ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia

Ghia, Paolo; Stamatopoulos, Kostas; Belessi, Chrysoula; Moreno, Carol; Stilgenbauer, Stephan; Stevenson, Freda K.; Davi, Frédéric; Rosenquist, Richard

doi:10.1038/sj.leu.2404457

Cited by 220 publications

(186 citation statements)

References 22 publications

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“…Biologic work-up, including minimal residual disease (MRD) in CR patients, is detailed in the Supporting Information [15][16][17][18][19][20][21][22].…”

Section: Methodsmentioning

confidence: 99%

Chlorambucil plus rituximab with or without maintenance rituximab as first‐line treatment for elderly chronic lymphocytic leukemia patients

et al. 2014

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In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m 2 /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m 2 ; cycles 4-8, 500 mg/ m 2 ). Responders were randomized to 12 8-week doses of R (375 mg/m 2 ) or observation. As per intention-totreat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; 75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.

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“…Biologic work-up, including minimal residual disease (MRD) in CR patients, is detailed in the Supporting Information [15][16][17][18][19][20][21][22].…”

Section: Methodsmentioning

confidence: 99%

Chlorambucil plus rituximab with or without maintenance rituximab as first‐line treatment for elderly chronic lymphocytic leukemia patients

et al. 2014

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“…17,36 For this, genomic DNA was prepared from cryopreserved cells and IGHV gene rearrangements were amplified in duplicate by multiplex PCR using a mixture of heavy chain variable region framework 1 (VHFR1; VH1-VH6) family primers in combination with a consensus heavy chain joining region (JH) primer, as designed by the BIOMED-2 Concerted Action 37,38 and according to the recommendations of the ERIC group (European Research Initiative on CLL, http://www.ericll.org). 39 After amplification, PCR products were purified and directly sequenced. Sequencing analysis was started using the consensus JH primer as the sequencing primer on PCR products from the two independent reactions.…”

Section: Patient Cohort and Classificationmentioning

confidence: 99%

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

et al. 2010

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Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a 1 H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n ¼ 29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n ¼ 9). Differences in metabolic profiles between unmutated (UM-IGHV; n ¼ 10) and mutated IGHV (M-IGHV; n ¼ 19) patients were determined using partial least square discriminatory analysis (PLS-DA; R 2 ¼ 0.74, Q 2 ¼ 0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with diseaserelated metabolic profiles. Our results highlight the usefulness of 1 H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.

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“…4 These recommendations detailed the various steps and minimum requirements for reliable and reproducible analysis of the rearranged IGHV genes in CLL with the aim of precisely determining the actual mutational status for each individual patient. The guidelines emphasize the need for determination of the mutational status of a functional IGHV gene involved in a productive (and supposedly expressed) IGHV/immunoglobulin heavy diversity immunoglobulin heavy joining (IGHV/IGHD/ IGHJ) rearrangement, thereby requiring the amplification and sequence analysis of the entire variable heavy complementaritydetermining region 3 (VH CDR3).…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, as for any mathematical cutoff value used for assessing a biological phenomenon, great caution is warranted when dealing with cases of 'borderline' mutational status. 4 Occasionally, a straightforward interpretation of the sequencing results is not possible because of various types of 'problems'. There are three main categories of 'problematic' cases: (1) those in which only a single unproductive IGHV/ IGHD/IGHJ rearrangement is amplified; (2) those in which double rearrangements with discordant mutational status are coamplified; and (3) those in which the VH CDR3 lacks critical residues (VH CDR3 'anchors', as defined by IMGT, the international ImMunoGeneTics Information system; 5,6 see http://imgt.cines.fr/textes/IMGTScientificChart/), which are crucial for the structural integrity of the antigen-binding loop.…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

et al. 2011

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Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called 'problematic sequences' that do not fit the 'classic' interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication.

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ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia

Cited by 220 publications

References 22 publications

Chlorambucil plus rituximab with or without maintenance rituximab as first‐line treatment for elderly chronic lymphocytic leukemia patients

Chlorambucil plus rituximab with or without maintenance rituximab as first‐line treatment for elderly chronic lymphocytic leukemia patients

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

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