Increased Serum Transforming Growth Factor-beta1 (Tgf-beta1) Is Related to a Better Outcome in MM, WM and CLL Patients

TGF-beta1 normally down-regulates B-cell proliferation. Resistance to its effects is reported in malignant cells of B-lineage such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells. There are however very few studies on serum TGF-beta1 levels in patients with B-cell lymphoproliferative diseases and their eventual correlations with parameters of disease activity and survival. The purpose of our study was to assess any eventual relationship between serum TGF-beta1 levels and disease parameters, as well as time to first treatment (TFT) and overall survival (OS) in a series of MM, Waldenstrom's macroglobulinemia (WM) and CLL patients at diagnosis.

92 MM, 64 WM and 110 CLL patients were studied. In the MM group, paraprotein was IgG in 64, IgA in 18, LC in 8 and IgD in 2 patients while 32, 25 and 43% of patients were in ISS stage 1, 2 and 3 respectively. MM patients' median follow-up was 51 months. All patients required treatment a some point, 55% immediately. In the WM group, 44, 27 and 29% of patients were in WM – IPSS stage 1, 2 and 3 respectively. WM patients' median follow-up was 49 months; 75% of them required treatment during follow – up. In the CLL group, 54% and 74%, 25% and 20%, 14% και 6%, were in stage 0 and A, 1 and β, 2 and C according to Rai and Binet respectively. Median follow up was 43 months; 14 patients needed immediate treatment, 30 more required treatment during follow up while the others are still just followed. Patients' frozen sera, drawn at diagnosis, were retrospectively analyzed while sera from 20 healthy individuals (HI) were tested as controls. Serum TGF-beta1 measurements were done by ELISA according to the manufacturer's instructions. Statistical analysis was performed by SPSS software, version 15. 0.

Median serum TGF-beta1 levels were 36330 pg/ml (range 4. 6 – 77976) in MM patients, 33965 pg/ml (range 1665–615000 pg/ml) in WM, 12207 pg/ml in CLL (range 0 – 42970) and 32902 pg/ml in HI (range 1941 – 58123). CLL patients presented significantly lower TGF-beta1 levels than those with MM and WM (p<0. 00001). Patients with TGF-beta1 levels above median presented a longer TFT than the others in MM and CLL (p=0. 0003, and p=0. 002 respectively) while in addition a longer OS was observed in MM and WM patients with increased serum TGF-beta1 median (p=0. 001, and 0. 02 respectively). Furthermore, serum TGF-beta1 levels stongly correlated with clinical and laboratory parameters of adverse prognosis such as staging, anemia, beta-2 microglobulin levels, serum LDH and serum free light chain concentrations.

Our results of longer TFT in MM and CLL and improved OS in MM and WM patients with increased serum TGF-beta1 levels, suggest that a degree of sensitivity to the suppressive effect of TGF-beta1 may remain in neoplastic B-cells in the majority of B-cell lymphoproliferative disorders.

No relevant conflicts of interest to declare.