Treatment of Advanced Cancer-related Lymphocytopenia: Comparison among the Effects of Subcutaneous Low-dose Interleukin-2, High-dose Pineal Hormone Melatonin and Checkpoint Inhibitors

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.