Clinical features and occurrence of other cancers in patients with chronic lymphocytic leukemia and their families with <i>POT1</i> tumor predisposition syndrome.

Abstract

10585 Background: Protection of telomere 1 (POT1) tumor predisposition syndrome (POT1-TPD) is a hereditary leukemia predisposition syndrome that is identified in up to 5% of patients with chronic lymphocytic leukemia (CLL) and is characterized by a predisposition to other cancers such as gliomas, melanomas, angiosarcomas, and cardiac myxomas. Herein, we report clinical features and cancer diagnoses of the largest cohort of patients with CLL and members of families with POT1-TPD published to date. Methods: Patients and family members with pathogenic or likely pathogenic germline POT1 variants evaluated in the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center were included. Individuals with a variant of uncertain significance (VUS) in the POT1 gene were also included if found to have telomeres &gt;90 th percentile of age predicted length. Results: A total of 24 individuals in 17 families were identified. At the time of referral, 11 (46%) had a diagnosis of CLL, and 1 (4%) had monoclonal B-cell lymphocytosis (MBL). The remaining 12 individuals had no history CLL or MBL and were referred based on family history; however, 4 were found to have MBL at the time of referral (4/12, 17%). Among the 24 individuals, additional malignancies included: 6 melanoma, 3 hematologic cancers (1 CML, 2 NHL), and 1 papillary thyroid cancer. Among the 17 families, we documented a high reported prevalence of melanoma (8/17, 47%), CLL (6/17, 25%), glioblastoma (3/17, 18%) and sarcoma (2/17, 12%). Details of the POT1 variants were available for 16 families. Variants were classified as pathogenic in 7 (44%), likely pathogenic in 7 (44%), and as VUS in 2 (19%). Additional pathogenic germline variants in CHEK2 , BRCA2 , and MITF were observed in 3 (19%) families, respectively . Five families had telomere length testing performed (31%), and lymphocyte telomere lengths were above the 99 th percentile in 60% and above the 90 th percentile in 100%. The patients with CLL (n=11) had a median age at diagnosis of 55 years (range 29-68). 82% of patients had diploid karyotype, 64% had del13q by FISH, and 60% had mutated IGHV. Of the 7 patients with NGS testing performed, additional somatic mutations were present in 6 (86%) and NOTCH1 was the most common (43%). Five patients (45%) have received treatment for CLL with a median time to treatment of 4.5 years from diagnosis (95% CI 4.3, 4.6). Median overall survival of all patients was 13.8 years (95% CI 9.4, 18.3). Conclusions: This analysis provides insights into familial patterns of malignancy and the natural history of CLL in individuals with POT1-TPD. Patients with germline POT1 variants appear to develop CLL and MBL at an early age. Evaluation from a genetic counselor and augmented cancer screening due to the high risk of solid tumors and other hematological malignancies is paramount.