Abnormalities in Lipoprotein Metabolism Provide Insight into Novel Therapeutic Approaches for Waldenstrom’s Macroglobulinemia (WM).

WM is an incurable B-cell disorder characterized by the presence of lymphoplasmacytic cells in the bone marrow and an IgM monoclonal protein. The presence of hypocholesterolemia has often been observed in WM patients, though the incidence and significance has not been investigated. As part of these studies, we evaluated lipoprotein levels in 110 patients with WM. The median age for this cohort was 62, and median number of prior therapies was 1. Twenty-one (19.1%) patients were on a lipid-lowering agent (lovastatin, simvastatin, pravastatin). We observed decreased total cholesterol (<160 mg/dL), LDL (<100 mg/dL) and VLDL (<40 mg/dL) levels in 41 (37.3%), 68 (61.8%) and 90 (81.8%) patients, respectively. Among the 41 patients with a cholesterol level of <160 mg/dL, only 7 patients were on a lipid lowering agent. Importantly, median serum IgM levels which serve as a surrogate marker for WM disease burden were higher among patients with hypocholesterolemia (3440 vs. 1587 mg/dL; p=0.0004). Moreover, significantly lower levels of serum IgM (885 vs. 1960 mg/dL; p=0.004) were observed among patients on a lipid-lowering agent. Given these results, which suggested a possible disease dependency on cholesterol metabolism, as well as possible anti-tumor effect of statins, we explored the impact of two statins (lovastatin, simvastatin) on the growth and survival of BCWM.1 WM cells. The studies demonstrated that both lovastatin and simvastatin inhibited proliferation (by MTT assay), and induced apoptosis (by Annexin-PI assay) in a dose dependent manner (0.5–50 um) at concentrations that overlapped pharmacologically achievable levels. Taken together, these studies suggest that lipoprotein metabolism may be essential for WM growth and survival, and that statin agents may represent clinically useful agents for the treatment of WM.