Patients with CLL have raised levels of both total and unmethylated cfDNA, which correlate with high CD38, short LDT, high leukemic burden, and reduced time to first treatment (TTFT). Levels of cfDNA were measured in the plasma of 37 patients with a confirmed diagnosis of CLL. (A) There was a positive correlation between the levels of cfDNA and percent CD38⁺ CLL cells. (B) Using a cutoff of 12 months, patients with an LDT <12 months had higher plasma cfDNA than those with an LDT >12 months. (C) There was also a strong positive correlation between the levels of cfDNA and leukemic burden (white blood cell count × 10⁹/L). (D) Patients were segregated into high (red) or low (blue) plasma DNA depending on whether their levels were higher or lower than the median. Those with higher levels of plasma cfDNA had a much shorter TTFT. (E) Unmethylated DNA was quantified in the plasma of patients with CLL (n = 15) and healthy age-matched control subjects (n = 27) and presented here as the fold difference compared with the mean of the control subjects. Patients with CLL had a mean 28.1-fold higher unmethylated DNA. (F) The fold difference in unmethylated DNA was normalized to the total DNA concentration and was still 2.1-fold higher in plasma of patients with CLL compared with that from healthy control subjects. GE, genome equivalents; HR, hazard ratio.