Differential micro-RNA expression in primary CNS and nodal diffuse large B-cell lymphomas

Most primary CNS lymphomas (PCNSL) are diffuse large B-cell lymphomas (DLBCL). However, clinical behavior and prognosis differ considerably from those for nodal DLBCL (nDLBCL), and their pathogenesis is still not fully understood. Micro-RNAs (miRNAs) have been associated with cancer development and progression. We investigated a large miRNA panel for differential expression in PCNSL and nDLBCL, to determine new mechanisms potentially involved in PCNSL pathogenesis. Using paraffin-embedded biopsy specimens from 21 HIV-negative patients with newly diagnosed PCNSL (n = 11) and nDLBCL (n= 10), we measured the expression of 365 miRNA species by quantitative real-time PCR using low-density PCR arrays. We found that 18 miRNAs were differentially expressed: median expression levels of 13 miRNAs were 2.1-13.1 times higher in PCNSL, and median expression levels of 5 miRNAs were 2.6-3.3 times higher in nDLBCL. MiRNAs upregulated in PCNSL were associated with the Myc pathway (miR-17-5p, miR-20a, miR-9), with blocking of terminal B-cell differentiation (miR-9, miR-30b/c), or with upregulation by inflammatory cytokines (miR-155). Putative tumor-suppressor miRNAs (miR-199a, miR-214, miR-193b, miR-145) were downregulated in PCNSL. There was no overlap of miRNAs dysregulated in PCNSL with those differentially expressed between immunohistologically defined germinal center B cell-like (GCB) and non-GCB types or, apart from miR-9, with miRNAs known to be overexpressed in human brain. We conclude that PCNSL exhibits a distinct pattern of miRNA expression compared with nDLBCL. This argues for the involvement of different molecular mechanisms in the pathogenesis of these two lymphoma types.     

miR-320d与弥漫大B细胞淋巴瘤预后的相关性研究

目的 探讨miR-320d表达与弥漫大B细胞淋巴瘤（DLBCL）预后的关系.方法 应用EnVision法对山西省肿瘤医院有随访资料的原发于淋巴结的DLBCL 62例石蜡标本进行CD20、CD3、CD10、bcl-6、Mum-1免疫标记检测,根据Hans分类方法将DLBCL分为生发中心B细胞（GCB）型和非生发中心B细胞（non-GCB）型.采用安捷伦16.0高密度芯片对24例DLBCL石蜡标本进行miRNA表达谱筛选,用实时荧光定量PCR方法对62例DLBCL石蜡标本进行miR-320d表达验证.将1 1例淋巴结反应性增生标本作为对照.结果 62例DLBCL中,GCB型22例（35.5％）,non-GCB型40例（64.5％）,GCB型miR-320d表达水平是non-GCB型的3.43倍（P=0.034）.miR-320d在对照组的表达量是DLBCL的5.65倍（P＜ 0.001）.单因素分析示DLBCL中miR-320d低表达组总生存期低于高表达组,差异有统计学意义（P=0.021）.多因素Cox回归模型分析示62例DLBCL中,miR-320d低表达（RR=2.434,95％CI1.148～5.159,P=0.020）为独立于国际预后指数（IPI）的预后不良因素.结论 miR-320d表达下调预示DLBCL预后不良.     

微小RNA-21在弥漫大B细胞淋巴瘤中的表达及其临床意义

 【摘要】　目的　研究微小RNA-21（miR-21）在弥漫大B细胞淋巴瘤（DLBCL）中的表达,探讨miR-21表达与DLBCL发生、发展的意义及其与临床病理特征和预后的关系。方法　采用实时荧光定量聚合酶链反应（RT-PCR）检测50例DLBCL存档蜡块和12例正常淋巴结中miR-21的表达,并采用免疫组织化学EnVision法检测bcl-2、p53在DLBCL中的表达。结果　miR-21在DLBCL中高表达,且在非生发中心B细胞样（non-GCB）亚型中高于GCB亚型,50例DLBCL中有18例（36.0 %）表达bcl-2,21例（42.0 %）表达p53。DLBCL中miR-21表达水平与bcl-2呈负相关（P＝0.020）,与p53表达、DLBCL临床分期呈正相关（P＝0.022;P＝0.005）,miR-21高表达的DLBCL患者3年生存率较miR-21低表达者低。结论　miR-21高表达可能是DLBCL恶性度高的标志,是促进DLBCL肿瘤细胞增殖的重要因素,可能对预后有一定的指导意义。bcl-2、p53可能是miR-21在DLBCL中发挥作用的靶标。     

miR-155在弥漫性大B细胞淋巴瘤预后预测中的应用价值

目的:探讨miR-155在弥漫性大B细胞淋巴瘤预后预测中的应用价值。方法:选取我院收治的120例弥漫性大B细胞淋巴瘤作为研究对象,采用qRT-PCR检测所有患者癌组织miR-155的相对表达水平,根据miR-155的表达水平将所有患者分成miR-155高表达组（n=72）和miR-155低表达组（n=48）,比较两组患者的临床病理资料、生存率,采用 Cox比例风险回归模型对弥漫性大B细胞淋巴瘤患者的预后进行单因素和多因素分析,并分析miR-155对弥漫性大B细胞淋巴瘤细胞增殖和迁移能力的影响。结果:miR-155高表达组患者结外侵犯比例显著高于miR-155低表达组（P＜0.05）;miR-155高表达组患者3年无进展生存率（29.2%）及总体生存率（40.3%）均显著低于miR-155低表达组（81.3%和83.3%）;单因素和多因素分析结果均显示miR-155表达水平是DLBCL无进展生存期和总体生存期的影响因素;miR-155低表达组细胞划痕愈合速度(0.53±0.04)显著低于对照组细胞（1.0±0.03）(P＜0.05),miR-155低表达组细胞在培养的3、4 d的吸光度值显著低于对照组（0.38±0.01 vs 0.56±0.03;0.56±0.02 vs 0.76±0.02）（P＜0.05）。结论:弥漫性大B细胞淋巴瘤患者的miR-155表达水平显著影响患者的预后,其可能机制是通过影响弥漫性大B细胞淋巴瘤细胞的增殖和迁移能力,提示miR-155可能是弥漫性大B细胞淋巴瘤新的和可靠的预后生物标志物,值得进一步深入研究。     

Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF‐κB pathway

Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center‐like (GCB) and activated‐B‐cell‐like DLBCL (ABC). The most aggressive type, ABC‐DLBCL, displays dysregulation of both canonical and noncanonical NF‐κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF‐kB pathway, the precise role of the noncanonical NF‐kB pathway remains unknown. Here we show that activation of the noncanonical NF‐κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF‐κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin‐induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF‐κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53‐independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF‐κB sites to their promoter region. Overall, these results indicate that the noncanonical NF‐κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF‐kB pathway should be considered as an important component in DLBCL therapeutic approach.     

Gene expression profiling of primary vitreoretinal lymphoma

The characteristics of tumor cells of primary vitreoretinal lymphoma (PVRL) have not been defined, although researches have shown that most cases are of diffuse large B‐cell lymphoma (DLBCL). To determine the subtype and biological characteristics of tumor cells of PVRL, we performed a gene expression profiling analysis. RNA was extracted from the vitreous fluid of 7 PVRL patients and from nodal samples of 10 DLBCL patients: 6 of germinal center B‐cell (GCB) type and 4 of activated B‐cell (ABC) type determined by Hans’ criteria. Six PVRL samples showed gene expression profiles that were similar to each other. The patterns were different from those of the ABC‐type nodular DLBCL but relatively close to those of the GCB‐type nodular DLBCL. Interestingly, all of the 6 examined PVRL samples had either MYD88^L265P or mutation in the immunoreceptor tyrosine‐based activation motif (ITAM) region of CD79B. Five PVRL patients with similar gene expression profiles were treated with a standardized regimen: intravitreal administration of methotrexate (MTX) followed by six courses of systemic high doses of MTX. As a result, 2 patients had CD79B mutations and showed early central nervous system (CNS) progression. Patients without CNS progression did not have this mutation. In conclusion, PVRL had unique genetic features: an expression pattern different from ABC‐type and relatively close to GCB‐type DLBCL. CD79B mutations showed potential to serve as prognostic markers for CNS progression.     

Immunophenotype and intermediate‐high international prognostic index score are prognostic factors for therapy in diffuse large B‐cell lymphoma patients

BACKGROUND.

The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B‐cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B‐cell (ABC), and not classified (NC) diffuse large B‐cell lymphoma. This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC‐DLBCL subtypes in identifying those high‐risk patients who may benefit from a more aggressive first‐line therapeutic approach.

METHODS.

From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC‐DLBCL. GCB patients received 6 courses of rituximab, cyclophophosphamide, doxorubicin, vinicristine, and prednisone (R‐CHOP) chemotherapy, with a subsequent, autologous stem cell transplantation in case of partial response. All ABC and NC‐DLBCL patients received 6 R‐CHOP cycles and autologous stem cell transplantation.

RESULTS.

Complete response rate for each treatment arm was 84.6% for GCB and 89.7% for ABC&NC‐DLBCL (P = .50), with a continuous complete response rate of 81.8% and 84.6%, respectively (P = .59). Projected 4‐year overall survival is 100% for GCB and 82% for ABC&NC patients (P = .12). Progression‐free survival is 77% and 79% (P = .7), respectively.

CONCLUSIONS.

The autologous stem cell transplantation consolidation in the ABC&NC‐DLBCL subtypes induced the same rate of complete response (and similar progression‐free survival rate) compared with GCB‐DLBCL. In ABC&NC‐DLBCL patients the authors observed a complete response rate of 89.7% vs. 84.6% in the GCB‐DLBCL subset, without any significant difference in progression‐free survival rate. Cancer 2010. © 2010 American Cancer Society.     

bcl-2与NF-κB／p65在弥漫性大B细胞淋巴瘤不同亚型中表达的意义

 目的　探讨bcl-2与NF-κB／p65蛋白在弥漫性大B细胞淋巴瘤（DLBCL）不同亚型中的表达及其意义。方法　用免疫组织化学方法检测DLBCL患者CD10、bcl-6、MUM-1蛋白的表达,以Hans等的分型原则将其划分为GCB和非GCB／ABC亚型,同时标记bcl-2与NF-κB／p65抗体,比较bcl-2与NF-κB／p65蛋白在GCB和ABC亚型中的表达情况并分析二者与DLBCL两种主要亚型生存率的相关性。结果　bcl-2与NF-κB／p65蛋白在DLBCL中的表达率为67.1 %和77.1 %, 二者表达呈正相关;GCB亚型中bcl-2与NF-κB／p65的表达率分别为52.0 %和56.0 %,ABC亚型中bcl-2与NF-κB／p65蛋白的表达率分别为75.6 %和88.9 %,ABC亚型中bcl-2与NF-κB／p65的表达率高于GCB亚型;在GCB亚型中,bcl-2与NF-κB／p65蛋白的表达与总生存率无显著的相关性,而在ABC亚型DLBCL中,bcl-2与NF-κB／p65蛋白的表达与生存率密切相关。结论　仅在ABC亚型DLBCL中,bcl-2与NF-κB／p65蛋白的表达是影响预后的重要不利因素,因此,需在DLBCL亚分型的基础上评估bcl-2与NF-κB／p65蛋白表达的预后意义。     

Gene expression profiling of diffuse large B-cell lymphoma

Initial gene expression profiling studies of diffuse large B-cell lymphoma (DLBCL) revealed that this single diagnosis actually encompasses two distinct diseases that differ in the expression of hundreds of genes. One subtype, germinal center B-cell-like (GCB) DLBCL, strongly resembles normal germinal center B-cells and has a good prognosis following chemotherapy, whereas activated B-cell-like (ABC) DLBCL resembles mitogenically activated blood B cells and has a poor outcome. An expanded analysis of 274 DLBCL cases confirmed the existence of the GCB and ABC subgroups, but demonstrated that additional subgroups exist. Furthermore, two recurrent oncogenic events in DLBCL, t(14;18) and amplification of the c-rel locus on chromosome 2p, were only observed in GCB DLBCL, whereas constitutive activation of NF-kappaB was seen in ABC DLBCL, showing that the gene expression subgroups represent pathogenetically distinct diseases. Gene expression profiling has also been used to identify individual genes that predict overall survival in DLBCL, the majority coming from gene expression signatures that reflect the cell of origin, proliferation rate, and host immune response to the tumor. A multivariate model including 17 genes representing these biological features divided patients with DLBCL into quartiles with strikingly distinct 5-year survival rates, ranging from 73% to 15%. The use of gene expression profiling should eventually lead to an integration of molecular diagnosis and consequent selection of the most appropriate treatment.     

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.     

Cerdulatinib,a novel dual SYK/JAK kinase inhibitor,has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma

B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways.     

Characterization of genomic imbalances in diffuse large B‐cell lymphoma by detailed SNP‐chip analysis

The pathogenesis of diffuse large B‐cell lymphomas (DLBCL) is only partly understood. We analyzed 148 DLBCL by single nucleotide polymorphism (SNP)‐chips to characterize genomic imbalances. Seventy‐nine cases were of the germinal center B‐cell like (GCB) type of DLBCL, 49 of the activated B‐cell like (ABC) subtype and 20 were unclassified DLBCL. Twenty‐four regions of recurrent genomic gains and 38 regions of recurrent genomic losses were identified over the whole cohort, with a median of 25 imbalances per case for ABC‐DLBCL and 19 per case for GCB‐DLBCL. Several recurrent copy number changes showed differential frequencies in the GCB‐ and ABC‐DLBCL subgroups, including gains of HDAC7A predominantly in GCB‐DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 predominantly in ABC‐DLBCL (35%), hinting at disparate pathogenetic mechanisms in these entities. Correlating gene expression and copy number revealed a strong gene dosage effect in all tumors, with 34% of probesets showing a concordant expression change in affected regions. Two new potential tumor suppressor genes emerging from the analysis, CASP3 and IL5RA, were sequenced in ten and 16 candidate cases, respectively. However, no mutations were found, pointing to a potential haploinsufficiency effect of these genes, considering their reduced expression in cases with deletions. Our study thus describes differences and similarities in the landscape of genomic aberrations in the DLBCL subgroups in a large collection of cases, confirming already known targets, but also discovering novel copy number changes with possible pathogenetic relevance.     

Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling.

Constitutive activation of the NF-kappaB pathway is required for survival of the activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IkappaB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell-like DLBCL. Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-kappaB, confirming the effectiveness and specificity of this compound. Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle. To test further the specificity of this toxicity, an inducible form of NF-kappaB was created by fusing the p65 NF-kappaB subunit with the ligand-binding domain of the estrogen receptor (p65-ERD). In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-kappaB target genes. Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-kappaB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-kappaB target genes. These studies validate the NF-kappaB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-kappaB for survival and proliferation.     

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.     

R-CHOP和CHOP方案治疗两种亚型弥漫大B细胞淋巴瘤患者的近期疗效

背景与目的：根据肿瘤细胞起源不同,可将弥漫大B细胞淋巴瘤（diffuselarge Bcelllymphoma,DLBCL）分为生发中心来源（germinalcenter Bcell like,GCB）及非生发中心来源（non-GCB）两种亚型。在以CHOP方案为标准的化疗基础上,前者预后优于后者。本研究通过比较R-CHOP（Rituximab联合CHOP）和CHOP方案治疗不同亚型DLBCL患者的近期疗效,寻找初诊DLBCL患者最佳一线治疗方案。方法：将2006年11月至2008年2月中山大学肿瘤防治中心内科收治的83例初治DLBCL患者分为GCB和non-GCB两组。按照修订版淋巴瘤疗效评价标准,比较接受R-CHOP或CHOP方案治疗患者的近期疗效;观察Bcl-2在两种亚型中的表达情况,并分析其与近期疗效的关系。结果：83例DLBCL患者中GCB组35例（42．2％）,non-GCB组48例（57．8％）。GCB组一线化疗近期总缓解率74．3％,non-GCB组60．4％,两组相比差异有显著性（P=0．006）。Bcl-2在GCB和non-GCB两亚组的表达差异没有显著性：Bcl-2阳性患者采用R．CHOP方案治疗的近期缓解率（75．6％）明显高于用CHOP方案治疗者（47．8％）,两组相比差异有显著性（P=0．031）：采用不同方案化疗的Bcl-2阴性患者的近期缓解率则差异无显著性（P〉0．05）。结论：GCB组患者接受标准R—CHOP或CHOP方案治疗近期缓解率高于non-GCB组,提示预后良好。加用Rituximab可提高Bcl-2阳性患者的近期缓解率。     

Cellular (FLICE) like inhibitory protein (cFLIP) expression in diffuse large B-cell lymphoma identifies a poor prognostic subset, but fails to predict the molecular subtype

Immunohistochemistry can sub‐classify diffuse large B‐cell lymphoma (DLBCL) into germinal centre B‐cell like (GCB) and non‐GCB subtypes. The latter consists predominately of the activated B‐cell like subgroup in which nuclear factor kappa‐B activation is its characteristic. Expression of cellular caspase 8 (FLICE)‐like inhibitory protein (cFLIP), a caspase 8 homologue, is regulated by nuclear factor kappa‐B signalling, and it is the main inhibitor of Fas ligand activated apoptosis. To determine if cFLIP expression was confined to non‐GCB subtype, we studied 66 cases of DLBCL. cFLIP expression showed no significant correlation to DLBCL subtypes (GCB or non‐GCB) but was associated with a worse clinical outcome. For cFLIP positive and negative patients, the five‐year event free survival was 20 and 31%, respectively (p = 0.049), and the five‐year overall survival was 20 and 57%, respectively (p = 0.041). Copyright © 2011 John Wiley & Sons, Ltd.     

Leukemic High Grade B Cell Lymphoma is Associated With MYC Translocation,Double Hit/Triple Hit Status,Transformation, and CNS Disease Risk: The Mayo Clinic Experience

Introduction: Leukemic involvement in high grade B cell lymphoma (L-HGBL) is rare and has been sparsely described in the literature. We report our experience in a large single institution multicenter academic setting. Materials and Methods: Medical records of patients with HGBL who received care at Mayo Clinic between 2003 and 2020 were reviewed. L-HGBL was confirmed by peripheral blood smear and flow cytometry with corroboration from tissue and bone marrow biopsy findings. Results: Twenty patients met inclusion criteria. All patients had significant bone marrow involvement by HGBL. Leukemic involvement presented in 11 of 20 (55%) in the de novo and 9 of 20 (45%) in the relapsed setting. Seven of 20 patients had DLBCL, NOS, 6 of 20 had transformation (t-DLBCL), 3 of 20 had transformed double/triple hit lymphoma (t-DHL/THL), 2 of 20 had double hit lymphoma (DHL), and 2 of 20 had HGBL with intermediate features between DLBCL and Burkitt lymphoma. Nine of 15 patients had MYC translocation. Based on Hans criteria, 11 of 20 had germinal center B-cell (GCB) cell of origin (COO) and 9/20 had non-GCB COO. Five of 11 de novo patients experienced CNS relapse/progression. All de novo patients received anthracycline-based chemoimmunotherapy. Eighteen of 20 patients died of progressive disease. Median overall survival was significantly better in the de novo compared to relapsed group (8.9 months vs. 2.8 months, P = .01). COO, MYC status, DHL/THL status, HGBL subtype, or treatment group did not demonstrate a significant effect on overall survival. Conclusion: L-HGBL carries a poor prognosis and is associated with MYC translocation, DHL/THL status, transformation, and high CNS risk. Novel therapeutic approaches are needed for L-HGBL.