Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Cancer 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)

Abstract

Summary Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high‐throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD‐box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non‐malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene‐CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).

Implementation of and Systems-Level Barriers to Guideline-Driven Germline Genetic Evaluation in the Care of Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia

“…With the yield of germline genetic testing for known HMMSs in patients with MDS/AML being similar to germline genetic testing yields in other cancers for which testing is recommended for all, 29-31 a universal screening strategy has been proposed in which all patients diagnosed with MDS/AML undergo germline evaluation, regardless of their personal or family history. 15,16,32 Our data, showing that the majority of patients with newly diagnosed MDS/AML will meet NCCN guidelines for germline genetic testing and that nearly all who are evaluated and counseled will elect to proceed, support such a universal genetic testing approach. However, despite our QI committee increasing awareness of HMMSs, providing formalized recommendations for Genetics referral, and having accessible, trained HMMS-focused genetic counselors and cancer geneticists, only approximately 30% of patients meeting criteria were ultimately referred.…”

Rare Hematologic Malignancies and Pre-Leukemic Entities in Children and Adolescents Young Adults

“…Broadly, these may be classified as germline predisposition syndromes with or without pre-existing platelet disorders or a risk of organ dysfunction ( Table 8 ). Constitutional pathogenic variants in DDX41 , ETV6 , CEBPA , RUNX1 , ANKRD26 , and GATA2 are especially prone to an increased risk of developing hematologic malignancies [ 154 ]. The clinical presentation of the syndromes is variable but may include isolated cytopenias or pancytopenia, with or without bone marrow failure [ 155 ].…”

“…Allo-HSCT is often considered for a cure. International best practice consensus guidelines detailing recommendations on the HSCT timeline, genomic assessment, donor selection, and genetic counseling have been published [ 154 ]. Briefly described below are the rare entities among these syndromes.…”

Extent of investigation and management of cases of ‘unexplained’ mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus

“…This approach has been successfully implemented for several other UKCGG-led national consensus meetings to generate clinical guidelines. [30][31][32][33][34]…”