Short Telomere Syndromes and Inherited Predisposition to Bone Marrow Diseases: The MDACC Experience

Introduction: Telomeres are noncoding nucleotide repeats at chromosomal ends, which provide genomic stability and are maintained and regulated by specific protein complexes. Their length physiologically decreases with age, although it is known that germline mutations in telomeric regulators can accelerate this process, which is related to a wide variety of clinical situations. Herein we report on the experience of patients diagnosed with Short Telomere Syndromes (STS) evaluated in the Hereditary Hematologic Malignancy Clinic (HHMC) of the MD Anderson Cancer Center.

Methods: We retrospectively analyzed clinical characteristics and outcomes of patients with a diagnosis of STS referred or diagnosed in the HHMC. Germline mutation origin was confirmed by genetic analysis of cultured skin fibroblasts or blood/saliva in patients without hematologic disease. Telomere length was assessed by Flow-FISH techniques in a clinically validated external laboratory (John Hopkins Medical Laboratories, Baltimore, MD). Individuals with confirmed STS were recommended to follow a specialized cancer surveillance program to achieve early-diagnosis or prevention of potential complications related to STS. A baseline bone marrow evaluation was recommended to evaluate underlying morphology and assess for somatic comutations.

Results: A total of 24 patients with STS were identified (13 males, 54%), with a median age of presentation to the clinic of 53 years old (5-78). Although the reasons of referral for STS testing for each individual patient were diverse, they can be summarized in these categories: unexplained cytopenia (n=9), myeloid malignancy with relevant PMH or FH (n=8), affected sibling (n=5), skin lesions (n=1) and multiple cancer diagnosis (n=1).

Pathogenic or likely pathogenic germline variants were confirmed in the TERT gene (n=13, 54%), TERC gene (n=7, 29%), RTEL1 (n=2, 8%), while 2 patients had no telomere-related detectable mutations (Figure 1). Telomere flow-FISH confirmed age-predicted telomere length <1^st percentile for age in 67(%). All patients underwent a bone marrow biopsy, being described as hypocellullar in 17 patients (71%). With the bone marrow evaluation, eleven patients were diagnosed with myelodysplastic syndrome (MDS, 46%), two patients with acute leukemia (myeloid and mixed phenotype, 8%), two patients with clonal cytopenia of unknown significance (CCUS, 8%), one aplastic anemia (4%) and eight patients (33%) did not have hematologic malignancy. During the follow-up, three patients underwent an allogeneic stem cell transplantation due to their hematologic disease.

Solid neoplasms are frequent in patients with STS, and 11 patients (46%) had a PMH of at least one solid tumor with a median age of 54 (33-78 yrs). Squamous cell carcinoma was the most frequent histology (6/11 patients). Sixteen patients (67%) had a positive FH of cancer in one or more first or second-degree sibling.

Pulmonary fibrosis (PF) was diagnosed in 4 patients (17%), two with TERT mutations and two with TERC mutations. Moreover, 7 patients (4 diagnosed with PF,30%) had a positive FH of PF in first degree siblings. Liver diseases were also frequent: 3 patients had non-alcoholic hepatic cirrhosis, one patient had chronic hepatitis with periportal fibrosis and one with idiopathic portal hypertension. One patient had received a liver transplantation and one required a lung transplantation prior to presentation to the HHMC. Finally, twelve patients (50%) were reported to have premature grey hair and eight patients were reported to have nail dysplasia and/or skin abnormalities related to STS (such as unexplained reticular rash). A summary of the described patients is depicted in Figure 2.

Conclusion: STS are genetic diseases that can go unnoticed until adulthood. Patients with myeloid malignancies (especially MDS) with hypocellular bone marrow and suspicious findings (i.e. FH or PMH of PF, premature grey hair, long standing cytopenias) should be considered for underlying STS. An early diagnosis is essential to start cancer surveillance programs and provide timely genetic counseling to the patient and relatives.

Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Issa:Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding; Novartis, Kura Oncology, Nuprobe: Consultancy. Takahashi:Celgene/BMS: Consultancy; GSK: Consultancy; Agios: Consultancy; Ostuka Pharmaceuticals: Honoraria; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy; Mission Bio: Honoraria; Illumina: Honoraria. Kadia:PinotBio: Consultancy; Astellas: Research Funding; Ascentage: Research Funding; Servier: Consultancy; Genfleet: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; Delta-Fly: Research Funding; Iterion: Research Funding; cyclacel: Research Funding; Amgen: Research Funding; JAZZ: Consultancy, Research Funding; Glycomimetics: Research Funding; Novartis: Consultancy; Astex: Honoraria; Genentech: Consultancy, Research Funding; cellenkos: Research Funding; Regeneron: Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding. Garcia-Manero:AbbVie: Honoraria, Research Funding; Acceleron Pharma: Consultancy; Novartis: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; Curis: Honoraria, Research Funding; Aprea: Honoraria; Genentech: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Consultancy; Syos: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Xencor: Research Funding; AstraZeneca: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Jazz Pharmaceuticals: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. DiNardo:Jazz: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; LOXO: Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Cleave: Research Funding; Forma: Research Funding; Novartis: Honoraria; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; Gilead: Honoraria.