MYC/BCL2 Double Hit Lymphoma: What Really Matters
Authors: Saksena Annapurna , Desai Parth , Zuo Zhuang , Xu Jie , Lin Pei , Seegmiller Adam C. , Yin C. Cameron , Tang Guilin , Miranda Roberto N. , Jorgensen Jeffrey L. , Reddy Nishitha M , Medeiros L. Jeffrey , Li Shaoying 
Published: October 2019

Abstract
Introduction: MYC/BCL2 double hit lymphoma (DHL), defined as a large B-cell lymphoma with concurrent MYC and BCL2 translocations, is the most common type of DHL. Although multiple studies focused on DHL have been published, several issues regarding impact on prognosis remain controversial including: 1) history of low grade B cell lymphoma; 2) morphology (diffuse large B-cell lymphoma [DLBCL] versus B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma [BCLU)]; 3) Absence or low expression of MYC or BCL2; 4) MYC translocation partner gene; and especially 5) most effective therapy. The aim of this study was to attempt clarify the prognostic importance of these factors in DHL.
Methods: 157 patientsdiagnosed with MYC/BCL2 DHL between 2003 and April 2015 at two institutions were included in this study. MYC and BCL2 gene rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual color dual fusion probes. BCL6/3q27gene status was tested either by FISH using breakapart probe or by karyotype. MYC partner gene was identified by karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2 but not BCL6. Positive for MYC or BCL2 by immunohistochemistry was defined by >40% and >50% of lymphoma cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the clinicopathologic features. Statistical analysis was performed using SPSS 23 software.
Results: There were 103 men and 54 women with a median age of 61 years (range, 18-87). 110 patients had de novo disease and 47 patients had a history of low-grade B-cell NHL, mostly follicular lymphoma. The clinicopathologic features were similar (P>0.05) between patients with a history of low-grade B-cell NHL and patients with de novo NHL, and therefore analysis was performed on all 157 DHL cases. Using the 2008 WHO classification, there were 91 DLBCL, 61 BCLU, and 5 composite lymphoma (4 DLBCL + follicular lymphoma and 1 DLBCL + B-lymphoblastic lymphoma). 99% of cases had a germinal center B-cell immunophenotype by the Hans algorithm. MYC expression was observed in 39/47 (83%) and BCL2 in 129/141(91%) of cases. MYC and BCL2 dual expression was present in 34/46(74%) cases. Of the 39 cases assessed, the MYC translocation partner was IGH in 13, IG light chain in 19, and a non-IG gene in 7 cases. 144 patients had complete treatment information: 61 received the R-CHOP regimen initially, 31 R-EPOCH, 29 R-HCVAD, and 23 various other chemotherapy regimens. 39 patients also received stem cell transplant (SCT) including 31 autologous and 8 allogeneic. 62 patients reached complete remission (CR) after initial chemotherapy. The median overall survival was 19 months. In a univariate analysis that evaluated 17 clinicopathologic parameters including those mentioned in introduction, extranodal sites of disease, bone marrow involvement, CNS involvement, advanced stage, and high/high-intermediate International Prognostic Index score were associated with a worse overall survival (OS, P<0.05), whereas CR and SCT were associated with a better OS (P<0.05). By multivariate analysis, stage, IPI, SCT, and CR predicted OS (Table 1 and Figure 1).
Conclusion: MYC/BCL2 DHL are clinically aggressive B cell lymphomas with a germinal center phenotype and patients have a poor prognosis. In this study, a history of low grade B cell lymphoma, morphology (DLBCL vs BCLU), MYC expression, BCL2 expression, MYC/BCL2 dual expression (double expresser lymphoma), MYC translocation partner gene, and initial chemotherapy regimens were not associated with overall survival. The independent prognostic factors shown by multivariate analysis were IPI score, stage, achievement of CR, and a therapeutic regimen including SCT.
Table 1. Multivariate analysis Features HR 95% CI P BM involvement 0.92 0.48 - 1.80 0.817 Extranodal sites ≥ 2 1.12 0.48 - 2.65 0.793 Stage III /IV vs I/II 34.45 4.92 - 241.31 <0.001 IPI (H/H-I vs L/L-I) 3.00 1.14 - 7.77 0.026 Initial Chemotherapy R-EPOCH vs R-CHOP 1.17 0.49 - 2.84 0.723 R-HCVAD vs R-CHOP 0.95 0.47 - 1.93 0.894 Stem cell transplant 0.22 0.10 - 0.46 <0.001 CR after initial chemotherapy 0.14 0.07 - 0.30 <0.001
Figure 1. Figure 1.

Disclosures
Reddy: ImmunoGen: Consultancy; PCYC: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.