-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1326 Natural History and Predictors of Survival in Adult Patients with Telomere Biology Disorders

Program: Oral and Poster Abstracts
Session: 509. Bone Marrow Failure and Cancer Predisposition Syndromes: Congenital: Poster I
Hematology Disease Topics & Pathways:
Adult, Research, Inherited Marrow Failure Syndromes, Bone Marrow Failure Syndromes, Epidemiology, Elderly, Clinical Research, Genetic Disorders, Diseases, Young adult , Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Enrica Quattrocchi, MD1*, Eva M. Carmona Porquera, MD2*, Alejandro Diaz Arumir Vergara3*, Ana C. Zamora, MD3*, Laura Ongie, MS1*, Kristen B. McCullough, PharmD4, Brittany Burnap1*, Jenna A. Fernandez, PhD4, Doug A. Simonetto, MD5*, Patrick S. Kamath, MD5*, Avni Joshi, MD6*, Mark E. Wylam, M.D.7*, Cassie C. Kennedy, MD1*, Terra L. Lasho, PhD1, Christy Finke, BS4*, Rachel A. Simon4*, Mrinal M. Patnaik, MD, MBBS4, Alejandro Ferrer, PhD1 and Abhishek A. Mangaonkar, MBBS4

1Mayo Clinic, Rochester, MN
2Division of Pulmonary Medicine, Mayo Clinic, Rochester, MN
3Division of Pulmonary Medicine, Mayo Clinic, Arizona, AZ
4Division of Hematology, Mayo Clinic, Rochester, MN
5Division of Gastroenterology, Mayo Clinic, Rochester, MN
6Pediatric Allergy and Immunology, Mayo Clinic, Rochester, MN
7Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN

Introduction:

Telomere biology disorders (TBD) are multisystemic accelerated aging syndromes due to abnormal telomere length (TL) shortening and increased cancer risk. Pediatric-onset TBD is characterized by severely shortened TL and specific associations with germline pathogenic variants mainly in DKC1, TINF2, PARN genes and characteristic clinical features [bone marrow failure (BMF), abnormal nail/skin/oral mucosa]. Adult-onset TBD is genetically distinct (predominantly, TERT, TERC, and RTEL1 mutations) with varied organ involvement [interstitial lung disease (ILD), BMF, cirrhosis, or bone disease] and heterogenous outcomes. In our previous study of predominantly adult patients with short telomeres, multiple organ involvement (Mangaonkar A et al. Blood Cancer J 2021) predicted poor overall survival (OS). We sought to validate these findings in a larger, well annotated adult cohort of TBD patients.

Methods:

Patients with suspected TBD underwent comprehensive clinical and molecular evaluation through our TBD-dedicated clinic after regulatory approval. TL was assessed through clinical flow cytometry fluorescence in-situ hybridization (FlowFISH). Clinical and laboratory features, including pulmonary imaging, lung volumes/function testing, hepatic imaging (MR elastography/fibroscan) and bone density assessments were retrospectively abstracted. Germline and somatic genetic testing was performed on peripheral blood through targeted panels for known TBD and myeloid genes respectively. Cox proportional hazard model was used to identify significant variables that also retained independent prognostic impact.

Results:

Overall, 122 patients met criteria for TBD as defined by lymphocyte TL (LTL) <=10th percentile and/or a presence of a germline-TBD variant; 34 patients LTL <1st percentile, 84 1st and the 10th percentile (27 with TBD-germline variants) and 4 with only TBD-germline variants. Median age at diagnosis was 56 (18-77) years, with 72 (59%) males. Clinical features included presence of ILD (n=81, 66%), BMF (n=39, 32%), cirrhosis/hepatic fibrosis (n=19, 38%), bone disease osteopenia/osteoporosis/fractures, n=53, 70%), MDS/AML (n=11, 9%), non-hematological cancer (n=38, 31%), and head and neck cancer (n=2). Germline pathogenic variants were detected in 22 (18%), most frequently in TERT (n=10), RTEL1 (n=7) and TERC (n=2), while variants of uncertain significance (VUS) were seen in 35 (29%) patients, especially in TERT (n=20), TERC/RTEL1(n=6), NAF1 (n=4). Somatic variants in hematopoietic cells were detected in 37 (30%) patients with frequent alterations seen in DNA damage response and repair (PPM1D/TP53, n=11), and splicing component (U2AF1/SF3B1/ZRSR2, n=9) genes. At last follow-up [median of 3 (0-18) years], there were 26 (21%) deaths (most commonly, progressive ILD-18, cancer of lung/breast/pancreas-3, transplant-related complications-2). After censoring patients at the time of any transplantation (lung transplant-26, liver transplant-5, bone marrow transplant-8), the Kaplan-Meier estimate of median OS was not reached. Univariate survival analysis found adverse OS predicted by older age at diagnosis (P=0.006), presence of ILD (P=0.0002), hepatic fibrosis/cirrhosis (P=0.02), and somatic DNA repair variants (P=0.03). Multivariate model analysis found that only presence of ILD retained independent prognostic impact (HR=2, P=0.02). Among radiographic ILD subtypes, UIP was the most common (51%), followed by NSIP (10%), and others (6%), with median FEV1 of 2L (range: 0.5-4.6), FVC 2.4L (0.7-6.2), and TLC 4L (1.9-7.4). TBD-ILD patients were older (P<0.0001) with a male preponderance (P=0.03), 52 (64%) with multi-organ involvement, and had a less severe hematological phenotype [lower incidence of BMF (P<0.0001) and fetal hemoglobin elevation (P=0.01)], more frequent bone disease (P=0.0009), relatively longer telomeres in lymphocytes (P=0.04), and no particular association with any germline or somatic genetic alterations.

Conclusions:

Presence of ILD is an independent and significant predictor of adverse survival in adult TBD. Within adult TBD, patients with ILD represent a unique clinical subtype without any obvious genetic or pathologic correlates. Focusing on definitive therapeutic measures in this subgroup of adult TBD has the best chance to alter natural history and improve outcomes.

Disclosures: Patnaik: Kura Oncology: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Epigenetix: Research Funding; Solu therapeutics: Research Funding; Polaris: Research Funding; StemLine: Research Funding. Mangaonkar: BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding.

*signifies non-member of ASH