Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma.
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SUBMITTER: Yu H
PROVIDER: S-EPMC8620941 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma.
Yu Hui H Sotillo Elena E Harrington Colleen C Wertheim Gerald G Paessler Michele M Maude Shannon L SL Rheingold Susan R SR Grupp Stephan A SA Thomas-Tikhonenko Andrei A Pillai Vinodh V
American journal of hematology 20161121 1
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Project description:Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. It is unknown whether copy-neutral loss of heterozygosity (CN-LOH) contributes to the pathogenesis of this tumor. To get insight into the CN-LOH landscape of PMBL, we performed Single Nucleotide Polymorphism array (SNPa) analysis of two PMBL-derived cell lines and 33 primary tumors. The study uncovered large-scale CN-LOH lesions in both cell lines and 90.9% (30/33) of primary tumors. The latter cases showed 133 CN-LOH stretches of size >25Mb which affected up to 14 chromosomes per case (mean of 4.4). Involvement of chromosomal segments was predominant (81.2%), which, in a heterozygous diploid context, suggests the implication of B-cell specific crossover events. Further analysis indicated that the CN-LOH lesions were triggered by one or two consecutive molecular hits. Notably, CN-LOH segments were non-randomly clustered on chromosome 6p (60%), 15 (37.2%) and 17q (40%). Preliminary whole-exome sequencing data yielded coincidence of these lesions with mutations in MHC I and histon-related genes (6p21), B2M (15q15) and GNA13 (17q23), respectively. We hypothesize that CN-LOH-associated hits occurred early during lymphomagenesis, following mutagenesis but preceding genomic gains. Screening of the cohort of 2,658 cancer whole-genomes revealed that the CN-LOH landscape in PMBL is unique and distinguishes this tumor from other malignancies. Altogether, CN-LOH lesions rank as the most frequent genetic defect identified so far in this disease and the CN-LOH landscape suggest a hitherto undescribed mitotic recombinational driver. The aberrations affect the expression of key driver genes and functionally alternate genomic deletions which are infrequent in PMBL.
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Project description:PurposePatients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade.MethodsIn the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity.ResultsThe objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.ConclusionPembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.
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Project description:BackgroundThe upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib.MethodsRelapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD).ResultsWe analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable.ConclusionsRuxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification.Trial registrationThe study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).
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Project description:Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). PMBCL comprises approximately 10% of DLBCLs, thus making it a rare variant of DLBCL. Cure rates for PMBCL with upfront regimens like DA-REPOCH exceed 90%. However, if there is a poor response to this first-line therapy, relapsed/refractory PMBCL (rrPMBCL) has limited treatment options. The historic trend is to treat rrPMBCL with salvage regimens commonly used for DLBCL followed by high-dose therapy and autologous stem cell transplant (HDT-ASCT); however, response rates to salvage therapy remain low and few patients are able to proceed to transplant. An interesting feature of PMBCL is that even though it is classified as a subtype of DLBCL, PMBCL actually shares many clinical, pathologic, and genetic features with classical Hodgkin lymphoma (cHL). For example, both frequently express program death ligand 1 and 2 (PD-L1/2), which is not seen in other mature B-cell lymphomas. The expression of PD-L1/2 in PMBCL makes PDL1 inhibitors, such as pembrolizumab, an attractive therapeutic target. Pembrolizumab is an effective and well-tolerated therapy now approved for a number of cancer types from advanced melanoma to relapsed/refractory cHL. There are now multi-institutional trials underway assessing the role of pembrolizumab in the treatment of rrPMBCL.
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Project description:High-throughput sequencing of cell-free DNA (cfDNA) has emerged as a promising noninvasive approach in lymphomas, being particularly useful when a biopsy specimen is not available for molecular analysis, as it frequently occurs in primary mediastinal large B-cell lymphoma (PMBL). We used cfDNA for genomic characterization in 20 PMBL patients by means of a custom NGS panel for gene mutations and low-pass whole-genome sequencing (WGS) for copy number analysis (CNA) in a real-life setting. Appropriate cfDNA to perform the analyses was obtained in 18/20 cases. The sensitivity of cfDNA to detect the mutations present in paired FFPE samples was 69% (95% CI: 60-78%). The mutational landscape found in cfDNA samples was highly consistent with that of the tissue, with the most frequently mutated genes being B2M (61%), SOCS1 (61%), GNA13 (44%), STAT6 (44%), NFKBIA (39%), ITPKB (33%), and NFKBIE (33%). Overall, we observed a 75% concordance to detect CNA gains/losses between DNA microarray and low-pass WGS. The sensitivity of low-pass WGS was remarkably higher for clonal CNA (18/20, 90%) compared to subclonal alterations identified by DNA microarray. No significant associations between cfDNA amount and tumor burden or outcome were found. cfDNA is an excellent alternative source for the accurate genetic characterization of PMBL cases.
| S-EPMC9324191 | biostudies-literature
Project description:Micro RNAs (miRNAs) are a class of small, non-coding RNAs that post-transcriptionally control the translation and stability of mRNAs. In our study, we found a higher level of miR-92a in PMBL versus DLBCL. A bioinformatics approach combining in silico prediction and transcriptomic analyses on patient samples and transduced cell lines, enabled us to identify miR-92a target genes in PMBL.
2016-12-18 | E-MTAB-4165 | biostudies-arrayexpress
Project description:BackgroundPrimary mediastinal large B-cell lymphoma (PMBL) shares pathological features with diffuse large B-cell lymphoma (DLBCL), and molecular features with classical Hodgkin lymphoma (cHL). The miR-17~92 oncogenic cluster, located at chromosome 13q31, is a region that is amplified in DLBCL.MethodsHere we compared the expression of each member of the miR-17~92 oncogenic cluster in samples from 40 PMBL patients versus 20 DLBCL and 20 cHL patients, and studied the target genes linked to deregulated miRNA in PMBL.ResultsWe found a higher level of miR-92a in PMBL than in DLBCL, but not in cHL. A combination of in silico prediction and transcriptomic analyses enabled us to identify FOXP1 as a main miR-92a target gene in PMBL, a result so far not established. This was confirmed by 3'UTR, and RNA and protein expressions in transduced cell lines. In vivo studies using the transduced cell lines in mice enabled us to demonstrate a tumor suppressor effect of miR-92a and an oncogenic effect of FOXP1.A higher expression of miR-92a and the down-regulation of FOXP1 mRNA and protein expression were also found in human samples of PMBL, while miR-92a expression was low and FOXP1 was high in DLBCL.ConclusionsWe concluded to a post-transcriptional regulation by miR-92a through FOXP1 targeting in PMBL, with a clinico-pathological relevance for better characterisation of PMBL.
| S-EPMC5369960 | biostudies-literature
Project description:Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.
| S-EPMC6265647 | biostudies-literature
Project description:IntroductionPrimary mediastinal large B-cell lymphoma (PMBL) is a rarely occurring lymphoid malignancy which typically affects young adults and presents itself as an anterior mediastinal mass. Gene expression profiling as well as somatic genetic analysis revealed that it is closely related to classical Hodgkin lymphoma, whereas morphologically, it tends to resemble diffuse large B-cell lymphoma. Familial clustering of PMBL is rare - only two reports have been published to date. While it is generally accepted that positive family history is associated with increased risk of developing a lymphoma, genetic risk factors which might predispose to PMBL are largely unknown.Case presentationWe performed germline and tumor genetic analyses by whole-exome sequencing and array-CGH of a family, in which the father and the son both developed a PMBL. Germline investigations of both affected patients and of their two unaffected family members have not been able to provide a single risk factor associated with lymphoma predisposition. In addition, genes that were previously implicated in increased risk for PMBL, namely MLL (KMT2A) and TIRAP, were found to be intact in all investigated family members. Somatic genetic investigations identified known as well as novel genetic aberrations in tumors of the affected subjects.ConclusionWe conclude that predisposition to a PMBL might be inherited through a combination of low- or moderate-risk factors and provide a shortlist of the most likely selected candidates, which can be used in future studies.
| S-EPMC10733924 | biostudies-literature