Outcomes of Germline Genetic Testing in Children with Hematologic Malignancies Undergoing Allogeneic Transplantation
Authors: Pandey Arti S. , Mostafavi Roya , Lewis Sara , McGee Rose , Blake Alise , Hines-Dowell Stacy , Taylor Leslie , Grieve LilyAnne , Perrino Melissa , Triplett Brandon M , Nichols Kim E. 
Published: December 2024

Allogeneic hematopoietic cell transplantation (HCT) is an established therapeutic strategy for many hematologic malignancies (HM). Consideration of heritable predisposition to HM is especially relevant for decision-making in HCT when family members are being considered as donors. For example, germline pathogenic variants (PV) are estimated to be present in up to 14% of patients with acute myeloid leukemia (AML) (Guijarro F et. al., Blood Adv, 2023) and 4% of those with acute lymphoid leukemia (ALL) (Bloom M et al. 2020 Expert Rev Hematol, 2020). Nevertheless, it remains unclear how often patients being considered for HCT undergo genetic evaluation and whether the information is used in real-world clinical practice. To address this gap, we investigated the outcomes of cancer predisposition evaluation and germline genetic testing (GGT) for pediatric patients with HM undergoing HCT.
Retrospective data were gathered through record review for pediatric patients with HM (AML, ALL, myelodysplastic syndrome) undergoing HCT at St. Jude Children's Research Hospital between 1/1/2017 and 12/31/2023. Descriptive data analysis was done using the R statistical program. Genetic counseling and GGT for genes associated with cancer predisposition (CP), bone marrow failure (BMF), and/or primary immunodeficiency (PID) were offered. Variants of uncertain significance in genes associated with hereditary HM (VUS-HM) were also explored.
Of 287 HCT recipients, 224 (78%) met with a genetic counselor and 189 (66%) underwent GGT. GGT was completed before the 1st, 2nd or 3rd transplants in 140 (74%), 20 (11%) and 1 (0.5%) case, respectively, and after the final transplant in 28 (15%). Among these recipients, 34 (18%) tested positive for a PV and 37 (19.6%) harbored a VUS-HM. Genes with PV and VUS-HM aligned with the recipient's HM in 11/34 (32%) and 13/37 (35%) cases. Two VUS, one in BRCA2 and one in ETV6, were subsequently upgraded to likely pathogenic based on internal laboratory data and persistent thrombocytopenia/leukemia, respectively. Thus, the diagnostic yield of GGT was 36/189 (19%) with 12/36 (33%) PV aligning with the clinical presentation.
Of the 34 recipients with a PV in a CP, BMF or PID gene, 25 underwent transplantation using a family donor (FD), among whom 4 (16%) were positive for the same PV. One FD underwent GGT 12 years after her son's HCT and tested positive for the CEBPA PV present in her son. He developed donor-derived AML and underwent a 2nd HCT using a FD negative for the CEBPA PV and remains in remission 7 years later. A patient with B-ALL and an ATM PV received HCT from a FD harboring the ATM PV and is in remission 4 years post-HCT. Two FDs harbored germline PVs, one in ELP1 and the other in MUTYH. The FD with an ELP1 PV was chosen as donor for a B-ALL patient with germline FANCA and ELP1 PVs, since the only other FD carried the FANCA PV; this recipient died 1-year post-HCT. Finally, a FD with a MUTYH PV was chosen due to the lack of other donor options; the patient died 1-year post-HCT. Among 19 recipients harboring VUS-HM, 4 FD underwent GGT for the VUS-HM and were negative. Testing was not deemed indicated for 15 FD based on absence of the relevant clinical phenotype (e.g., in NF1, PTPN11) or normal blood counts (e.g., ANKRD26, RUNX1).
In conclusion, almost one in five recipients undergoing GGT were carriers of a PV, with most PVs involving genes not generally associated with the child's HM. Since not all patients were seen by a genetic counselor, it is possible that the prevalence of germline PV is greater than reported. Given the high incidence of germline PV in this population, it is critical that both recipients and FD are evaluated as early as possible in the transplantation evaluation process for the presence of PV and concerning VUS, such as those affecting HM genes, to ensure optimal donor selection, minimize post-HCT adverse events, enable surveillance for subsequent malignancies, and inform genetic counseling and GGT testing of relatives. While the implications following use of FD with PV affecting HM genes are well understood, further study is needed to elucidate the impacts of using FD harboring PV in genes not generally associated with HM (e.g., BRCA1, BRCA2, etc.).