Development of a Comprehensive Program for Evaluation of Hereditary Predisposition to Hematologic Malignancies

Introduction

Germline pathogenic variants underlie or contribute to an estimated 20% of leukemia and up to 50% of aplastic anemia. Early diagnosis of inherited predisposition to hematologic malignancy (IPHM) and bone marrow failure is critical for treatment planning both due to the risk of subjecting patients to excessive toxicity from standard doses of chemotherapy or radiation and because affected relatives who are potential donors for stem cell transplant (SCT) should be identified. Further, identification of associated risks for other non-hematologic cancers and multisystem diseases provide opportunities for screening, monitoring, and early treatment. Family members may also be at risk for complications related to the IPHM identified in the proband and therefore are candidates for screening with counseling and surveillance.

Methods

We established a multicenter collaborative program between three hospitals [Huntsman Cancer Institute at University of Utah, LDS Hospital at Intermountain Healthcare, and Primary Children's Hospital (all in Salt Lake City, UT)] with specific criteria for genetic evaluation defined prospectively (Table 1). All patients identified for evaluation were assessed by a certified genetic counselor. Germline genetic testing was performed using DNA from culture fibroblast derived from skin biopsies. Laboratory selection for germline genetic testing was based on the patient's insurance coverage, admission status, personal history, family history, requested turnaround time, time to SCT, and comprehensiveness of panel. Germline genetic testing was performed at one of the following laboratories: Prevention Genetics, GeneDX Laboratories, ARUP Laboratories, Ambry Genetics, and Invitae Genetics. Chromosome breakage analysis and telomere length measurement were performed on patients with clinical suspicion of Fanconi anemia or a telomere biology disorder, respectively.

Results

Between October 2021 and April 2022, 61 patients were identified prospectively who met evaluation criteria for referral to genetic counseling (Table). Of these patients, 42 were males and 19 were females. Median age was 35 years (range newborn to 77 years). The most common reasons for evaluation were cytopenia (n=14), myelodysplastic syndrome (n=10), and acute myeloid leukemia (n=16). Four potential SCT donors were evaluated. Of 61 patients, 60 patients were referred directly to a genetic counselor. Of the 58 patients who kept their appointment (58/61, 95%), the median time from referral to clinic evaluation was 6 days (range, same day to 99 days,). Fifty-two patients underwent genetic testing with 47 having panel testing and 5 having gene specific testing. Twenty-nine patients underwent skin biopsy (all hematologic malignancies and one case of aplastic anemia), and 23 patients underwent testing on saliva or blood samples. Of the 52 patients who underwent germline genetic testing, eight were found to have pathogenic/likely pathogenic variants and eight were identified with suspicious variants of uncertain significance (Table 2). Identification of 16 patients with pathogenic or suspicious genetic test results led to testing of four potential HSCT donors.

Conclusion

The results of this study show the feasibility of developing a comprehensive, collaborative program for evaluation of IPHM. Essential to the success of such a program is a genetic counselor who is readily available for consultation and whose breath of knowledge is sufficient both to guide patient evaluation and to interpret findings that impact directly on management of patients and family members. Other important contributors to program success include active communication with pediatric and adult clinicians who treat patients with hematologic malignancies and bone marrow failure, and laboratory support for obtaining skin biopsies, culturing fibroblasts, and extracting and preserving DNA. Our program can serve as a blueprint for establishing a service line for comprehensive germline testing for IPHM at other medical centers.

Vagher:Invitae: Consultancy, Other: Invitae. Maese:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Osman:Syros Pharmaceuticals: Research Funding; Karyopharm Therapeutics: Research Funding. Patel:Incyte: Research Funding; Stemline: Research Funding; Genentech/Roche: Research Funding. Tashi:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Kovacsovics:Abbvie: Research Funding; Caelum: Research Funding; Gilead: Research Funding; Glycomimetics: Research Funding; Janssen: Research Funding; Jazz Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Syndax: Research Funding; Kite: Honoraria. Tantravahi:Karyopharm Therapeutics Inc.,: Research Funding; Karyopharm Therapeutics Inc., Novartis, AbbVie, Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.