Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations

Rosenquist, Richard; Ghia, Paolo; Hadzidimitriou, Anastasia; Sutton, Lesley-Ann; Agathangelidis, Andreas; Baliakas, Panagiotis; Darzentas, Nikos; Giudicelli, Véronique; Lefranc, Marie‐Paule; Langerak, Anton W.; Belessi, Chrysoula; Davi, Frédéric; Stamatopoulos, Kostas

doi:10.1038/leu.2017.125

Cited by 127 publications

(144 citation statements)

References 32 publications

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“…Pretreatment peripheral blood mononuclear cells (PBMC) were available from all patients, with matching posttreatment samples as outlined in Figure a . The IGHV mutation status was determined according to the most recent European Research Initiative on CLL recommendations with deletions 13q, 11q and 17p, as well as trisomy 12 analyzed by interphase fluorescence in situ hybridization using Vysis probe sets (Abbott Molecular, Lake Bluff, IL). The proportion of CLL cells in the samples was assessed by flow cytometry using CD5/CD19/CD23/CD45 staining.…”

Section: Methodsmentioning

confidence: 99%

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

Gángó

Alpár

Gálik

et al. 2019

Intl Journal of Cancer

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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or with TP53 defect, with BTK and phospholipase C gamma 2 (PLCG2) mutations representing the predominant mechanisms conferring secondary ibrutinib resistance. To understand the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment, an ultra‐deep next‐generation sequencing analysis of 30 recurrently mutated genes was performed on sequential samples of 20 patients, collected before and during single‐agent ibrutinib treatment. Mutations in the SF3B1, MGAand BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in posttreatment samples. Besides the canonical mutations, four novel BTK mutations and three previously unreported PLCG2 variants were identified. BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR and were detectable on average 10.5 months before clinical relapse. With a median follow‐up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease progression based on clinical and/or laboratory features. In conclusion, subclonal heterogeneity, dynamic clonal selection and various patterns of clonal variegation were identified with novel resistance‐associated BTK mutations in individual patients treated with ibrutinib.

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Section: Methodsmentioning

confidence: 99%

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

Gángó

Alpár

Gálik

et al. 2019

Intl Journal of Cancer

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“…The BIOMED‐2 primers, which is the more established primer set, provides efficient detection of clonal patterns, while the IGHV ‐leader primer set allows for sampling of the entire IGHV region. Although methods using both primer sets have been recommended, in their most recent guidelines, the European Research Initiative on CLL (ERIC) have recommended the Leader primer set be employed for the analysis of IGHV mutational status in CLL (Rosenquist et al , ). The resulting data are then aligned to germline sequences from databases, such as Immunogenetics Information System V‐Query and Standardization Alignment Tool (IMGT/V‐Quest) [http://imgt.cines.fr] and the per cent variation from germline calculated.…”

Section: Immunoglobulin Heavy Chain Variable (Ighv) Gene Sequencing mentioning

confidence: 99%

Molecular pathogenesis of chronic lymphocytic leukaemia

Crassini¹,

Stevenson²,

Mulligan

et al. 2019

Br J Haematol

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Summary Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.

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“…Az átrendeződött immunglobulin-nehézlánc variábilis régiójában (IGHV) megtalálható szomatikus hipermutá-ciók (SHM) vizsgálata (IGHV-mutáció-analízis) CLLben régóta elterjedt, az IGHV-mutációs státusz ugyanis a kezdeti tanulmányok óta stabilan az egyik legerősebb prognosztikus, valamint prediktív biomarker [30]. Megközelítőleg a CLL-es betegek fele hordoz mutálatlan IGHV-t (unmutated CLL, U-CLL).…”

Section: Az Ighv-státuszunclassified

“…A standardizált IGHV-státusz elterjedése ahhoz a felismeréshez vezetett, hogy a betegek harmadában úgymond identikus/sztereotíp immunglobulin expresszálódik, amit a nehézlánc úgyneve-zett "complementarity determining region 3" (CDR3) specifikus szekvencia motívumai alapján úgynevezett "subset"-ekbe, alosztályokba sorolhatunk. Ezen alosztá-lyok biológiai és klinikai paramétereket tekintve meglepően homogén csoportokba sorolják a betegeket, a sztereotíp subset #2 (IGHV3-21/IGLV3-21) például SHM jelenlététől függetlenül az agresszív kórlefolyás erős prediktora [30].…”

Section: Az Ighv-státuszunclassified

“…Mivel az IGHV-státusz a CLL lefolyása során nem vál-tozik, továbbá számos tanulmány alapján egy erős prognosztikus és prediktív biomarker, vizsgálata továbbra is a nemzetközi ajánlások részét képezi, amely a mutációs státusz vizsgálata mellett a jövőben feltehetően a sztereotíp alosztályokba sorolással is kiegészül majd [30]. A vizsgálat eredménye -amellett, hogy előrevetíti a kórle-folyást -befolyásolja a monitorozás gyakoriságát és az első vonalbeli terápia modalitásának megválasztását is [18].…”

Section: Az Ighv-státuszunclassified

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A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

et al. 2017

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A krónikus lymphocytás leukaemia (CLL) heterogén klinikai lefolyású lymphoproliferativ betegség, amelyben számos klinikai és molekuláris prognosztikai marker nyújt segítséget a leghatékonyabb terápia megválasztásában. Eddig a TP53-defektus bizonyult kulcsfontosságú prognosztikai és prediktív faktornak, amely befolyásolja a terápiás döntést, különösen az új célzott kezelések érájában. A tünetmentes, korai stádiumú betegek nem igényelnek kezelést, követé-sük javasolt (úgynevezett "watch and wait"). Első vonalban a standard rizikójú CLL-es betegek többségében a standard kezelés továbbra is a kemo-immuno terápia. Az új orálisan alkalmazható kis molekulájú gyógyszereknek, mint a kinázinhibitorok (KI) és a Bcl-2-gátlók (ibrutinib, idelalisib és venetoclax), elsősorban relabáló/refrakter CLL kezelésében van helyük, ez alól kivétel az ibrutinib-monoterápia, amely a nagy rizikójú (TP53-defektust hordozó) betegek első vonalbeli kezelésére is javasolt. A nem túl távoli jövőben az új generációs szekvenálás diagnosztikába történő integrálása támogathatja majd a CLL-es betegek személyre szabott ellátását és az optimális kezelési stratégia megvá-lasztását. Orv Hetil. 2017; 158(41): 1620-1629.Kulcsszavak: krónikus lymphocytás leukaemia, prognosztikai marker, TP53-defektus, kemo-immuno terápia, célzott kezelés, ibrutinib, venetoclax State of the art molecular diagnostics and therapy of chronic lymphocytic leukaemia in the era of new targeted therapiesChronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients. New classes of drugs like kinase inhibitors and BCL-2 inhibitors (ibrutinib, idelalisib and venetoclax) are the treatment of choice in CLL patients with relapsed/refractory disease, with the exception of high risk disease, where the optimal treatment is frontline ibrutinib monotherapy. In the near future, integrating next generation sequencing into the routine diagnostics would help the development of individual CLL patient management and to choose an optimal treatment strategy.

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Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations

Cited by 127 publications

References 32 publications

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

Molecular pathogenesis of chronic lymphocytic leukaemia

A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

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