Toward risk-adjusted hematologic surveillance for telomere biology disorders Free

Telomere biology disorders (TBDs) are a heterogeneous group of diseases caused by inherited defects in telomere maintenance, which can lead to dysfunction of several organs that worsens with age. TBDs can lead to bone marrow failure (BMF) and have an increased risk of myeloid neoplasms (MNs). The current TBD Diagnosis and Management Guidelines (2nd ed.) recommend a baseline bone marrow (BM) evaluation for all TBD patients. Historically, the guidelines recommended annual BM biopsies for children with genetically confirmed TBD starting at age 10, while in adults (age 22 and over) routine annual BM surveillance has not been recommended. However, optimal MN surveillance in TBD remains unknown due to the lack of formal studies of BM surveillance in TBD.

To address this gap, we analyzed 344 TBD patients (166 pediatric and 178 adult) from our centers and published data from the National Institutes of Health. Of these, 29 (8.4%) developed MNs. 67 (19.5%) underwent HSCT—5 for MNs (8.5%), and 62 for other indications, with 33 (49%) died post-HSCT; 13 of 33 (39%) were from transplant-related complications. Among adults with TBD, 26/178 (14.6%) had a myeloid neoplasm compared to 3/166 (1.8%) of children (RR = 8.2, 95% CI 2.5-26.5; p<0.001).

We next reviewed serial BM biopsy outcomes at our pediatric/adult BMF center. Among 53 pediatric TBD patients with accessible health records, 29 had individual BM biopsy data spanning 140 person-years (median 4.5 years) of follow-up. No MN transformations occurred; four children died (liver failure, complications of kidney disease, post-HSCT infections). Among 69 BM biopsies (median 2 per patient, range 1-6), 27 (39%) were for routine surveillance without clinical change. Clonal hematopoiesis (CH) was identified on clinical testing in 3 children, and contributed to the decision to proceed to HSCT in two: 1) a child with TERC-mutant TBD whose U2AF1 variant VAF rose from 3% to 11% on surveillance at age 14; 2) a patient with telomeres <1st percentile without identified germline mutation who had a 3% VAF PTEN variant identified at age 6 that rose to 5% and had a transient 7% del(20q) detected by FISH at age 7. The third patient with telomeres <1st percentile without identified germline mutation had a 6% VAF KMT2C variant identified on surveillance at age 9, and is being monitored.

Overall, of the 53 children, 12 (23%) underwent HSCT at a median age of 7.7 years (two with CH, nine for BMF, one for immunodeficiency). Three died from post-HSCT infections, and the fourth died at age 22 from pulmonary fibrosis, having been declined a lung transplant despite full hematopoietic recovery post-HSCT 21 years prior because of other organ complications. Eight patients are alive post-HSCT (median post-transplant follow-up 1.9 years, range 0.18-5.65 years).

Among 46 adult TBD cases with available health records, six initially presented with MN prior to the diagnosis of TBD. 3 additional adults were subsequently diagnosed with MN after TBD diagnosis: one on the initial biopsy, and two on biopsies prompted by new clinical findings. The median age of MN diagnosis was 56 (range 28-67). Of the 40 patients without MN at presentation, 39 had individual-level BM biopsy data, contributing 169 person-years of follow-up (median 3.6 years). Of 71 BM biopsies (median 1 per patient, range 1-8), 26.8% (19 biopsies) were for routine surveillance in 11 patients, 4 of whom had new or changing chromosomal or mutational alterations. 19/46 (41%) adults died. Leading causes were respiratory failure (42%), progressive/relapsed MN (16%), septic shock/infection (16%), and decompensated cirrhosis (11%).

Our analysis shows that the MN risk in TBD increases with age, from under 2% in children to ~15% in adults, peaking in middle age, amid competing risks of pulmonary and other TBD complications. Our data suggest that current guidance of intensifying routine BM surveillance at age 10-21 in the absence of evolving clinical or laboratory abnormalities may offer limited benefit for early detection of MN for most children, while potentially missing that opportunity in young and middle-aged adults. Future studies are needed to identify subgroups of TBD patients most likely to benefit from routine BM surveillance, and to incorporate non-invasive monitoring allowing for a personalized surveillance strategy more closely aligned with dynamic changes in MN risk and the availability and risks of early intervention in this lifelong systemic disease.