Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue

Scott, David W.; Wright, George W.; Williams, P. Mickey; Lih, Chih Jian; Walsh, William; Jaffe, Elaine S.; Rosenwald, Andreas; Campo, Elı́as; Chan, Wing C.; Connors, Joseph M.; Smeland, Erlend B.; Mottok, Anja; Braziel, Rita M.; Ott, German; Delabie, Jan; Tubbs, Raymond R.; Cook, James R.; Weisenburger, Dennis D.; Greiner, Timothy C.; Glinsmann-Gibson, Betty; Fu, Kai; Staudt, Louis M.; Gascoyne, Randy D.; Rimsza, Lisa M.

doi:10.1182/blood-2013-11-536433

Cited by 549 publications

(534 citation statements)

References 21 publications

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“…Ennek az az oka, hogy az algoritmus nem tudja 100%-os biztonsággal elkülöníteni a csoportokat, de még az R-CHOP protokollt használva is egyértelműen segít a prognózis becslésében [4]. Scott és mtsai 2014-ben közölték, hogy a Lymph2CX GEP-módszert biztonsággal lehet alkalmazni formalinfixált szöveteken, és így biztonsággal el lehet különíteni az ABC és GCB típust [5]. Később egy új prognosztikai modellt is javasolnak, amely a fentiek mellett figyelembe veszi a nemzetközi prognosztikai indexet (IPI) és a bcl-2/myc expressziót [6].…”

Section: öSszefoglaló Közleményunclassified

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

Gergely

Illés

2016

Orvosi Hetilap

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A diffúz nagy B-sejtes lymphoma a leggyakoribb a non-Hodgkin-lymphomák között. A ciklofoszfamid-vincristinadriablastin-prednisolon kemoterápiával a betegeknek már közel 50%-a meggyógyítható volt, majd a rituximab hozzáadásával a gyógyulási arány már 60% fölé emelkedett. Ez a javulás jelentős, de további növekedést kellene elérni a betegek gyógyulási arányában. Az utóbbi években elvégzett genetikai vizsgálatok számos új, a patogenezisben is szerepet játszó és terápiás célpontként is szolgáló mutációt azonosítottak a betegségben. A diagnosztika ma már rutinszerűen alkalmazza a 18-fluoro-deoxi-glükóz-pozitronemissziós komputertomográfiás vizsgálatokat a Lugano klasszifikációs rendszer részeként. Ezen adatok alapján egyre pontosabban meghatározható a betegek prognózisa, és kiválaszthatók azok a betegek, akik valamelyik új, szelektíven ható gyógyszerre esetleg reagálhatnak. Mindezeknek a kérdéseknek a megválaszolása, az újabb kezelések bevezetése várhatóan a közeli jövőben tovább fogja javítani a betegek túlélési esélyeit. Az összefoglaló közlemény áttekintést ad a közelmúlt újdonságairól, kiemeli a ma használatos és javasolt kezeléseket, továbbá áttekintést ad a jelenleg kipróbálás alatt álló és bevezetendő kezelésekről is. Orv. Hetil., 2016, 157(31), 1232-1241. Kulcsszavak: lymphoma, DLBCL, kezelés Recent advances in the understanding and treatment of diffuse large B-cell lymphomaDiffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Using the conventional cyclophosphamide adriablastin vincristin prednisolon polychemotherapy about 50% of the patients were cured. The addition of rituximab to the regimen increased the cure rate to 60%. This is a major improvement, however, further advance is still needed to increase the cure rate. The extensive genetic testing performed recently revealed several important pathognomic mutations as potential targets in this disease. Routine diagnosis of patients now includes the use of 18 Fluor-deoxy-glucose positron emission computer tomography, according to the recent Lugano classification system. With all these data we can better predict the prognosis of patients, and we can select candidates for novel targeted therapies as well. Answering these questions, and utilizing novel therapies possibly will further increase the cure rate in the near future. This paper summarizes current diagnostic and therapeutic approaches and describes recent understanding in the mutations and pathognomic changes resulting in the disease. The authors also summarize the data available on experimental therapies possibly entering clinical pratice in the forthcoming years. Keywords: lymphoma, DLBCL, treatmentGergely, L., Illés, Á. [Recent advances in the understanding and treatment of diffuse large B-cell lymphoma]. Orv. Hetil., 2016, 157(31), 1232-1241. (Beérkezett: 2016 elfogadva: 2016. május Rövidítések 18 FDG = 18-fluoro-deoxi-glükóz; ABC = aktivált B-sejtes; ADCC = antitest-közvetített sejt mediálta citotoxicitás; antiHBc = hepatitis B-vírus-mag-antigén elleni ellenanyag; ...

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Section: öSszefoglaló Közleményunclassified

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

Gergely

Illés

2016

Orvosi Hetilap

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“…These findings are very similar to those found in previous studies irrespective of the nature (fresh frozen or FFPE) of DLBCL specimens investigated. 10,13,14,21 In general, the samples showing discrepant classes by different classifiers had a low confidence score for either ABC or GCB class assignment. 13 It is possible that these cases are in a 'molecular grey zone' , and their class cannot be accurately defined, no matter which classifiers used.…”

Section: Dlbcl Coo Classification By Qrt-pcr With Fluidigm Dynamic Arraymentioning

confidence: 99%

“…[6][7][8][9] Several studies have investigated the possibility of COOclassification of DLBCL using FFPE tissues by quantitative measurement of mRNA expression, including quantitative nuclease protection assay, 10 (GEP) with the Affymetrix HG U133 Plus 2.0 platform or the Illumina whole-genome DASL assay, [11][12][13] and NanoString technology. 14 In general, these studies demonstrated high confidence of COO-classification of DLBCL using FFPE tissues and a robust separation in overall survival between ABC and GCB-DLBCL.…”

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confidence: 99%

Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR

Xue

Zeng

Gao

et al. 2015

Laboratory Investigation

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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Gene expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III subtypes, with ABC-DLBCL characterized by a poor prognosis and constitutive NF-kB activation. A major challenge for the application of this cell of origin (COO) classification in routine clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies. In this study, we investigated the possibility of COO-classification using FFPE tissue RNA samples by massive parallel quantitative reverse transcription PCR (qRT-PCR). We established a protocol for parallel qRT-PCR using FFPE RNA samples with the Fluidigm BioMark HD system, and quantified the expression of the COO classifier genes and the NF-kB targeted-genes that characterize ABC-DLBCL in 143 cases of DLBCL. We also trained and validated a series of basic machine-learning classifiers and their derived meta classifiers, and identified SimpleLogistic as the top classifier that gave excellent performance across various GEP data sets derived from fresh-frozen or FFPE tissues by different microarray platforms. Finally, we applied SimpleLogistic to our data set generated by qRT-PCR, and the ABC and GCB-DLBCL assigned showed the respective characteristics in their clinical outcome and NF-kB target gene expression. The methodology established in this study provides a robust approach for DLBCL sub-classification using routine FFPE diagnostic biopsies in a routine clinical setting. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Among the many biomarkers investigated so far, only the molecular subtypes by cell of origin (COO) classification, the MYC involved chromosome translocation and TP53 mutation, have been consistently shown to bear prognostic value in the setting of rituximab-containing chemotherapy regimens. The COO-classification by whole-genome expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III (unclassified) subtypes, with the ABC-DLBCL characterized by a poor prognosis and constitutive NF-kB activation. 1-5 The original classification was based on similarity of DLBCL gene expression to the activated peripheral blood B cells or normal germinal center B cells by hierarchical clustering analysis. 1 Subsequently, Wright et al 3 identified 27 genes that were most discriminative in their expression between ABC and GCB-DLBCL, and developed a linear predictor score (LPS) algorithm for COO-classification. These seminal works are entirely based on retrospective investigations of fresh-frozen (FF) lymphoma tissues. A major challenge for the application of this COO-classification in clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies.Several immunohist...

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“…First, data from Vancouver suggest MYC and BCL2 protein dual expressers (DEs) are at increased risk of CNS relapse. Savage et al examined the correlation between DE status, cell of origin (COO; Lymph2Cx nanostring 57 and Hans algorithm), and CNS relapse in 428 patients with de novo DLBCL treated with R-CHOP (largely without CNS prophylaxis).…”

Section: Casementioning

confidence: 99%

How I treat patients with aggressive lymphoma at high risk of CNS relapse

Chin

Cheah

2017

Blood

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Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis. (Blood. 2017;130(7):867-874) IntroductionNon-Hodgkin lymphomas are biologically and clinically diverse hematological malignancies. Treatment is influenced by patient fitness, disease biology, and tumor burden. Identifying patients at high risk of central nervous system (CNS) relapse is important as the outcome of secondary CNS lymphoma is poor. [1][2][3][4] Risk of CNS progression is influenced by histologic subtype and subtype-specific clinicopathologic features (eg, site of involvement, protein expression, or gene rearrangements). Patients with highly aggressive lymphomas (eg, lymphoblastic, Burkitt lymphoma) are at high risk and frontline protocols include CNS-directed prophylaxis. In contrast, indolent lymphomas rarely involve the CNS and CNS prophylaxis is not required. Between these extremes fall diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) with MYC and BCL2 or BCL6 rearrangements, so-called "double-hit" lymphomas (HGBL-DH), and (nodal) peripheral T-cell lymphomas (PTCLs). The addition of rituximab has slightly reduced CNS relapse in DLBCL, probably through superior systemic control as there is negligible CNS penetration of the drug across the intact blood-brain barrier. 1,5 However, ;4% of unselected patients with DLBCL treated with prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-CHOP) experience CNS relapse, 6,7 and considerable efforts have been made to identify those at greatest risk. In this review, we will summarize our approach to this problem with case vignettes drawn from our practice. How I identify patients at increased risk for CNS relapseMany investigators have examined risk factors for CNS relapse, but studies have yielded inconsistent results, due to heterogeneity in patient populations, treatment, and/or limited sample size. [8][9][10][11][12][13][14][15][16] To address some of these limitations, Schmitz et al developed a 6-point score from 2164 patients treated on prospective German studies and validated in 1597 patients with DLBCL treated with R-CHOP in the British Columbia Cancer Agency (BCCA) Lymphoid Malignancies Database. 6 The components of the s...

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Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue

Abstract: Key Points A 20-gene gene expression-based assay accurately and robustly assigns COO subtypes of DLBCL using formalin-fixed paraffin-embedded tissue.

Cited by 549 publications

References 21 publications

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR

How I treat patients with aggressive lymphoma at high risk of CNS relapse

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