Abstract Background: Current clinical guidelines recommend evaluation for suspected hereditary myeloid malignancy predisposition syndromes (HMMPS) in an increasing number of clinical scenarios. This has correlated with the growing focus on the role that inheritance may play in the pathobiology of both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), with recent studies suggesting a higher preponderance of HMMPS occurring than previously recognized. Next Generation Sequencing (NGS) is now part of the routine workup for newly diagnosed MDS and AML patients and has helped to identify potential germline mutations. There is limited data about the referral utilization for clinical cancer genetics in patients with newly diagnosed AML. Prior smaller studies have evaluated this question in patients with both AML and MDS, with 8/27 younger patients (Smith et al, 2020) and 59/90 of pediatric and adult patients (Banaszak et al, 2024) identified that should have been recommended for genetics referral. Our goal was to determine this rate for our own institution and to acquire baseline data on appropriate referrals. Methods: This single-center experience included all newly diagnosed de novo AML patients at the Mount Sinai Health System from 1/2015-7/2022. Patients with a prior history of MDS or myeloproliferative neoplasms were excluded. Somatic NGS was performed via various commercial platforms. Manual chart review was performed, including comprehensive clinical, pathology, and molecular data, in order to determine appropriateness for referral to Cancer Genetics at Mount Sinai if they met the following criteria adopted from the National Comprehensive Cancer Network (NCCN) guidelines: Age 50 years, additional cancer history, a relative with MDS or AML or other hematologic malignancy, pathogenic mutations with variant allele frequency (VAF) ≥ 40% at both diagnosis and in remission, clinical symptoms of a hereditary myeloid neoplasm, or harboring mutations in DDX41, CEBPA, GATA2, BRCA1/2, ANKRD26. Results: We identified 363 patients with newly diagnosed de novo AML, n=172 female and n=191 male. From this cohort, 38.3% (139/363) met criteria for referral to clinical genetics based on NCCN guidelines, while 32.2% (117/363) did not. Among the 107 remaining patients (29.5%), 47 either did not have NGS performed (n=40) at diagnosis, or the NGS done did not list the VAF (n=7); 60 patients had NGS with ≥1 mutation with a VAF of ≥ 40%, though they did not have a follow up NGS sample done while in remission, making it difficult to discern if the mutation was somatic or germline. Out of the 137 who met criteria for referral, only 9 (6.6%) patients were referred to genetics, with 4 of those confirmed to have a germline mutation by skin biopsy. Many patients met more than one criterion for referral. Among the overlapping reasons to recommend genetics referral, 76 were for age 50 years, 59 were for having a prior malignancy (most common: n=15 breast cancer, n=15 prostate cancer), germline associated mutations included: CEBPA (n=13), DDX41 (n=5), GATA2 (n=3). Eight patients had a family history of hematologic malignancy (n=6 leukemia). No patients had documented clinical symptoms suggestive of HMMPS. Discussion: To our knowledge, this is the largest retrospective review of AML to date to identify patients who should ideally have been referred to clinical cancer genetics to ascertain whether a hereditary component to their disease was present. Despite the change in guidelines which may render some of these patients newly eligible for referral, our data indicate that only a small fraction of our historic patients were referred, and highlights the need for standardization of referral streams and increased awareness among providers as to the criteria for appropriate referrals. Given the need to optimize transplant planning for patients with HMMPS and increase screening for their families, a comprehensive education initiative is planned for fellows and leukemia/transplant faculty. Planned analyses include the change in referral rate pre- and post-education, measures of clinical burden from increased referral volume to our clinical geneticists, and increased health care costs/utilization for clinic visits and skin biopsies from the expanded eligibility guidelines. In conclusion, we have identified a critical gap in the care of patients with suspected HMMPS and are developing strategies for improvement in the delivery of care to this population.
Brander et al. (Mon,) studied this question.