By John Gever, Senior Editor, MedPage Today
Published: September 21, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Shortened telomeres in peripheral blood leukocytes may predict relapse, malignant progression, and poorer survival in patients with severe aplastic anemia, researchers at the National Institutes of Health (NIH) reported.
An analysis of average pretreatment telomere length in almost 200 patients with severe aplastic anemia treated at the NIH, revealed that patients in the first quartile for telomere length -- the shortest telomeres -- had an overall six-year survival rate of 66% (95% CI 52.9% to 82.5%) compared with 83.8% (95% CI 77.3% to 90.0%) among those in the other three quartiles (P=0.008), according to the Sept. 22 issue of the Journal of the American Medical Association.
Having the shortest telomeres was also associated with greater risk of progression to malignancy (24.5% versus 8.4%, P=0.009) and with evolution to monosomy 7 or complex cytogenetics (18.8% versus 4.5%, P=0.002), wrote Phillip Scheinberg, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and colleagues.
"Clonal evolution to myelodysplasia is a major adverse event in severe aplastic anemia; it cannot be routinely predicted and usually signals a poor prognosis," Scheinberg and colleagues noted.
They suggested their findings point toward a practical method of identifying patients at heightened risk for progression who might receive more aggressive treatment.
"Higher-risk protocols such as stem cell transplants in older patients and alternative sources of stem cells might be considered earlier in younger patients," the researchers wrote.
They also indicated that androgen treatment may lengthen telomeres, potentially altering patients' risk profiles.
Telomeres are the protective end-caps on chromosomes. Portions are lopped off with each round of cell division, although they may be restored by the telomerase enzyme complex.
Cell senescence has been associated with critically short telomeres, but mutations in telomerase genes that result in extremely short telomeres have been found in some patients with severe aplastic anemia.
Scheinberg and colleagues measured telomere lengths in pretreatment peripheral blood samples from 183 patients treated for severe aplastic anemia at the NIH from 2000 to 2008.
They found no relationship between telomere length and initial treatment responses. Hematologic response rates were nearly identical in each quartile of telomere length, ranging from 54% to 60%.
But the subsequent course for patients in the first quartile -- those with the shortest telomeres -- differed significantly over as long as six years from patients in the second to fourth quartiles -- those with longer telomeres.
By far the worst survival outcomes were in first-quartile patients who also had absolute reticulocyte counts below 25,000 per μL.
With four years of follow-up, just over 50% of these patients were still alive. The four-year survival rate among those in the first quartile but higher reticulocyte counts, and those with low counts but longer telomeres, was close to 80%.
Nearly all of those with longer telomeres and high reticulocyte counts survived at least four years. Few deaths occurred in study patients after year four irrespective of telomere or reticulocyte status.
For other outcomes -- hematologic relapse, clonal evolution, progression to monosomy 7 or complex cytogenetics -- differences according to telomere length were apparent in about two years.
Scheinberg and colleagues asserted that truncated telomeres are "not simply a biomarker," but may play a direct role in the disease process.
"Ample in vitro and animal experimentation indicate that critical shortening of telomeres causes chromosome instability, tumor formation, and cancer progression," they wrote.
Although short telomeres would ordinarily lead to senescence, the chromosomal damage that may result from defective end-caps may instead allow cells to turn malignant, especially if they also lack functional p53 or other tumor suppressor mechanisms, the researchers suggested.
Scheinberg and colleagues noted some limitations of their study. Its retrospective nature was one; another was the relatively small number of patients that precluded assembling a separate validation cohort. They also noted that the NIH patient pool may not be representative of patients elsewhere.
"Our results need to be replicated to validate the observed associations and to determine reliable telomere length thresholds that could be incorporated in treatment algorithms," the researchers concluded.
The study was funded by the National Heart, Lung, and Blood Institute.
One author obtained salary support from a training program partially funded by Pfizer.
The authors declared they had no relevant financial interests.
Primary source: Journal of the American Medical Association