Tumoural Pellino-1 expression and Pellino-1-expressive cytotoxic T-cells are associated with poor prognosis in diffuse large B-cell lymphoma.

Pellino-1 plays a role in regulating inflammation and immune responses, and its effects on tumours are complex, with different outcomes reported in various studies. Additionally, the role of Pellino-1 in diffuse large B-cell lymphoma (DLBCL) has not been thoroughly investigated. We aimed to examine the expression of Pellino-1 in tumour cells and tumour-infiltrating lymphocytes (TILs) separately and identify the clinicopathological significance of Pellino-1 expression in DLBCL. We evaluated Pellino-1 expression in 104 patients with DLBCL. The density of specific cell types was quantitatively analysed using digital image analysis after a multiplex immunofluorescence staining with Pellino-1, CD20, CD8, FOXP3, and PD-1. Pellino-1 expression was mostly observed in CD20+ tumour cells and CD8+ TILs. The high CD8+/Pellino-1+ group was significantly associated with the non-GCB subtype and higher numbers of Foxp3+ T-cells. Patients with high CD20+/Pellino-1+ and high CD8+/Pellino-1+ cell densities had significantly shorter event-free survival (EFS) rates. The multivariate Cox-regression analysis showed that CD20+/Pellino-1+ cell density and CD8+/Pellino-1+ cell density were independent poor prognostic factors for EFS. Furthermore, patients with low densities of both CD20+/Pellino-1+ and CD8+/Pellino-1+ cells demonstrated a prognosis superior to that of patients with high Pellino-1+ cell densities, either alone or in combination. Additionally, the multivariate analysis demonstrated that the combination of CD20+/Pellino-1+ and CD8+/Pellino-1+ cell densities was an independent prognostic factor for EFS and overall survival. Pellino-1 expression was observed in both tumour cells and TILs, particularly in cytotoxic T-cells, and was correlated with poor outcomes in DLBCL. Thus, Pellino-1 might have an oncogenic effect on DLBCL and might be a potential target for improving cytotoxic T-cell activity.

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.

A New Prognostic Index for Extranodal Natural Killer/T-Cell Lymphoma:Incorporation of Serum ß-2 Microglobulin to PINK.

PURPOSE: Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline-based therapy. We aimed to evaluate the prognostic implications of serum ß-2 microglobulin (ß2M) in the context of PINK and proposed a new prognostic model. MATERIALS AND METHODS: A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum ß2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum ß2M into PINK was proposed and validated in an independent validation cohort (n=88). RESULTS: The patients' median age was 53.5 years (range, 19 to 80 years). Patients with high serum ß2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum ß2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum ß-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort. CONCLUSION: Serum ß2M is an independent prognostic factor for ENKTL patients. The new serum ß2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.

Extra copy number of BCL2 is correlated with increased BCL-2 protein expression and poor survival in diffuse large B-cell lymphoma treated with chemoimmunotherapy.

The clinical significance of extra copy (EC) genotypes of BCL2, MYC, and BCL6 have not been fully elucidated. We evaluated the EC and translocation statuses of BCL2, MYC, and BCL6 in 190 diffuse large B-cell lymphoma (DLBCL) cases using fluorescence in situ hybridization. EC genotype was sub-classified according to copy number-gained tumor cell ratio (EC1, >20% but ≤50%; EC2, >50%). Only the BCL2-EC groups, not MYC-EC or BCL6-EC groups, displayed significantly increased immunoreactivity of the corresponding protein. Moreover, the BCL2-EC2 group was significantly associated with poor overall survival (OS) and progression-free survival (PFS) in a 147 R-CHOP-treated patient subset, which was also statistically significant as per the multivariate survival analysis for PFS. No significant differences in the survival of MYC, BCL6, concurrent BCL2/MYC, BCL6/MYC, BCL2/BCL6, or triple EC groups were observed. BCL2-EC may contribute to increased BCL-2 protein expression and serve as a predictor of treatment outcomes in DLBCL.

Modified Stage Grouping of Diffuse Large B-Cell Lymphoma Involving the Same Side of the Diaphragm in the Rituximab Era.

Among patients with diffuse large B-cell lymphoma (DLBCL) involving the same side of the diaphragm, the prognostic implications of extranodal disease or its contiguity with the nodal lesion remain unclear. In this study, patients with DLBCL treated with R-CHOP whose disease was limited to the same side of the diaphragm were included. Survival was assessed by the presence, contiguity, and number of extranodal lesions. Among the 508 patients included, overall survival (OS) and progression-free survival (PFS) did not differ according to the presence of single extranodal involvement or its anatomical contiguity with the nodal lesion. However, patients with ≥2 extranodal involvement showed significantly inferior OS and PFS. We re-classified these patients into two groups: modified stage IIEe (≥2 extranodal involvement, n=92) and modified stage II (nodal or single extranodal involvement irrespective of anatomical contiguity, n=416). This modified staging showed improved prognostic performance based on the time-dependent ROC curve compared with Ann Arbor staging. In conclusion, the survival outcomes of patients with DLBCL on the same side of the diaphragm were associated with the number of extranodal lesions, but not with the contiguity of the lesions or presence of a single extranodal involvement. Based on these results, we propose a modified staging system (modified stage IIEe and II) for these patients.

Determining clinical course of diffuse large B-cell lymphoma using targeted transcriptome and machine learning algorithms.

Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology; however, these biological subgroups overlap clinically. Using machine learning, we developed an approach to stratify patients with DLBCL into four subgroups based on survival characteristics. This approach uses data from the targeted transcriptome to predict these survival subgroups. Using the expression levels of 180 genes, our model reliably predicted the four survival subgroups and was validated using independent groups of patients. Multivariate analysis showed that this patient stratification strategy encompasses various biological characteristics of DLBCL, and only TP53 mutations remained an independent prognostic biomarker. This novel approach for stratifying patients with DLBCL, based on the clinical outcome of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, can be used to identify patients who may not respond well to these types of therapy, but would otherwise benefit from alternative therapy and clinical trials.

Significance of Single-cell Level Dual Expression of BCL2 and MYC Determined With Multiplex Immunohistochemistry in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a fatal heterogenous neoplasm. Recent clinical trials have failed partly due to nebulous criteria for defining high-risk patients. Patients with double-expresser lymphoma (DEL) have a poor prognosis and are resistant to conventional treatment. However, many diagnostic and clinical controversies still surround DEL partly due to the arbitrariness of criteria for the diagnosis of DEL. In this study, we suggest a refined method for diagnosing DEL by evaluating the concurrent expression of BCL2 and MYC at the single-cell level (dual-protein-expressing lymphoma [DUEL]). For the proof of concept, a multiplex immunofluorescence assay for CD20, BCL2, and MYC was performed and quantitatively analyzed using spectral image analysis in patients. The analysis results and clinical applicability were verified by using dual-color immunohistochemistry performed on 353 independent multicenter patients who had been uniformly treated with standard therapy. DUEL showed significantly worse overall survival (OS) and event-free survival (EFS) (P=0.00011 and 0.00035, respectively). DUEL status remained an independent adverse prognostic variable with respect to the International Prognostic Index risk and the cell of origin. Moreover, the advantage of determining DUEL status by dual-color immunohistochemistry was shown by more robust classification and more homogeneous high-risk subgroup patient identification in both training (n=271) (OS: P<0.0001; EFS: P<0.0001) and validation sets (n=82) (OS: P=0.0087; EFS: P<0.0001). This concept of DUEL is more consistent with carcinogenesis and has greater practical utility, hence it may provide a better basis for both basic and clinical research for the development of new therapeutics.

Prognostic significance of serum ß2-microglobulin levels in patients with peripheral T-cell lymphoma not otherwise specified.

We aimed to investigate the prognostic value of serum ß2-microglobulin in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). A cohort study of PTCL-NOS patients (n = 147) was conducted. An elevated serum ß2-microglobulin level was associated with the presence of previously identified predictors of a poor prognosis for PTCL-NOS. Patients with an elevated serum ß2-microglobulin level exhibited a significantly worse progression-free survival (PFS) and overall survival (OS). Multivariate analyses revealed that an elevated serum ß2-microglobulin level was independently associated with a shorter PFS and OS. A new prognostic index incorporating the serum ß2-microglobulin level allowed for the stratification of patients into three distinct risk subgroups. The index was validated to stratify patients with distinct survival outcomes in an independent cohort of PTCL-NOS (n = 89). In conclusion, serum ß2-microglobulin level is an independent prognostic factor in patients with PTCL-NOS. Our ß2-microglobulin-based prognostic index for PTCL-NOS deserves further investigation and validation.

BCL2 super-expressor diffuse large B-cell lymphoma: a distinct subgroup associated with poor prognosis.

Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.

Upward trend in follicular lymphoma among the Korean population: 10-year experience at a large tertiary institution.

BACKGROUND: Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in Western countries. However, it is relatively rare in Asia. This study examined epidemiologic characteristics of FL in South Korea, with an emphasis on recent trends of increase in cases. METHODS: We retrospectively examined 239 cases of newly diagnosed FL at a large tertiary institution in Korea (Asan Medical Center, Seoul, Republic of Korea) between 2008 and 2017. Age-adjusted incidence rates and clinicopathological variables were analyzed, and joinpoint regression analysis was used to identify the changes. RESULTS: The age-adjusted incidence of FL significantly increased during the study period (p = .034), and the ratio of (relative incidence) patients with FL to patients with NHL increased from 4.28% to 9.35% in the same period. Over the 10-year study assessment duration, the proportion of patients with stage III/IV FL (p = .035) and expression of BCL2 (p = .022) or BCL6 (p = .039) significantly increased. From 2013-2017, the proportion of patients with highrisk Follicular Lymphoma International Prognostic Index (FLIPI) score increased (21.5% to 28.7%), whereas that of low-risk FLIPI decreased (55.4% to 38.6%), although those results were not statistically significant (p = .066). CONCLUSIONS: We found an increasing incidence of FL, with a disproportionate increase in the incidence of high-stage disease and recent changes in the clinicopathologic features of the Korean patient population.

Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations.

Recent studies identified germline mutations in HAVCR2 (encoding T-cell immunoglobulin mucin 3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2 wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 patients with SPTCL diagnosed at 8 Korean institutions was established. Whole-exome sequencing and RNA-sequencing were performed on 8 patients in the discovery set. In the validation set, targeted gene sequencing or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 25 (51.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in tumor necrosis factor-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the messenger RNA level and at the protein level. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (P = .031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting prognosis for patients with SPTCL.

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.

Efficacy and safety of prophylactic high-dose MTX in high-risk DLBCL: a treatment intent-based analysis.

Despite central nervous system (CNS) relapse occurring in >10% of high-risk diffuse large B-cell lymphoma (DLBCL) patients, the role of CNS-directed prophylaxis is controversial in the absence of randomized controlled trials. In this retrospective study, we aimed to evaluate the safety and efficacy of prophylactic high-dose methotrexate (HD-MTX) on CNS relapse and survival outcomes in 258 newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-treated high-risk DLBCL patients, based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX. Patients were classified into an ITT HD-MTX group (n = 128) and a non-ITT HD-MTX group (n = 130). The CNS relapse rate was not significantly different between these groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = 0.96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs 64.5% (P = 0.94) and 71.7% vs 71.4% (P = 0.7), respectively. Also, propensity score-matched analyses showed no significant differences in the time-to-CNS-relapse, progression-free survival, or overall survival. The ITT HD-MTX group showed a higher incidence of grade ≥ 3 oral mucositis and elevated alanine aminotransferase. Prophylactic HD-MTX does not improve CNS relapse rate or survival outcomes in high-risk DLBCL patients, and it is accompanied by increased toxicities.

Reappraisal of the prognostic value of Epstein-Barr virus status in monomorphic post-transplantation lymphoproliferative disorders-diffuse large B-cell lymphoma.

The role of the Epstein-Barr virus (EBV) status in the blood for predicting survival in post-transplantation lymphoproliferative disorders-diffuse large B-cell lymphoma (PTLD-DLBCL) is unknown. We evaluated the prognostic values of pre-treatment EBV-encoded small RNA (EBER) detected with in situ hybridization in tissues and EBV DNA in the whole blood (WB) and plasma in 58 patients with monomorphic PTLD-DLBCL after solid organ transplantation. There were no significant differences in the rates of overall response, complete response, and survival according to EBER EBV and WB EBV status. In contrast, patients with positive plasma EBV DNA had significantly lower rates of overall response (60.0% vs. 94.4%, P = 0.043) and complete response (40.0% vs. 88.9%, P = 0.019) as well as worse progression-free survival (PFS) (P = 0.035) and overall survival (OS) (P = 0.039) compared with patients with negative plasma EBV DNA. In multivariate analysis, plasma EBV DNA positivity was a significantly unfavorable prognostic factor for PFS [hazard ratio (HR) 4.92, 95% confidence interval (CI) 1.22-19.86, P = 0.025] and OS (HR 4.48, 95% CI 1.14-17.63, P = 0.032). Despite small number of 6 patients with plasma EBV positivity, plasma EBV DNA positivity might be more prognostic for survival than EBER or WB EBV DNA positivity in patients with monomorphic PTLD-DLBCL.

Prognostic Stratification of Patients with Burkitt Lymphoma Using Serum ß2-microglobulin Levels.

PURPOSE: We aimed to investigate the prognostic value of serum ß2-microglobulin for patients with Burkitt lymphoma (BL) and to propose a risk-stratifying classification system. MATERIALS AND METHODS: A prospective registry-based cohort study of BL patients treated with dose-intensive or effective dose-adjusted chemotherapies (n=81) was conducted. Survival outcomes were compared based on previously reported risk groups and/or serum ß2-microglobulin levels. A risk-stratifying classification system incorporating serum ß2-microglobulin levels was proposed and validated in an independent validation cohort (n=60). RESULTS: The median age was 47 years, and 57 patients (70.4%) were male. Patients with high serum ß2-microglobulin levels (> 2 mg/L) had significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.01 for both). Serum ß2-microglobulin levels further stratified patients in the low-risk and high-risk groups in terms of PFS (p=0.010 and p=0.044, respectively) and OS (p=0.014 and p=0.026, respectively). Multivariate analyses revealed that a high serum ß2-microglobulin level (> 2 mg/L) was independently associated with a shorter PFS (hazards ratio [HR], 3.56; p=0.047) and OS (HR, 4.66; p=0.043). The new classification system incorporating the serum ß2-microglobulin level allowed the stratification of patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. In an independent cohort of BL, the system was validated by stratifying patients with different survival outcomes. CONCLUSION: Serum ß2-microglobulin level is an independent prognostic factor for BL patients. The proposed ß2-microglobulin-based classification system could stratify patients with distinct survival outcomes, which may help define appropriate treatment approaches for individual patients.

Prognostic Impact of Age at the Time of Diagnosis in Korean Patients with Diffuse Large B-cell Lymphoma in the Rituximab Era: A Single Institution Study.

PURPOSE: In contrast to the Western diffuse large B-cell lymphoma (DLBCL), prognostic impact of age in a Korean population with DLBCL has not been fully evaluated. MATERIALS AND METHODS: Six hundred and eight DLBCL patients treated with rituximab-containing chemotherapeutic regimens from January 2002 to March 2012 in Asan Medical Center were enrolled. Survival models using the restricted cubic spine-transformed age variable were constructed to evaluate non-linear relationships between age and survival outcome. Finally, age was categorized according to the conventional international prognostic index (IPI), National Comprehensive Cancer Network (NCCN)-IPI, and Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GELTAMO)-IPI schemes and the prognostic implications were evaluated. RESULTS: The relative hazard did not change significantly during the first to fifth decades, but began to increase exponentially in patients aged over 62 years. This pattern or relationship was also retained in a multivariate model fitted to the age-adjusted IPI and relative dose intensity. Multivariate survival analysis revealed that age > 75 years, but not age > 60 years, was associated independently with poor overall and progression-free survival when the relative dose intensity and age-adjusted IPI were taken into account. CONCLUSION: The outcome of DLBCL in Korean populations may deteriorate rapidly as age exceeds 62 years. Therefore, a consensus cutoff value for age in Korean DLBCL patients should be determined to better predict prognosis.

A prognostic index for extranodal marginal-zone lymphoma based on the mucosa-associated lymphoid tissue International Prognostic Index and serum ß2-microglobulin levels.

The mucosa-associated lymphoid tissue (MALT) International Prognostic Index (IPI) was recently proposed as a prognostic index for patients with MALT lymphoma. We aimed to investigate the prognostic value of the serum ß2-microglobulin level in the context of MALT-IPI, and we proposed a new prognostic index. Survival outcomes were analysed with regard to ß2-microglobulin level, MALT-IPI, and the new prognostic index in MALT lymphoma patients (n = 571). The validity of the new prognostic index was assessed using an independent cohort (n = 216). Patients with high ß2-microglobulin levels had significantly worse progression-free survival (PFS) and overall survival (OS) outcomes. A high ß2-microglobulin level was independently associated with poor PFS and OS. ß2-microglobulin levels further stratified patients in the MALT-IPI intermediate-risk group in terms of PFS and OS. A new prognostic index based on the MALT-IPI and the ß2-microglobulin level, MALT-IPI-B, was proposed. The MALT-IPI-B was able to stratify patients into subgroups having distinct PFS and OS outcomes in both the training and validation cohorts. MALT-IPI-B enabled the identification of patients with poor survival outcomes who were classified into the intermediate-risk group by the MALT-IPI. In conclusion, this new ß2-microglobulin-based prognostic index may have the specific advantage of identifying high-risk patients who may require systemic treatment.

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.

Superiority of Epstein-Barr Virus DNA in the Plasma Over Whole Blood for Prognostication of Extranodal NK/T Cell Lymphoma.

BACKGROUND: Extranodal natural killer T cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma with invariable infection of lymphoma cells with Epstein-Barr virus (EBV), and the presence of EBV-DNA in the blood is a well-known prognosticator. However, there is no consensus on which blood compartment is more optimal for predicting survival outcomes. METHODS: We analyzed 60 patients who were newly diagnosed with ENKTL from a prospectively collected database. EBV-DNA was measured in the whole-blood (WB) and plasma at the time of diagnosis and after treatment completion. RESULTS: EBV-DNA was detected in pre-treatment WB and plasma in 37 (61.7%) and 23 (38.3%) patients, respectively. The presence of pre-treatment plasma EBV-DNA was significantly associated with advanced stage while presence of WB EBV-DNA did not. Positivity of pre-treatment plasma-EBV, but not WB EBV-DNA, was independently associated with poor PFS (HR, 4.22;95% CI, 1.79-9.97; P=0.001) and OS (HR, 8.38; 95% CI, 3.03-23.19; P<0.001) in the multivariate analysis. After treatment completion, positivity of plasma-EBV was independently associated with poor PFS (HR, 9.41; 95% CI, 2.27-39.02; P=0.002) and OS (HR, 32.38; 95% CI, 3.25-322.56; P=0.003), whereas no significant association was observed between WB-EBV status and survival outcomes. CONCLUSIONS: Our results suggest that EBV-DNA in the plasma has better prognostic values than WB in patients with ENKTL.