A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies.

Interleukin-2 (IL-2) has proven to be able to generate an effective anticancer immunity against both solid and hematologic malignancies. Moreover, recent advances in the knowledge of psychoneuroimmunology have demonstrated that anticancer immunity is under neuroendocrine control and that the pineal hormone melatonin (MLT) may stimulate the IL-2-dependent anticancer reaction. Finally, preliminary clinical studies have already shown that the concommitant administration of MLT may amplify the efficacy of IL-2 in the treatment of advanced solid neoplasms, whereas there are no data about MLT influence on IL-2 activity in hematologic malignancies. The aim of the present study was to evaluate the efficacy and tolerability of a neuroimmunotherapeutic combination of low-dose IL-2 plus MLT in advanced hematologic malignancies which did not respond to previous standard therapies. The study included 12 evaluable patients. Tumor histotypes were as follows: non-Hodgkin's lymphoma (NHL) 6; Hodgkin's disease (HD), 2; multiple myeloma, 2; acute myelogenous leukemia (ALM), 1 and chronic myelomonocytic leukemia (CMML), 1. IL-2 was injected subcutaneously at a dose of 3 million IU/day for 6 days per week for 4 weeks, corresponding to one cycle. MLT was given orally at 20 mg/day in the evening, without interruption. In non-progressing patients, a second IL-2 cycle was planned after a 3 week-rest period. A partial response was achieved in one patient with multiple myeloma. Stable disease occurred in 7 other patients (NHL, 3; HD, 1; AML, 1; CLLM, 1; multiple myeloma, 1), whereas the other 4 patients progressed. Therefore, lack of progression was obtained in 8 out of 12 (67%) patients, with a median duration of 21+ months (14-30+ months). The treatment was well tolerated in all patients. These preliminary results would suggest that the concomitant administration of low-dose IL-2 plus the pineal hormone MLT may prolong the survival time in untreatable advanced hematologic malignancies, with results comparable to those previously reported using a more toxic immunotherapy, consisting of high-dose IL-2 alone.