬ .003) and overall survival (hazard ratio ‫؍‬ 2.98; 95% confidence interval, 1.28-6.95, P ‫؍‬ .011). Cases of MYC ؉ DLBCL also had a higher risk of central nervous system relapse (P ‫؍‬ . IntroductionDiffuse large B-cell lymphomas (DLBCLs) are recognized to be a heterogeneous group of diseases with clinical, morphologic, immunohistochemical, and molecular subtypes defined in the updated World Health Organization (WHO) classification. 1 Further, a new category has been created defined as "borderline cases," which are considered B-cell lymphomas, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. 2 Morphologically, these tumors typically have a mixture of medium-to large-sized cells, a high proliferation rate, and 35% to 50% of cases have an 8q24/MYC translocation. 2 However, approximately 5% to 10% of DLBCLs with typical morphology also harbor an MYC rearrangement (herein after referred to as MYC ϩ ), and these cases are considered in the category of DLBCL, not otherwise specified, in the updated WHO classification. 3 There is very little information regarding the prognostic importance of an isolated MYC rearrangement in DLBCL using modern diagnostic criteria. A recent study suggested that MYC gene rearrangements identified by fluorescence in situ hybridization (FISH) in pathologically defined DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy are associated with an inferior prognosis. 4 However, it is unclear whether there are identifiable clinical or pathologic characteristics that suggest that a case may harbor an MYC rearrangement to prompt evaluation. Further, prior studies evaluating the prognostic implications of MYC in DLBCL have been performed before the use of rituximab. With studies showing improved outcome using rituximab in combination with CHOP (R-CHOP) or CHOP-like therapies in the treatment of DLBCL, 5-8 the importance of MYC rearrangement status in this population must be reestablished.The purpose of this study was 2-fold: (1) to screen an unselected series of patients with DLBCL for MYC rearrangements to determine the frequency of this occurrence and whether there were any pathologic or ...

Simple karyotype and bcl-6 expression predict a diagnosis of Burkitt lymphoma and better survival in IG-MYC rearranged high-grade B-cell lymphomas

“…These results are in keeping with the previously reported poor overall survival of patients with MYC-rearranged diffuse large B-cell lymphoma, 14,25 and unclassifiable cases. The latter likely represent atypical Burkitt lymphoma classified by 2001 WHO classification system, and 'double-hit' lymphomas.…”

“…[25][26][27] In this study, all IG-MYC rearranged diffuse large B-cell lymphomas had complex karyotypes, as has been previously reported. 14 Three plasmablastic lymphomas in this cohort carried IG-MYC rearrangement with a variable karyotypic complexity; such rearrangement was found in about one-third of such lymphoma in our recent study.…”

“…4,6,24 It is interesting to note that all three cases of MYC-rearranged diffuse large B-cell lymphoma in this study were treated with R-CHOP (rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, prednisone), which may not be as effective in these patients compared with those without MYC-rearrangement. 13,25 In multivariate analysis, only bcl-6 expression remained an independent predictor of better overall survival. Nonetheless, within the subgroup of bcl-6 positive patients, survival could be further stratified by karyotypic complexity, as patients with positive bcl-6 and simple karyotype had the best clinical outcomes.…”

“…Nonetheless, within the subgroup of bcl-6 positive patients, survival could be further stratified by karyotypic complexity, as patients with positive bcl-6 and simple karyotype had the best clinical outcomes. Although unclassifiable and MYC-rearranged diffuse large B-cell lymphomas may benefit from intensified chemotherapeutic regimens used for BL, 6,25,29 future prospective studies in a large number of patients are needed to investigate the optimal therapy for these aggressive lymphomas.…”

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

“…The presence of MYC rearrangements in patients with diffuse large B-cell lymphoma treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) has been shown to be associated with poor prognosis. 3,4 In particular, the so-called 'double-hit' lymphomas that are characterized by MYC rearrangement and a concurrent rearrangement of other B-cell lymphomaassociated genes such as BCL2 or BCL6 are associated with poor response to therapy, aggressive clinical course and dismal prognosis. [5][6][7] These lymphomas are classified as 'B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma' in the current 2008 WHO classification of hematopoietic neoplasms.…”