Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia

Abstract

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×10(9)/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia.

Figure 1.

Relative telomere length in responders and non-responders. (A) Scatter plot of relative telomere length (RTL) versus age in patients with aplastic anemia (AA). The regression line for healthy individuals is shown as a solid line (Y= −0.0907X + 14.751). Results for AA patients were shown for responders (n=33; open squares) and non-responders (n=31; closed circles). (B) Comparison for telomere length between responders and non-responders. Box plots representing the distribution of telomere length in responders (n=33) and non-responders (n=31). The upper and lower limits of the boxes represent the 75^th and 25^th percentiles, respectively; the horizontal bar across the box indicates the median and the ends of the vertical lines indicate the minimum and maximum data values. Dots indicate outliers.

Figure 2.

Response rates for immune suppressive therapy at three and six months according to telomere length. A poorer response rate was observed with each quartile as the telomere length shortened from the fourth to the first quartile.