Abemaciclib,a CDK4/6 inhibitor,exerts preclinical activity against aggressive germinal center‐derived B‐cell lymphomas

The revised WHO classification newly defined the entities “High‐grade B‐cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL‐DH/TH)” and “HGBL, NOS.” Standard immunochemotherapy for diffuse large B‐cell lymphoma (DLBCL), R‐CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)‐derived B‐cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC‐derived B‐cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B‐cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC‐derived B‐cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B‐cell (ABC)‐like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B‐cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GC‐derived B‐cell lymphomas.     

Hematopoietic stem cell transplantation for diffuse large B‐cell lymphoma having 8q24/MYC rearrangement in Japan

The prognosis of diffuse large B‐cell lymphoma (DLBCL) having MYC rearrangement (MYC‐R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC‐R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC‐R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21–67) years. Twenty‐six (54%) patients had MYC‐R only (single hit), and 22 (46%) had MYC‐R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto‐SCT during the first complete response (CR), both the 2‐year overall survival (OS) and progression‐free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%–91.2%). In 20 patients who received auto‐SCT after relapsed or refractory state, the 2‐year OS and PFS rates were 68.2% (95% CI, 41.9%–84.5%) and 59.6% (95% CI, 35.1%–77.4%), respectively. In 17 patients who received allo‐SCT, only 4 patients underwent SCT in CR. The 2‐year OS and PFS rates were 29.4% (95% CI, 10.7%–51.1%) and 17.6% (95% CI, 4.3%–38.3%), respectively. The rate of non‐relapse mortality at 1 year was 41.2% (95% CI, 17.1%–64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto‐SCT may be effective for MYC‐R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo‐SCT not in CR, the outcome of allo‐SCT was unsatisfactory due to high non‐relapse mortality and early relapse. To clarify the role of allo‐SCT for MYC‐R DLBCL, further accumulation of patients is necessary.     

Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

BACKGROUND:

B‐cell lymphoma, Unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B‐cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms.

METHODS:

The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B‐cell lymphoma treated with either a standard DLBCL regimen (R‐CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone‐related therapy]) or more intensive regimens, such as R‐hyper‐CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings.

RESULTS:

Thirty (58%) unclassifiable B‐cell lymphomas had MYC abnormalities (MYC⁺) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC⁺ and MYC^? groups were similar in their age distribution and International Prognostic Index scores. Progression‐free survival of patients with MYC⁺ unclassifiable B‐cell lymphoma treated initially with R‐CHOP was significantly worse than patients treated with R‐hyper‐CVAD (P = .0358). In contrast, for the MYC^? unclassifiable B‐cell lymphoma group, some patients responded to R‐CHOP, and others were refractory to R‐hyper‐CVAD.

CONCLUSIONS:

MYC aberrations are common in unclassifiable B‐cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R‐CHOP. In contrast, MYC^? unclassifiable B‐cell lymphoma patients responded variably to either R‐CHOP or aggressive therapy, and the latter showed no survival advantage. Cancer 2011;. © 2011 American Cancer Society.     

Patterns of Utilization and Outcomes of Autologous Stem Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Diffuse Large B-cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements

BackgroundPatients with Diffuse Large Bcell Lymphoma (DLBCL) with MYC and BCL2 and/or BCL6 gene rearrangements [double-hit lymphoma/triple-hit lymphoma (DHL/THL)] have poor prognosis in the relapsed/refractory setting.MethodsWe utilized a real-world deidentified database of DLBCL patients and report patterns of therapy utilization in relapsed/refractory DLBCL. We used log-rank test to compare real-world overall survival (rwOS) among DHL and non-DHL subgroups for CAR Tcell therapy or ASCT respectively, stratified for prior lines of therapy.ResultsOf all 7,877 patients with DLBCL, 367 patients had DHL while 6113 had non-DHL. Second line chemotherapy was administered to 147 DHL patients and 1517 non-DHL. 1393 were excluded, including 934 with unknown DHL/THL status. Approximately 47% received salvage intent chemotherapy in the DHL subgroup, of which 19% patients eventually received ASCT, while 34% received salvage intent chemotherapy in the non-DHL/THL group with 32% receiving ASCT. DHL/THL status negatively influenced median rwOS for patients who underwent ASCT in the second-line while it was associated with numerically inferior but without statistically significant rwOS among patients that underwent CAR Tcell therapy on multivariable analysis.ConclusionrwOS of relapsed DHL/THL is inferior to non-DHL/THL. Fewer patients with DHL/THL were able to proceed with ASCT after salvage chemotherapy compared to non-DHL/THL. ASCT as second-line therapy for relapsed DHL/THL had worse rwOS than for non-DHL/THL, consistent with the natural history of DHL/THL. This difference was not seen for CAR Tcell therapy, which combined with promising results from clinical trials, suggests a greater role for CAR T-cell therapy in relapsed/refractory DHL.     

MYC translocation and/or BCL 2 protein expression are associated with poor prognosis in diffuse large B‐cell lymphoma

Genomic alterations and protein expression levels have been established as prognostic factors for survival in patients with diffuse large B‐cell lymphoma (DLBCL). In particular, double‐hit DLBCL (DHL), which exhibits translocations in MYC and BCL2 and/or BCL6, is known to be associated with a poor prognosis. However, the clinical significance of gene alterations and protein expression levels for MYC, B‐cell lymphoma (BCL)2, and BCL6 are unclear. In this study, we analyzed 61 adult patients diagnosed with DLBCL without DHL, who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, or similar regimens. There were no differences in the distribution of MYC expression rates among the different MYC gene statuses. In log–rank tests, MYC translocation was a prognostic factor for overall survival (OS; P = 0.011), whereas BCL2 and BCL6 translocation were not prognostic indicators (P = 0.999 and P = 0.925, respectively). Although the expression levels of MYC and BCL6 were not significantly associated with OS, the expression of BCL2 was a prognostic factor for OS (P = 0.027). Furthermore, copy number gains in the MYC, BCL2, and BCL6 genes did not affect OS. MYC translocation (hazard ratio, 4.769; range, 1.518–14.98; P = 0.007) and BCL2 protein expression (hazard ratio, 3.072; range, 1.002–9.413; P = 0.049) were independent prognostic factors for survival in multivariate analyses. In conclusion, MYC translocation and BCL2 expression may need to be investigated at the initial diagnosis to predict prognosis in patients with DLBCL.     

Double-Hit Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of NHL cases. It is a heterogeneous group of diseases. BCL2, BCL6, and MYC are the most frequent mutated genes in DLBCL. Double-hit lymphoma (DHL) is an aggressive form of DLBCL with an unmet treatment need, in which MYC rearrangement is present with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass with B symptoms. DHL has been linked to very poor outcomes when treated with RCHOP chemotherapy. Dual-expressor lymphoma is a form of DLBCL with overexpression of MYC and BCL2/BCL6. There is a paucity of prospective trials evaluating the treatment of DHL. Retrospective series suggest that more aggressive treatment regimens such as DA-EPOCH and hyper CVAD may be more efficacious. However, there remains a lack of consensus regarding optimal treatment for DHL. Further clinical trials, including novel agents, are needed for improvement in outcomes.     

MYC or BCL2 copy number aberration is a strong predictor of outcome in patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). Patients with DLBCL harboring MYC aberrations concurrent with BCL2 or/and BCL6 aberrations constitute a specific group with extremely poor outcome. In this study, we retrospectively investigated the incidence and prognosis of MYC, BCL2, and BCL6 aberrations with DLBCL patients in Chinese population. We applied fluorescence in situ hybridization and immunohistochemical analysis in 246 DLBCL patients. The results showed that patients with MYC or BCL2 copy number aberration (CNA) had significantly worse overall survival (OS) and progression-free survival (PFS) than negative cases (P < 0.0001). Patients with both MYC and BCL2 CNA had similar outcomes to those with classic double hit lymphoma or protein double expression lymphoma (MYC and BCL2/BCL6 coexpression). By multivariate analysis, MYC CNA, BCL2 CNA and double CNA were the independent worse prognostic factors. In conclusions, patients with MYC or BCL2 CNA constituted a unique group with extremely poor outcome and may require more aggressive treatment regimens.     

弥漫大B细胞淋巴瘤myc、bcl-2和bcl-6蛋白表达与基因异常的相关性研究

目的 探讨多重基因异常在弥漫大B细胞淋巴瘤(DLBCL)中的发生情况及其与蛋白高表达之间的关系.方法 收集2012年1月至2016年12月确诊的DLBCL非特指型患者50例,采用免疫组织化学法检测c-myc、bcl-2及bcl-6蛋白表达情况,采用间期荧光原位杂交(I-FISH)方法检测3个基因异常情况.结果 50例DLBCL患者中,男性27例,女性23例;年龄3~85岁,中位年龄50岁.发病部位:淋巴结23例(46.00%),结外27例(54.00%),以胃肠道最为多见(13例,48.15%).免疫组织化学检测c-myc蛋白阳性率94.00%(47/50),阳性细胞超过40%者41例(82.00%);bcl-2蛋白阳性率84.00%(42/50),阳性细胞超过70%者38例(76.00%);18例(36.00%)同时高表达c-myc和bcl-2.FISH检测结果显示,7例(14.00%)c-myc断裂,2例(4.00%)扩增;6例(12.00%)bcl-2断裂,4例(8.00%)扩增;8例(16.00%)bcl-6断裂,3例(6.00%)扩增,1例(2.00%)同时断裂及扩增;4例(8.00%)检测到多重基因异常,其中1例(2.00%)c-myc合并bcl-2基因异常,2例(4.00%)c-myc合并bcl-6基因异常,为双重打击淋巴瘤(DHL),1例(2.00%)同时检测到c-myc、bcl-2及bcl-6基因异常,为三重打击淋巴瘤(THL).4例多重基因异常病例中,3例起源于生发中心B细胞(GCB),1例起源于非GCB.18例c-myc和bcl-2蛋白双高表达组仅有3例(16.67%)检测到多重基因异常,包括2例DHL和1例THL.结论 多重基因异常在DLBCL中的检出率为8.00%.基因异常与蛋白高表达之间无明显相关性,DHL的检出依赖于分子遗传学检测.     

Clinical and biological significance of de novo CD5+ diffuse large B-cell lymphoma in Western countries

CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5⁺ DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5⁺ DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell–like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5⁺ DLBCL patients had significantly worse overall survival (median, 25.3 months vs. not reached, P< .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P< .0001) than CD5⁻ DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression abolished the prognostic significance of CD5 expression, suggesting a tumor-suppressor role of SSBP2 for CD5 signaling. Gene-expression profiling demonstrated that B-cell receptor signaling dysfunction and microenvironment alterations are the important mechanisms underlying the clinical impact of CD5 expression. This study shows the distinctive clinical and biological features of CD5⁺ DLBCL patients in Western countries and underscores important pathways with therapeutic implications.     

Should We Use Cell of Origin and Dual-protein Expression in Treating DLBCL?

Treatment outcomes in diffuse large B-cell lymphoma (DLBCL) following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy is highly variable and dependent on a number of clinical, biologic, and genetic features. The identification of molecular heterogeneity via gene expression profiling dichotomizes patients based on the cell of origin (COO) model into germinal center B–cell-like (GCB) and activated B–cell-like (ABC) subsets, with ABC-DLBCL having a worse outcome. Along with the COO classification, other molecular phenotypes have also been identified, further highlighting the clinical and biologic complexity of this disease. Double-hit lymphomas, with concurrent chromosomal translocations of the MYC and BLC2 genes, or less commonly MYC and BCL6 genes, are associated with an aggressive clinical course and adverse outcomes when treated with R-CHOP. Furthermore, dual overexpression of MYC and BCL2 proteins has emerged as an important adverse prognostic factor, can be present through different mechanisms in both GCB and ABC subsets, and further complicates treatment considerations. Studies investigating the biologic underpinnings of these diverse subtypes have revealed a number of novel targets, which may provide therapeutic benefit. Moving forward, clinical trials focusing on molecular subsets of DLBCL, and incorporating rational targeted agents, will ideally lead to improved outcomes and allow a more personalized treatment approach. This review will focus on emerging data regarding DLBCL management based on either COO or dual overexpression of MYC/BCL2 proteins.     

高级别B细胞淋巴瘤预后与治疗进展

高级别B细胞淋巴瘤(HGBL)在2016年世界卫生组织分类中被定义为一种独立的疾病种类,其具有侵袭性的临床特点.近年来对该病的亚组分析、精准治疗等有很多研究,如HGBL非特指型(HGBL-NOS)与双打击淋巴瘤(DHL)预后比较、转化的DHL与原发DHL预后比较、myc伙伴基因/bcl-2/bcl-6易位、TP53表达、血清清蛋白与预后关系研究及化学免疫治疗、造血干细胞移植、嵌合抗原受体T细胞(CAR-T)等治疗方法的探索.文章就第58届美国血液学会(ASH)年会关于HGBL预后与治疗进展进行总结.     

Cell of origin is not associated with outcomes of relapsed or refractory diffuse large B cell lymphoma

Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R-CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well-characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non-GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI₉₅: 38–54] vs. non-GCB: 44% [CI₉₅:36–55], p > 0.05) or GEP (2 years OS ABC: 42% [CI₉₅: 29–59] vs. GCB: 40% [CI₉₅: 30–54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI₉₅:6–45] vs. 45% [CI₉₅: 34–59], p < 0.01) and DEL (2 years OS 33% [CI₉₅: 20–56], vs. 50% [CI₉₅: 41–60], p < 0.05) had lower OS than non-DHL and non-DEL/non-DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.     

Prognostic Significance of BCL-2 and BCL-6 Expression in MYC-positive DLBCL

Background

Double-expression lymphoma (DEL) is a rare subgroup of diffuse large B-cell lymphoma (DLBCL), which has coexpression of MYC and BCL-2. Coexpression of MYC and BCL-2 is considered a prognostic marker portending poor outcomes. However, the prognostic effect of BCL-2 and BCL-6 expression in DLBCL remains controversial.

Diffuse large B-cell lymphoma with MYC gene rearrangements: Current perspective on treatment of diffuse large B-cell lymphoma with MYC gene rearrangements; case series and review of the literature

In the past decade, patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Standard treatment is now changing as a result of deeper understanding of underlying biologic differences of such lymphomas. One of the most powerful predictors of an adverse outcome on R-CHOP therapy is the presence of a MYC gene rearrangement (MYC+ lymphoma). Determination of MYC gene rearrangement by FISH (fluorescent in situ hybridisation) has recently become a standard diagnostic procedure.In this paper, an overview of current literature on MYC function and MYC+ lymphoma patient outcome is presented. Furthermore, we present 26 patients from our tertiary referral centre who were diagnosed with MYC+ lymphoma between 2009 and 2014. In our patient series, we confirm the dismal prognosis of MYC+ lymphoma patients. Intensification of classical chemotherapy does not lead to better overall survival, justifying new treatment modalities. First line therapy should be more specifically targeted against MYC and the genes and proteins that are deregulated by MYC. To this end, the first clinical trial in which MYC+ patients will be offered targeted treatment has recently been launched.     

Chromosome abnormalities in diffuse large B‐cell lymphomas: analysis of 231 Chinese patients

Genome instability is a hallmark of cancer. Diffuse large B‐cell lymphoma (DLBCL) is the most common form of non‐Hodgkin lymphoma with high levels of chromosomal aberrations. The purpose of this study was to characterize chromosomal aberrations in Chinese DLBCL patients and to compare chromosomal abnormalities between germinal centre B‐cell‐like (GCB) and non‐GCB subgroups. Fluorescence in situ hybridization, G‐band cytogenetics and immunohistochemistry were performed in 231 cases of de novo DLBCL. We demonstrated that the rate of abnormal and complex karyotypes was 89.1% (139/156) and 92.8% (129/139), respectively. We found a total of 490 structural chromosomal aberrations, including 96 frequent and recurring structural alterations. Most importantly, we identified several rare or novel chromosomal alterations: eight gains (5, 13, 14q, 17, 19p, 20, 21p, Y), one loss (21) and three recurrent translocations [t(7;15)(q22;q22), t(3;20)(p24;q13.1), t(2;3)(q21;q25)]. Moreover, the frequent recurrent genomic imbalance between GCB and non‐GCB subgroups was different. Finally, we discovered two cases of concurrent IGH‐BCL6 and MYC rearrangements. The rate of abnormal karyotypes in DLBCL patients of Chinese descent was similar to that of Western countries, but some common karyotypes were different, as were the abnormal karyotypes of GCB and non‐GCB subgroups. Our discovery of rare and novel abnormal karyotypes may represent unique chromosomal alterations in Chinese DLBCL patients. Copyright © 2012 John Wiley & Sons, Ltd.     

Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era

BACKGROUND:

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

METHODS:

The authors retrospectively analyzed 1221 patients treated uniformly with standard R‐CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax‐associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15‐91 years).

RESULTS:

Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).

CONCLUSIONS:

Extranodal involvement affects the prognosis of patients undergoing R‐CHOP therapy for DLBCL. Cancer 2012. © 2011 American Cancer Society.     

Low lymphocyte-to-monocyte ratio predicts unfavorable prognosis in non-germinal center type diffuse large B-cell lymphoma

The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis has been used to predict survival in diffuse large B-cell lymphoma (DLBCL) patients, but its prognostic significance with respect to different cell-of-origin (COO) subtypes remains unknown. We retrospectively analyzed 168 de novo DLBCL patients in this study and found that a low LMR (≤2.6) correlates with B symptoms, elevated LDH, advanced Ann Arbor stage and higher international prognostic index (IPI) score (p < 0.05). The low LMR is a negative prognostic parameter for overall survival (OS) and event-free survival (EFS) in non-germinal center (GC) type DLBCL patients, as compared with the high LMR, especially in those treated with R-CHOP. However, the LMR has less correlation with the OS and EFS in GC type DLBCL patients (p = 0.545 and 0.547, respectively). Multivariate analysis adjusting for IPI revealed that the low LMR indicates a shorter survival retain both OS and EFS in non-GC subtypes (p = 0.023 and 0.005, respectively). In the non-GC DLBCL patients treated with R-CHOP a low LMR still showed a trend to predict poor EFS (p = 0.052). In conclusion, these data suggest that a low LMR at diagnosis may imply a poor prognosis in non-GC subtype DLBCL patients, especially in those treated with R-CHOP, but not in those GC subtype DLBCL patients.     

MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that accounts for nearly 40% of all lymphoid tumors. This heterogeneous disease can be divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes by gene expression and immunohistochemical profiling. Using microarray analysis on prototypic cell lines, we identified microRNAs (miR-155, miR-21 and miR-221) that were more highly expressed in ABC-type than GCB-type cell lines. These microRNAs were over-expressed in de novo DLBCL (n = 35), transformed DLBCL (n = 14) and follicular center lymphoma cases (n = 27) compared to normal B cells. Consistent with the cell line model, expression levels were higher in DLBCL cases with an ABC-type immunophenotype than those that were GCB-type (p < 0.05). Moreover, using multivariate analysis we found that expression of miR-21 was an independent prognostic indicator in de novo DLBCL (p < 0.05). Interestingly, expression levels of both miR-155 and miR-21 were also higher in nonmalignant ABC than in GCB cells. As we also demonstrate that expression of microRNAs can be measured reliably from routine paraffin-embedded biopsies of more than 8-years-old (p < 0.001), we suggest that microRNAs could be clinically useful molecular markers for DLBCL as well as other cancers.     

Clinical outcome of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly in the rituximab era

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)‐positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV‐positive DLBCL is controversial. To compare the clinical outcome of EBV‐positive and EBV‐negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV‐encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV‐positive DLBCL patients. The median overall survival and progression‐free survival times in patients with EBV‐positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression‐free survival could not be determined in EBV‐negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV‐positive DLBCL remains poor, even in the rituximab era.