BCR::ABL1 Kinase Domain Variant (Mutation) Status (Accredited)

 

Programme objective: To assess a laboratory's ability to qualitatively detect (and describe using standardised nomenclature) clinically relevant BCR::ABL1 kinase domain variants (mutations) using molecular methods.

 

Clinical/scientific background: The introduction of tyrosine kinase inhibitors (TKIs), initially with imatinib and subsequently further generations of TKIs, significantly changed the clinical management of patients with chronic myeloid leukaemia (CML) and to a degree those with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL).

 

Despite their clinical success, some patients experience progressive TKI resistance after an initial response. Over 100 different point mutations (variants) in the BCR::ABL1 kinase domain (KD) have been identified in CML and Ph+ ALL patients with TKI resistance. This programme focuses on detection of a subset of variants (mutations) with conclusive in vitro sensitivity and patient resistance profile evidence, which play an important role in therapeutic decision making; particularly when switching TKI treatment. Of note, the detection of the p.Thr315Ile (T315I) variant (mutation) is a poor prognosis marker conferring resistance to first and second generation TKIs.

 

Suitability: Most RNA/cDNA based molecular genetic approaches to BCR::ABL1 kinase domain variant analysis, including Sanger sequencing and NGS. Please note, this programme utilises mouse cell lines stably transfected with BCR::ABL1 cDNA constructs that do not feature introns and as such may not be compatible with some genomic DNA based assays. The current ELN guidelines (Cross et al., 2023) recommend that cDNA is used as input material for BCR::ABL1 kinase domain assays. The authors do note that high sensitivity techniques could circumvent the targeted amplification of BCR::ABL1 fusion transcripts but state a systematic comparison would be needed before gDNA strategies could be endorsed. Please contact admin@ukneqasli.co.uk if you use a genomic DNA based assay.

 

Cross, N.C.P., Ernst, T., Branford, S. et al. European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia. Leukemia 37, 2150–2167 (2023). 

 

Sample type/distribution: Two lyophilised cell line-based samples are issued three times per annum. Trial schedule can be found here: https://www.uknegasli.co.uk/ega-pt-programmes/trial-schedules/

 

Laboratories are asked to submit (using Human Genome Variation Society (HGVS) recommended standardised sequence variant nomenclature) any clinically actionable BCR::ABL1 kinase domain variant(s) detected, along with details of their methodology. The programme is qualitative; however, optional quantitative information (‘mutation load’) may also be submitted for educational purposes.

 

An additional educational sample(s) featuring a ‘low level’ variant(s) (approximately 5-20% VAF), may be included in a given distribution; however, the result of this sample(s) will not be subject to performance monitoring.

 

Instructions for the storage, reconstitution and use of the lyophilised samples are included with each sample distribution.

   

Trial duration: Trials for this programme are live/open for a minimum of 4 weeks. Please note that trials issued/closing in August or December are extended by 1 week.

 

Subcontracted areas: Pre-issue and post-closure testing of samples for this programme are currently subcontracted, although the final decision about sample suitability lies with the EQA provider; no other activities in relation to this EQA programme are subcontracted.

 

Updates to the programme for current or upcoming year: Samples will continue to be formulated with the aim of suitability for analysis by several commonly employed techniques, including Sanger sequencing (variant(s) representing >20% VAF). An additional low-level variant(s) sample(s) (5-20% target VAF) will be periodically provided as an educational exercise. Variants <5% VAF are beyond the scope of the current scheme.

 

The performance monitoring system for this programme references Human Genome Variation Society (HGVS) nomenclature v21.0.

 

To register for this programme, please clickhere. 

Example BCR::ABL1 Kinase Domain Variant (Mutation) Status Report
KDV(M) 232403 Example Report.pdf
Adobe Acrobat document [718.6 KB]
BCR::ABL1 Kinase Domain Variant (Mutation) Status Performance Monitoring System
Performance Monitoring System for KDV(M)[...]
Adobe Acrobat document [338.7 KB]
KDV(M) 242502 cover sheet
KDV(M) 242502 Coversheet final.pdf
Adobe Acrobat document [110.8 KB]

We acknowledge Dr. Paul La Rosée (University of Jena), who kindly provided some of the initial cell line material for this programme.

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Last updated 16/12/2024 © UK NEQAS for Leucocyte Immunophenotyping not to be reproduced in all or part without permission.

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