Background: Despite the negative prognostic significance of lymphocytopenia is known for many years no clinical cancer study has been proposed up to now in an attempt to specifically correct the evidence of an abnormally low lymphocyte count. At present it is known that IL-2 is the main growth factor for T lymphocytes. Lymphocyte proliferation is also stimulated by the pineal indole hormone melatonin (MLT), which is provided by an anticancer activity, whereas it is inhibited by cortisol.Objective: On this basis a preliminary study was carried out to evaluate which may be the optimal therapeutic schedule of cancer-related lymphocytopenia. Methods:The study included 40 advanced solid tumor patients who were treated by the best supportive care (BSC) (n=9), high-dose MLT alone (n=12) at 100 mg/day in the night, subcutaneous low-dose IL-2 alone (n=9) at 1.8 MIU/day for 5 days/week for 2 weeks followed by 2 weeks-rest period, or IL-2 plus MLT. The duration of study was 6 weeks. Results:The results were compared to those found in 10 advanced cancer patients treated by the checkpoint inhibitor Nivolumab (NVB) at 3 mg/kg/b.w. every 15 days. Lymphocyte count rapidly increased in a significant manner on IL-2 therapy, and a greater increase was reached by Il-2 + MLT. Lymphocyte mean count also increased on MLT alone and on NVB, without, however any statistically significant increase. Finally lymphocyte mean count progressively decreased on BSC alone.Conclusions: This preliminary study shows that S.C. low-dose IL-2 is the only drug able to rapidly correct cancer-related lymphocytopenia, whose efficacy may be further amplified by the concomitant endocrine therapy with the pineal hormone MLT. Further studies will be required to evaluate the impact of the lymphocytopenia correction on the survival of advanced cancer patients.

No abstract

It is known that lymphocytopenia is one of the most negative biomarkers in cancer patients, being an expression of cancer-related immunosuppression. Today it is known that, despite its complexity, the antitumor immunity is mainly mediated by dendritic cell-T lymphocyte system and suppressed by the macrophage-regulatory T lymphocyte system. Then, lymphocyte-to-monocyte ratio (LMR) has been proven to represent a more appropriate prognostic clinical index than the simple lyphocytopenia alone. Because of the fundamental role of lymphocytes in mediating tumor cell destruction, the correction of cancer-related lymphocytopenia could influence the clinical history of the neoplastic disease. At present, the only cytokine able to induce a clear in vivo lymphocytosisis IL-2. However, it has been demonstrated that the immune system is physiologically under a neuroendocrine control, and that the pineal hormone MLT may stimulate T lymphocyte proliferation and activation. On these bases, we have evaluated the effect of highdose MLT therapy in metastatic solid tumor patients with persistent lymphocytopenia and abnormally low values of LMR. The study included 14 patients, and the results were compared to those found in a control group of 20 lymphocytopenic untreatable metastatic cancer patients treated with the only best supportive care alone. Patients received MLT at a dose of 100 mg/day orally in the evening for 3 consecutive months. Lymphocyte mean count increases on MLT therapy, and the values observed after two months of therapy were significantly higher than the pretreatment ones, with a normalization of lymphocyte number in 4/14 (29%) patients, whereas no spontaneous lymphocyte rise occurred in the control group. On the other hand, monocyte count rapidly diminished on MLT therapy, and LMR mean values observed after only one month of treatment was significantly higher than that found prior to therapy, whereas it significantly decreases in controls. This preliminary study shows that high-dose MLT may improve the immune status of cancer patients, and be effective in the treatment of disseminated cancer-related lymphocytopenia.