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Consensus guidance for germline predisposition to haematological malignancies

The UK Cancer Genetics Group (UKCGG), CanGene-CanVar, the NHS England Haematological Oncology Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT) recently published two best practice consensus guidelines for germline predisposition to haematological malignancies in the British Journal of Haematology. In the latest UKCGG journal roundup, Nancy Whish provided a summary of the key points from the guidelines.

 

Whole Genome Sequencing and large somatic gene panels in haematological malignancies are identifying an increasing number of individuals with either potential or confirmed germline predisposition to haematological malignancy. Establishing pathways for appropriate germline confirmation with the possibility of cascade predictive testing in family members is a relatively new area of expanding clinical and laboratory work. 


Germline predisposition to haematological malignancies: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar and the NHS England Haematological Oncology Working Group.
Speight et al. (2023). British Journal of Haematology. https://doi.org/10.1111/bjh.18675

Methods

The UKCGG, CanGene-CanVar and the NHS England Haematological Oncology Working Group held a 2-day workshop to establish consensus guidelines on clinical and laboratory pathways. 

  • The workshop focussed on the management of germline pathogenic variants in DDX41, CEBPA, RUNX1, ANKRD26, ETV6 and GATA2. The genes were chosen as the focus of the meeting based on the organising committee’s experience in clinical practice and existence of research evidence. 

  • Extensive review of the literature and clinical characteristics, genetics and prevalence of established inherited predisposition to haematological malignancy syndromes generated a background document that was sent to delegates prior to the meeting. 

  • Delegates were also sent a scoping survey to assess current practice and ideas on best practice pathways. Response themes were used to create key questions to be addressed in the meeting.

    • 42% response rate (including responses from all GLHs in England, Scotland and Wales). 

Attendees (106 on day 1, 93 on day 2) came from a broad range of specialties across the UK, including patient support group representatives, clinical cancer geneticists, genetic counsellors, paediatric and adult haematologists and clinical scientists. 


A number of related polls were conducted, with proposed statements for best practice in different scenarios.

  • Consensus was reached when ≥80% respondents selected ‘Agree/Strongly Agree’ or ‘Yes’ in response to the statement posed.

  • Time was allocated for whole group discussion around each polling question for feedback, discussion and debate, which helped inform any consensus reached.

Consensus outcomes

Somatic reporting

  • Consensus reached that a statement on the report suggesting possible germline origin of a variant should be considered for any variant where a confirmed germline finding would have potential clinical significance, especially if the variant allele frequency is >30%.

Confirmatory/predictive germline testing process

Sample selection

Patient information

Referral to clinical genetics

Age of predictive testing

Management of carriers

Key Recommendations

  1. There should be close liaison between somatic and germline teams for variant interpretation.

  2. There is a need for MDT working to provide the best patient care.

  3. Prospective data should be collected to inform future best practice.

  4. gene-specific guidance is required for the management of carriers and more evidence regarding the utility of screening in this patient group is needed. 

Unique challenges arose related to donor selection for those patients requiring allogenic transplant when potential related donors carry/are at risk of inheriting a constitutional variant predisposing to haematological malignancy.
Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).
Clark et al. (2023). British Journal of Haematology https://doi.org/10.1111/bjh.18682

Methods

Following on from the consensus meeting outlined in the above publication, a specific workshop was arranged to discuss the impact of germline predisposition to haematological malignancies on specific issues related to allogeneic BMT and reach consensus on management of these issues, particularly in relation to the testing and selection of related donors.


The organising committee included representation from four national collaborative groups:

  • The British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT),

  • UKCGG,

  • CanGene-CanVar research programme (CGCV), and

  • The NHS England GLH Haematological Malignancies Working Group.

Invitations to the workshop were sent to attendees of the previous consensus meeting, as well as additional key stakeholders and clinicians with specialist expertise in bone marrow transplantation.

  • No patient representatives participated in this meeting.

The organising committee generated statements upon which to gather consensus based on their expertise.

  • Consensus agreement was set at a threshold of ≥80% of at least 40 respondents selecting ‘agree’/‘strongly agree’.

  • Statements were debated and rephrased in real time in order to reach consensus if possible.

  • Of 82 participants, 66 participated in the in-meeting polling.

Consensus Recommendations

Patients requiring BMT should be assessed for a potential heritable cause for their phenotype

Timescales

  • For patients being considered for BMT, there is an urgency to identify genetic variation. Where germline status in a patient has already been confirmed, testing of potential related donors for the variant may occur simultaneously with tissue typing. In urgent situations, germline testing of potential donors can proceed in parallel with confirmatory testing in the patient.

  • Where there are concerns about possible or confirmed heritable risk, search and testing of unrelated volunteer donor (VUD) should happen in parallel with evaluation of related donors to allow donor options to be assessed without delay.

Donor selection

Genetic counselling

Considering VUS

Awareness and resources

 

References

1. Speight, B, Hanson, H, Turnbull, C, Hardy, S, Drummond, J, Khorashad, J, et al. Germline predisposition to haematological malignancies: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar and the NHS England Haematological Oncology Working Group. Br J Haematol. 2023; 00: 1– 10. https://doi.org/10.1111/bjh.18675

2. Clark, A, Thomas, S, Hamblin, A, Talley, P, Kulasekararaj, A, Grinfeld, J, et al. Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT). Br J Haematol. 2023; 00: 1– 10. https://doi.org/10.1111/bjh.18682

 

Acknowledgement

Thank you to the UKCGG Social Media & Communications Sub-Committee, in particular Nancy Whish, whom prepared this summary overview of the publications for the UKCGG/ERN GENTURIS/ICARE Monthly Journal Round-Up, February 2023.

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