Metronomic Effect as A New Hypothesis in Maintenance Therapy of Acute Lymphoblastic Leukemia

Growing evidence indicates that the innate and adaptive immune system has an important role in both development and treatment of cancer. The concept of metronomics therapy and mechanism of chemotherapeutic agents during maintenance phase of acute lymphoblastic leukemia (ALL) is an obscure topic for oncologists compared with treatment of other phases of this malignancy. Some new immunological mechanisms have been proposed for the treatment of ALL during the maintenance phase of chemotherapy in addition to traditional irradication mechanisms. Using regular continuous low-dose chemotherapeutic drugs during the maintenance phase is similar to metronomic strategy that may restore or mediate anticancer immune responses or antiangiogenic effects.1 Anti-pyrimidines (6-mercaptopurine or 6-thioguanine), dexamethasone or prednisone, oral methotrexate and vincristine are standard approaches in maintenance therapy of ALL. Malignant cells can escape from immune surveillance in different phases of tumor interaction with the host’s immune system. Regulatory T cells (Treg) are CD4+ CD25+ lymphocytes, enriched in FoxP3, glucocorticoidinduced TNF receptor and cytotoxic T-lymphocyte associated antigen-4 that can inhibit antigen-specific immune response both in a cytokine-dependent and cell contact-dependent method.2 Treg cells can inhibit anti-tumor immune response by suppressing the activity of both tumor-specific effector cells (CD8+ cytotoxic T lymphocytes and CD4+ T helper cells) and tumornonspecific effector cells (natural killer [NK] and NK T cells.1 Also, Treg cells have been shown to be increased in a variety of human cancers. Increased frequency of Treg cells is associated with tumor progression and loss of treatment response.3 Moreover, suppression of Treg cell activity by either specific blockade or depletion of them can enhance immune response against tumor-associated antigens.