Short Telomere Length Increases Non-Relapse Mortality Risk After Allogeneic Transplant for MDS

According to research published in Blood, shorter telomere length was an independent risk factor for non-relapse mortality (NRM) and overall survival (OS) in patients with myelodysplastic syndromes (MDS) who have undergone a hematopoietic cell transplantation. The effect of telomere length on NRM was most pronounced among patients who received higher-intensity conditioning or developed severe acute graft-versus-host disease (GVHD).

“If our results are validated, short telomere length could inform the clinical decision regarding conditioning intensity, which is based on relative risks of disease relapse and transplant-related toxicity,” said corresponding study author R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute in Boston.

Fairly recent genomic studies have centered their attention on identifying disease-associated genetic alterations that are predictive of a patient’s relapse risk. “After hematopoietic cell transplantation, NRM remains an important problem that is separate from relapse,” said Dr. Lindsley. “Predicting which patients are likely to experience fatal transplant-related toxicity is challenging, as it relies largely on clinical assessment of a broad range of recipient comorbidities.”

To define an objective measure of toxicity risk, Dr. Lindsley and colleagues collaborated with the Center for International Blood and Marrow Transplant Research (CIBMTR) to assess samples from a large cohort of 1,514 patients with MDS who had banked whole peripheral blood DNA. The DNA from these samples was extracted, and telomere length was measured successfully in 1,508 samples.

In the study population, women had longer telomere length compared with men (p<0.001). Shorter blood telomere length was associated with increased patient age, as well as mutations in the PPM1D (p=0.01), WT1 (p=0.03), and ATM (p=0.04) genes, while longer telomere length was associated with mutations in the SRSF2 (p<0.001), DNMT3A (p<0.001), and STAG2 (p=0.04) genes. “We observed significant associations between telomere length and somatic MDS gene mutations, suggesting that there may be a biological link between telomere biology and MDS pathogenesis,” commented Dr. Lindsley.

Shorter telomeres also were associated with more severe pre-transplant cytopenias, including lower hemoglobin (p<0.001), lower platelet count (p<0.001), and lower absolute neutrophil count (p<0.001).

Compared with the longest telomere quartile, intermediate and short blood telomere length were associated with worse OS (hazard ratio [HR] for death in shortest vs. longest = 1.49 [p<0.001]; HR for intermediate vs. longest = 1.34 [p=0.001]).

In patients >40 years of age (n=1,267), the shortest telomere length quartile correlated with worse survival (p<0.001), primarily due to a higher risk of NRM (p=0.001). “This allowed us to show that short telomere length defines an independent risk factor for NRM,” noted Dr. Lindsley, “and thus may complement current transplant comorbidity models.”

NRM also differed according to conditioning regimen, the authors reported. Patients with short telomeres who received fludarabine/melphalan-based reduced-intensity conditioning (RIC) regimens had a significantly higher 3-year cumulative incidence of NRM, compared with those who received other RIC regimens (51% vs. 28%, respectively; p=0.002).

There also were significant associations between shorter telomere length and increased frequency of pulmonary dysfunction (odds ratio [OR] for shortest vs. longest = 1.90; p=0.003), hepatic dysfunction (OR=3.80; p=0.003), and infection prior to transplantation (OR=4.46; p=0.003). Individuals with congenital syndromes that result in very short telomeres, such as dyskeratosis congenita, often develop pulmonary fibrosis or hepatic cirrhosis, so these adverse events are of special interest.

In the 265 patients with short telomeres who developed severe acute GVHD, rates of 5-year OS were worse than in those who did not develop GVHD (25% vs. 51%, respectively). Shorter telomere length among this patient group also was associated with lower OS rates than in those with severe acute GVHD and intermediate or longer telomere lengths, which was attributable to a high early NRM rate.

“The effect of shorter telomeres on NRM was prominent among patients who developed severe acute GVHD,” said Dr. Lindsley, “suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury.”

When asked about potential study limitations, Dr. Lindsley noted that he and his colleagues used a quantitative PCR method to measure telomere lengths, an approach that “cannot be directly translated to the clinic.”

The authors report no relevant conflicts of interest.

Reference

Myllymäki M, Redd RA, Reilly CR, et al. Short telomere length predicts non-relapse mortality after stem cell transplantation for myelodysplastic syndrome. Blood. 2020 August 17. [Epub ahead of print]