High Cumulative Illness Rating Scale (CIRS) Score in CLL Correlates with Short CLL Telomere Length and Decreased Survival

The impact of chronic disease on the development and progression of cancer is increasingly recognized. Chronic lymphocytic leukemia (CLL) is a disease of the elderly and many of these patients have multiple comorbidities, which could shorten an individual's life, either directly or by enhancing CLL progression. In normal cells, including buccal cells (BC), it is known that chronic illness and age can shorten telomere length and this is a surrogate marker of overall survival. In the present study, we have examined the relationship between comorbidities and BC telomere length in CLL patients and determined whether these features can predict patient survival and disease aggressiveness.

Telomere length in isolated genomic DNA from buccal and CLL cells of 196 CLL patients was measured at the time of diagnosis, using multiplex quantitative real-time PCR. Comorbidities were measured by the Cumulative Illness Rating Scale (CIRS) and CLL aggressiveness by leukemia cell telomere length. The median age of patients at diagnosis was 66 years (range, 39-89). With a median follow-up of 4.86 years (range, 0.05-7.69 years), approximately half the patients have progressed and one quarter have died. The median CIRS score of these patients was 3 (range, 0-12); a score of ≥7 was considered high. In patients with an elevated CIRS score, a direct correlation was found with increasing age (P<0.0001, r=0.42). In addition, independent of the effects of age, an increased CIRS score was found to correlate with poor overall survival (P=0.048, r=0.18).

The median BC relative telomere length (T/S) of 2.01 (range, 0.70-5.66) was longer than the median CLL T/S of 0.53 (range, 0.07-2.48). There was no correlation between buccal and CLL telomere lengths (P=0.21). BC telomere lengths shortened with increasing age (P=0.011), but showed no association with markers of CLL disease, survival or high CIRS scores (P=0.08, r=-0.16). Meanwhile, patients with shorter CLL telomeres showed more aggressive disease with unmutated IGHVstatus (P<0.0001), higher Rai stage (P=0.02), shorter lymphocyte doubling time (P=0.004), earlier time to treatment (P<0.0001) and shorter overall survival (P=0.02). More importantly, short CLL telomere lengths occurred independent of increasing age (P=0.47), and significantly correlated with high CIRS scores (P=0.03, r=-0.18).

In summary, while BC telomere lengths shorten with age in CLL cases, it is not predictive of survival or comorbidities in CLL. In contrast, independent of age, short CLL telomeres correlate with increasing CIRS scores and both predict poor survival. These results suggest that comorbidities in CLL may affect tumor biology, enhancing disease progression. This finding may partly explain the more aggressive clinical course of CLL in the elderly. Whether altering comorbidities in CLL can influence disease aggressiveness and survival requires further study.