Myc rearrangement and concurrent high protein expression of C-Myc/Bcl2 carry an adverse prognosis in diffuse large B-cell lymphoma.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin lymphoma, characterized by a variety of clinicopathological, histomorphological, immunophenotypic, and molecular genetic features. The subtype of DLBCL known as double-expressor lymphoma (DEL) is associated with an adverse prognosis when treated with R-CHOP. Our study aimed to investigate the clinicopathologic features of DEL and the prognostic roles of Myc rearrangement and C-Myc expression in DEL patients. PATIENTS AND METHODS: We conducted a retrospective study of 145 patients who were identified through fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) testing. RESULTS: We found that DEL patients were more likely to have a non-germinal center B-cell (GCB) subtype, stage III/IV disease, and a high International Prognostic Index (IPI) score. Our survival analysis indicated that Myc rearrangement and C-Myc expression were associated with poor prognosis. Although DEL patients with Myc rearrangement exhibited trends towards worse survival compared with patients without Myc rearrangement, the differences were not statistically significant (P = 0.4008). The median overall survival (OS) of DEL patients with ≥70 % C-Myc expression (DEL-C-Mychigh) was 5 months. In the DEL-C-Mychigh group, the non-GCB subtype showed nonsignificant trends towards poorer survival compared with the GCB subtype (P = 0.1042). CONCLUSION: In conclusion, our study shows that a cut-off of ≥70 % for C-Myc expression in DEL patients can improve risk stratification, and suggests that more intensive treatment regimens may be necessary to improve survival in this high-risk population.

Impact of initial chemotherapy regimen on outcomes for patients with double-expressor lymphoma: A multi-center analysis.

Diffuse large B-cell lymphoma featuring overexpression of MYC and B-Cell Lymphoma 2 (double expressor lymphoma, DEL) is associated with poor outcomes. Existing evidence suggesting improved outcomes for DEL with the use of more intensive regimens than R-CHOP is restricted to younger patients and based on limited evidence from low patient numbers. We retrospectively evaluated the impact of intensive frontline regimens versus R-CHOP in a multicenter analysis across 7 academic medical centers in the United States. We collected 90 cases of DEL, 46 out of 90 patients (51%) received R-CHOP and 44/90 (49%) received an intensive regimen, which was predominantly DA-EPOCH-R. Treatment cohorts were evenly balanced for demographics and disease characteristics, though the intensive group had a higher lactate dehydrogenase (LDH, 326 vs. 230 U/L p = 0.06) and presence of B-symptoms (50% vs. 22%, p = 0.01) compared to the R-CHOP cohort. There was no difference in PFS (median 53 vs. 38 months, p = 0.49) or overall survival (67 vs. not reached months, p = 0.14) between the R-CHOP and intensive therapy cohorts, respectively. On multivariate analysis, intensive therapy was associated with a hazard ratio of 2.35 (95% CI 0.74-7.41), though this was not statistically significant. Additionally, a subgroup analysis of intermediate high-risk lymphoma defined by IPI ≥3 did not identify a difference in survival outcomes between regimens. We conclude that in our multi-center cohort there is no evidence supporting the use of intensive regimens over R-CHOP, suggesting that R-CHOP remains the standard of care for treating DEL.

Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma.

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.

Upfront autologous hematopoietic stem cell transplantation for high-risk patients with double-expressor diffuse large B cell lymphoma.

Although MYC and BCL2 co-expression in diffuse large B cell lymphoma (DLBCL) is associated with inferior prognosis, it remains uncertain whether upfront autologous hematopoietic stem cell transplantation (ASCT) is beneficial in this lymphoma. This study aimed to investigate whether ASCT consolidation could have a positive role for patients with MYC and BCL2 co-expression (double-expressor lymphoma, DEL). We retrospectively evaluated 67 DLBCL patients who underwent upfront ASCT following rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. The 5-year overall survival (OS) and progression-free survival (PFS) were 82.3% and 79.2%, respectively. There were 23 (34.3%) patients with DEL and 51 (76.1%) patients with non-germinal center B cell (GCB) subtype. The 5-year OS and PFS of patients with DEL were not different from those with non-DEL (P = 0.429 and P = 0.614, respectively). No survival difference for OS and PFS was also observed between GCB and non-GCB subtypes (P = 0.950 and P = 0.901, respectively). The OS and PFS were comparable for patients with DEL and non-DEL and both GCB and non-GCB subtypes. In conclusion, MYC and BCL2 co-expression did not have a poor prognostic impact among high-risk patients with DLBCL treated with upfront ASCT regardless of molecular classification. This preliminary study suggested that the role of consolidative ASCT is needed to be evaluated in a prospective randomized clinical trial.

Phase 1 study of lenalidomide plus dose-adjusted EPOCH-R in patients with aggressive B-cell lymphomas with deregulated MYC and BCL2.

BACKGROUND: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL. METHODS: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. RESULTS: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months. CONCLUSIONS: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.

[MYC-associated B-cell lymphomas: pathophysiology and treatment].

The outcome of double-hit lymphoma (DHL) defined by concurrent rearrangements of MYC and BCL2 and/or BCL6 is extremely poor than that of diffuse large B-cell lymphoma (DLBCL). Patients with DHL are usually resistant to R-CHOP therapy and show a highly aggressive clinical course frequently involving the extranodal sites, such as the bone marrow, peripheral blood, pleural effusion, and central nervous system (CNS). However, several retrospective studies conducted recently have demonstrated a relatively favorable outcome with intensive chemotherapy, such as dose-adjusted EPOCH-R, than those receiving R-CHOP in patients with DHL. "Double expressor status" with concomitant expression of MYC and BCL2 protein by immunohistochemistry in DLBCL is considered a poor prognostic biomarker and has been associated with high risk of CNS relapse. Therefore, to reduce these risks, CNS-directed evaluation and consideration of CNS-prophylactic strategies should be performed in patients with double expressor lymphoma. This chapter reviews the clinical and pathological features, prognosis, treatment strategies, and new insights in MYC-associated B-cell lymphoma, such as Burkitt lymphoma.

Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma.

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.

Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.

Chidamide represses MYC expression and might improve survival for patients with double expressor lymphoma.

Double expressor lymphoma (DEL), characterized by high expressions of both MYC and BCL-2, displays poor prognosis after current therapies. The HDAC inhibitor chidamide has been approved for treatment of T cell lymphoma, but its efficacy on B cell lymphoma is unclear. Here, by combining inhibition screening and transcriptomic analyses, we found that the sensitivity of B lymphoma cells to chidamide was positively correlated with the expression levels of MYC. Chidamide treatment reduced MYC protein levels and repressed MYC pathway in B lymphoma cells with high MYC expressions. Ectopic expression of MYC in chidamide-insensitive B lymphoma cells increased their response to chidamide. Thus, we proposed that adding chidamide into R-CHOP (CR-CHOP) might be effective for DEL, and retrospectively analyzed 185 DEL patients treated in West China Hospital. 80% of patients showed response to CR-CHOP treatment. In the median follow-up of 42 months, CR-CHOP significantly improve the survival for DEL patients with R-IPI ≤2. Totally 35 patients underwent autologous stem cell transplantation (ASCT) in remission and demonstrated a trend for better survival. Combining CR-CHOP with ASCT resulted in the most superior PFS and OS above all. For response patients, CR-CHOP reduced relapse with better PFS than R-CHOP-like regimens with or without ASCT. Taken together, our data indicated that chidamide repressed the MYC pathway in B lymphoma and is potentially efficacious to treat DEL.

Clinicopathological differences in MYC and BCL2 protein expression between primary extranodal and nodal diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) exhibits clinical, genetic, and immunohistochemical heterogeneity. However, the differences between primary extranodal or nodal DLBCL and double-expressor lymphoma (DEL), which is characterized by high MYC and BCL2 expression, remain unclear. This study aimed to elucidate the clinicopathological features, response to therapy, and clinical outcomes of primary extranodal (n=61) and nodal (n=128) DLBCL. Patients with primary nodal DLBCL had higher BCL2 expression than those with extranodal DLBCL (p=0.048), with high MYC expression and DEL as poor prognostic factors. Conversely, in patients with primary extranodal DLBCL, high BCL2 expression, low BCL6 expression, non-germinal center B-cell-like type, and DEL indicated poor prognosis. DEL was significantly associated with progression free survival and overall survival in patients with primary extranodal DLBCL (p=0.014 and p=0.021, respectively) but not in patients with primary nodal DLBCL (p=0.37 and p=0.084, respectively). Our findings highlight primary extranodal DEL as a strong adverse prognostic factor in DLBCL.

Do Double-Expressor High-Grade B-Cell Lymphomas Really Need Intensified Treatment? A Report from the Real-Life Series of High-Grade B-Cell Lymphomas Treated with Different Therapeutic Protocols at the Institute of Oncology Ljubljana.

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are known for their aggressive clinical course and so are the ones with MYC and BCL2 protein overexpression. The optimal therapy for these lymphomas remains to be elucidated. A retrospective analysis of all diffuse large B-cell lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements diagnosed between 2017 and 2021 at the Institute of Oncology Ljubljana, Slovenia, has been performed. Only patients with double-expressor lymphoma (DEL), double-hit lymphoma (DHL), or triple-hit lymphoma (THL) were included. Demographic and clinical parameters were assessed, as well as progression-free survival (PFS) and overall survival (OS). In total, 161 cases out of 309 (161/309; 52,1%) were classified as DEL. Sixteen patients had DHL, MYC/BCL2 rearrangement was observed in eleven patients, and MYC/BCL6 rearrangement was observed in five patients. Five patients were diagnosed with THL. Out of 154 patients (according to inclusion/exclusion criteria) included in further evaluation, one-hundred and thirty-five patients had double-expressor lymphoma (DEL), sixteen patients had DHL, and three patients had THL. In total, 169 patients were treated with R-CHOP, 10 with R-CHOP and intermediate-dose methotrexate, 19 with R-DA-EPOCH, and 16 with other regimens. The median follow-up was 22 months. The 5-year OS for the whole DEL group was 57.1% (95% CI 45.9-68.3%) and the 5-year PFS was 76.5% (95% CI 72.6-80.4%). The log-rank test disclosed no differences in survival between treatment groups (p = 0.712) while the high-risk international prognostic index (IPI) carried a significantly higher risk of death (HR 7.68, 95% CI 2.32-25.49, p = 0.001). The 5-year OS for DHL patients was 32.4% (95% CI 16.6-48.2%) while all three TH patients were deceased or lost to follow-up. Our analyses of real-life data disclose that the R-CHOP protocol with CNS prophylaxis is a successful and curative treatment for a substantial proportion of DEL patients.

Targeting MYC-driven lymphoma: lessons learned and future directions.

MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.

Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma.

Predicting MYC and BCL2 double-expressor lymphoma prognosis using the system immune-inflammatory index (SII) and prognostic nutritional index (PNI) (DEL). From January 2015 to December 2021, 281 diffuse large B-cell lymphoma (DLBCL) wax blocks were used to make tissue chips. Screening double expressor lymphoma (DEL) instances involved immunocytochemistry and fluorescence in situ hybridization. Academic analysis used clinicopathological characteristics and follow-up data. SII, PNI, and DEL prognosis were correlated using univariate and multivariate cox regression analysis. The median age of 78 DEL patients is 60 (range: 43-74). SII and PNI cut-off values of 603.5, 3.07, and 144 predict PFS and OS well. Lower SII is associated with longer PFS (HR for SII = 0.34, 95% CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95% CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95% CI 0.17-0.94, P = 0.025; LMR = 0.39, 95%, CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95% CI 0.05-0.51, P = 0.005; HR for PNI = 0.20, 95% CI 0.06-0.62, P = 0.002). SII and PNI are promising predictors for twofold expressor DLBCL. Combining these increase prediction accuracy.

Clinicopathologic and genetic features of the starry-sky pattern in double-expressor diffuse large B-cell lymphoma.

Double expressor lymphoma (DEL) is a subset of diffuse large B-cell lymphoma (DLBCL) characterized by the co-expression of MYC and BCL2 proteins with a poor prognosis. However, there are no standard criteria for evaluating the morphologic features of DEL. We aimed to analyze the prognostic value of the starry-sky pattern (SSP) and its correlation with clinicopathologic and genetic features in 153 DEL cases. The SSP was significantly associated with aggressive parameters, including c-MYC overexpression, CD5 expression, higher IPI, and age-adjusted IPI. In the univariate survival analyses, the presence of SSP was associated with unfavorable progression-free survival (PFS) (p = 0.040), and tended towards an adverse overall survival (OS) (p = 0.061). However, when c-MYC was overexpressed, SSP was significantly correlated with inferior OS (p = 0.019). In the multivariate survival analysis, SSP was also associated with poor PFS (p = 0.048). Additionally, next-generation sequencing data revealed SSP was significantly associated with the KMT2D mutation and had different genetic mutation profiles from non-SSP. In conclusion, SSP may represent morphologic characteristics of aggressiveness in DEL.

[Effects of BET Bromodomain Inhibitor JQ1 on Double-Expressor Lymphoma Cell Lines and Its Mechanism].

OBJECTIVE: To investigate the effects and mechanism of bromodomain and extra-terminal (BET) inhibitor JQ1 on the double-expressor lymphoma (DEL) cell lines. METHODS: Protein expressions of cMyc and BCL-2 in 3 lymphoma cell lines were checked by Western blot so as to identify DEL cell lines. CCK-8 assay was used to detect the effects of JQ1 on anti-proliferation in the DEL cell lines. Western blot and RT-PCR were used to measure the protein and mRNA expressions of cMyc, BCL-2 and BCL-6 in DEL cell lines which treated by JQ1. Flow cytometry was used to detect the effect of JQ1 on cell apoptosis. RESULTS: Based on the expressions of cMyc and BCL-2, the SU-DHL6 and OCILY3 cell lines were confirmed as DEL cell lines. CCK-8 assay showed that the proliferation of DEL cell lines was inhibited by JQ1, which was similar to non-DEL cell lines and mainly regulated the expression of cMyc and BCL-6 but not BCL-2. JQ1 had no effects on apoptosis in the DEL cell lines. CONCLUSION: BET inhibitor JQ1 has anti-tumor effect in the DEL cell lines, thus providing evidence for the therapeutic potential of BET inhibitor JQ1.

R-CHOP Vs DA-EPOCH-R for Double-Expressor Lymphoma: A University of California Hematologic Malignancies Consortium Retrospective Analysis.

BACKGROUND: Managing double-expressor lymphomas (DEL) is controversial given the dearth of data and lack of standardized guidelines on this high-risk subset of lymphomas. No prospective and few retrospective studies limited by either their sample size or short follow-up address the question of initial treatment of choice for DEL. We performed the largest analysis to date exploring R-CHOP vs DA-EPOCH-R in DEL. METHODS: Adults with DEL diagnosed from 6/2012-2/2021 at 4 unique sites were retrospectively analyzed. Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints include overall survival (OS), overall and complete response rates (ORR and CRR), cumulative incidence of relapse, and autologous hematopoietic cell transplantation (autoHCT) utilization. RESULTS: 155 patients were included, 61 treated with R-CHOP and 94 with DA-EPOCH-R. 3-year PFS and OS were similar between R-CHOP and DA-EPOCH-R, 33.2% vs 57.2%,(P = .063), and 72.2% vs 71.6% (P = .43) after median follow-up times of 2.43 and 2.89 years, respectively. Patients <65 had improved PFS with DA-EPOCH-R, hazard ratio 0.41 (P = .01). CRR and ORR rates were also similar. Relapse rates were not statistically different, 51.9% vs 28.6% (P = .069). AutoHCT utilization was higher with R-CHOP vs DA-EPOCH-R, 23.0% vs 8.5% (P = .017). CONCLUSIONS: Our findings do not support the use of DA-EPOCH-R over R-CHOP for DEL. Patients <65 years may experience longer PFS with DA-EPOCH-R, but limitations to the analysis make this interpretation difficult.

Fitting double-hit lymphoma into the aggressive lymphoma spectrum: a square peg in a round hole?

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or both, commonly called double-hit lymphoma (DHL), is an aggressive B-cell lymphoma that is molecularly distinct from diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes. Recent advances in the molecular classification of DLBCL have identified distinct subsets, including genetic signatures which correlate with DHL and survival. DHL with concomitant TP53 mutation appears to be associated with a very poor prognosis. Standard chemo-immunotherapy is not an effective treatment for these patients and personalized, innovative strategies are needed. In this review, we summarize recent advances in the subclassification of DLBCL, with a focus on DHL. We also incorporate early, promising clinical trial data using CAR T and targeted therapies. Rationally designed clinical trials for DLBCL are needed to advance the care of patients with DHL and other adverse risk DLBCL subgroups.

Clinicopathological risk factors for a poor prognosis of primary central nervous system lymphoma in elderly patients in the Tohoku and Niigata area: a multicenter, retrospective, cohort study of the Tohoku Brain Tumor Study Group.

Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan-Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months; there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (p = 0.022, hazard ratio (HR) = 2.591) was the clinical risk factor, and double expressor lymphoma (p = 0.004, HR = 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (p < 0.001, HR = 5.455), and Epstein-Barr virus infection (p = 0.031, HR = 5.304) were the pathological risk factors.