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
Consensus reached that best practice would be to undertake diagnostic germline confirmatory testing in the proband prior to offering cascade germline testing to relatives, although this may not be feasible in all situations.
Sample selection
Fibroblast-derived DNA from a skin biopsy was shown to be the most common sample type used in both routine and time-sensitive situations.
Consensus reached that this is best practice/first option in list of possible sample types.
Practice does and will continue to depend on the clinical situation.
Patient information
Consensus reached that it is appropriate to inform patients of the possibility of finding a germline genetic variant when arranging genetic testing of patients with a known haematological disorder.
One patient representative wrote: ‘Us patients want to know what you might find. Whether or not we want to know what you did find is a separate issue, but if you are doing any test on a patient, you must tell them what it might show’.
Referral to clinical genetics
Consensus reached that it is preferable that the Haematology team arrange confirmatory testing of a likely pathogenic/pathogenic variant of potential germline origin in time sensitive situations.
Strong consensus that a referral to Clinical Genetics for genetic counselling is appropriate for all identified carriers and relatives as part of offering predictive testing, regardless of age or whether the relative is a potential bone marrow transplant donor.
Age of predictive testing
Best practice considered to be assessment on a case-by-case basis.
Regarding DDX41, delegates felt it would rarely be appropriate to consider predictive testing before adulthood.
Management of carriers
Consensus reached that all identified carriers of germline variants who develop a blood phenotype be referred to Haematology for monitoring and follow-up.
A minority of centres are currently offering screening to heterozygous carriers of CEBPA, ANKRD26, ETV6, GATA2, DDX41 and RUNX1.
No consensus reached on whether to offer screening to heterozygous carriers with no blood phenotype or what the type or frequency of screening should involve.
Key Recommendations
There should be close liaison between somatic and germline teams for variant interpretation.
There is a need for MDT working to provide the best patient care.
Prospective data should be collected to inform future best practice.
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
While every effort should normally be made to avoid using a carrier family member as a donor there may be situations where this is unavoidable, or uncertainty remains, for instance if a potential familial donor declines site-specific testing for the familial variant, or if the variant identified in the proband is of uncertain significance.
Where all related matched donors are either carriers or decline testing, careful assessment of risks and benefits of an unrelated donor versus a carrier family member/untested family member requires discussion at a MDT meeting with access to expert opinion and consideration on a gene-specific basis.
Genetic counselling
Dedicated, skilled genetic counselling in this area remains the ‘gold standard’ and this should become an essential component of future integrated haematological oncology service design.
Considering VUS
When a Class 3 VUS is identified then further assessment of clinical status and family history is warranted to inform MDT discussions
If MDT decision is made to test for VUS in relatives to inform transplant options then relatives should be offered genetic counselling to ensure they understand the uncertainty and outcomes of testing.
Awareness and resources
Need for education and guidance for HCPs working in transplant on the clinical significance of these genes.
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.