Patients with telomere biology disorders (TBDs) exhibited substantial hematologic and multiorgan morbidity as well as frequent clonal hematopoiesis with a high rate of PPM1D and U2AF1 mutations, according to a single-center retrospective cohort study led by Olisaemeka Ogbue, MBBS, of Mayo Clinic in Rochester, Minnesota. The data were presented at the Fourteenth Annual Meeting of the Society of Hematologic Oncology in Houston, Texas.
The analysis reviewed patients with genotypically characterized TBDs seen at the authors’ center from 2019 to 2024. Eligible patients had pathogenic or likely pathogenic germline telomere-related variants with telomere length in the first to 10th percentile, or had telomere length below the first percentile. The cohort included 59 patients (median age, 54 years; 61% male; 90% White), of which 69% had lymphocyte telomere length below the first percentile. Germline variants in TERT, RTEL1, TERC, and PARN were recorded in 21, eight, five, and three patients, respectively.
Overall, hematologic abnormalities were common as 63% of patients had persistent macrocytosis, 52% had cytopenias, and 23% had bone marrow failure. Multiorgan involvement included interstitial lung disease (ILD) in 56% of patients, hepatic disease in 34%, and osteoporosis in 41%. Patients with ILD tended to present at older ages (61 years vs 41 years; P<.001). At a median follow-up of 16 months, six patients died, including four due to ILD and two due to cancer.
Among 43 sequenced patients, 23 had clonal hematopoiesis, most commonly with PPM1D and U2AF1 S34F mutations. Clonal hematopoiesis was more prevalent in patients with pathogenic TERT variants compared with other TBD genotypes (71% vs 38%; P=.055). Patients with spliceosome-mutant clonal hematopoiesis had a higher prevalence of anemia versus other patients (100% vs 49%; P=.01), although extrahematologic manifestations were comparable. Spliceosome-mutant clonal hematopoiesis was also associated with more severe macrocytic anemia.
Among treatments, the hematologic response rate was 55.6% with danazol, 28.6% with immunosuppressive therapy, and 0% with erythropoietin-stimulating agents. Five patients underwent lung transplantation, one underwent liver transplantation, and one underwent both lung and allogeneic hematopoietic stem cell transplantation.
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