Low Serum Cholesterol Level Is a Significant Prognostic Factor That Improves CLL-IPI in Chronic Lymphocytic Leukaemia

Abstract

Hypocholesterolaemia is associated with elevated cancer risk and mortality, yet the relation between chronic lymphocytic leukaemia (CLL) and serum lipid profile remains unclear. Our study aims to evaluate the prognostic value of cholesterol levels in CLL and develop a prognostic nomogram that incorporates lipid metabolism. We enrolled 761 newly diagnosed CLL patients and separated them into either derivation (n = 507) or validation (n = 254) cohorts. The prognostic nomogram was constructed through multivariate Cox regression analyses, with performance evaluated using C-index, the area under the curve, calibration, and decision curve analyses. Decreased total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at diagnosis were significantly associated with worse time to first treatment (TTFT) and cancer-specific survival (CSS), and simultaneously, low HDL-C with low LDL-C was identified as an independent prognostic indicator for both TTFT and CSS. CLL patients achieving complete or partial remission post-chemotherapy had significantly increased TC, HDL-C, and LDL-C levels compared with the baseline, and post-therapeutic HDL-C and LDL-C elevation correlated with favourable survival. The prognostic nomogram augmenting the CLL international prognostic index with low cholesterol levels yielded higher predictive accuracy and discrimination capacity for both 3-year and 5-year CSS. In conclusion, cholesterol profiles can be used as a cheap and readily accessible tool for predicting prognosis in CLL practice.

Keywords: CLL-IPI; chronic lymphocytic leukaemia; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; prognosis.

Figure 1

Kaplan–Meier survival curves stratified by serum lipid profile in the primary cohort. Time to first treatment (TTFT) and cancer-specific survival (CSS) in relation to total cholesterol (TC) (A,B), high-density lipoprotein cholesterol (HDL-C) (C,D), low-density lipoprotein cholesterol (LDL-C) (E,F), triglycerides (TG) (G,H), and lipoprotein (a) (Lp(a)) (I,J).

Figure 2

Post-chemoimmunotherapeutic cholesterol fluctuation in relation to treatment response and prognosis. (A–C) Pre- and post-therapeutic levels of total cholesterol (TC) (A), high-density lipoprotein cholesterol (HDL-C), (B) and low-density lipoprotein cholesterol (LDL-C) (C) in patients with complete remission (CR) or partial remission (PR) and stable disease (SD) or progressive disease (PD). (D–F) Comparison of survival between patients with and without TC (D), HDL-C (E), or LDL-C (F) elevation after completion of therapies. Abbreviations: TTFT: time to first treatment; CSS: cancer-specific survival. **** p-value < 0.0001.

Figure 3

Nomogram and prognostic performance of Model_Lipo-IPI for cancer-specific survival (CSS). (A) A combined prognostic nomogram Model_Lipo-IPI for predicting CSS in CLL patients, including age, stage, β₂-microglobulin (β₂-MG) level, TP53, immunoglobulin heavy chain variable region (IGHV) status, and cholesterol profile as factors. (B,C) Calibration curves of Model_Lipo-IPI for predicting 3-year and 5-year CSS in the derivation (B) and internal validation (C) cohorts. (D,E) Decision curve analyses of different models for predicting 3-year and 5-year CSS in the derivation (D) and internal validation (E) cohorts. (F,G) Receiver operating characteristic (ROC) curves of different models for predicting 3-year and 5-year CSS in the derivation (F) and internal validation (G) cohorts. Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CLL-IPI, international prognostic index for chronic lymphocytic leukaemia.

Figure 4

T cell subset counts in relation to cholesterol levels. (A) Correlation between baseline CD4/CD8 ratio and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels; (B) Correlation between post-therapeutic fold change of CD4/CD8 ratio and fold change of TC, HDL-C, and LDL-C.