Biomarkers for acute myeloid leukemia (AML) – lessons from IL-2 immunotherapy with HDC

Anna Martner, PhD, from the University of Gothenburg, Gothenburg, Sweden, discusses the development of biomarkers for acute myeloid leukemia (AML) at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. She explains that IL-2 immunotherapy has been tested for melanoma, renal cell carcinoma and acute myeloid leukemia (AML), with most impressive results seen in a Phase III AML trial (NCT00003991). Patients receiving histamine dihydrochloride (HDC) and IL-2 while in complete remission (CR) after intensive chemotherapy had a significantly lower risk of relapse, which led to the approval of this drug in the European Union (EU) in AML patients in complete remission. Dr Martner explains her involvement in a post-marketing Phase IV trial, where AML patients in complete remission were treated with histamine and IL-2, with blood taken before and after immunotherapy in order to assess what happens to natural killer (NK) cells, T-cells and myeloid cells with treatment, and determine which of these effects correlate to patient outcomes (NCT01347996). Interestingly, a strong increase in NK cell numbers is seen during each round of histamine and IL-2 treatment. In addition, histamine type 2 receptor expression increases on myeloid cells, cytotoxic T-cells appear to be redistributed from effector memory T-cells to effector T-cells, and the expression of natural cytotoxicity receptors (NCR) on NK cells is increased with immunotherapy, all of which are correlated to good patient outcomes. However, Dr Martner highlights that as this is a one-armed study with no control group, it cannot be said without doubt that these effects would not be seen in the absence of histamine and IL-2 therapy, however there are strong indications that these parameters are related to therapy. She explains that this will now be studied in a randomized prospective trial to determine whether these markers are also predictive in the absence of histamine and IL-2 treatment, and hopes that these markers can be validated and used as biomarkers in future. Dr Martner adds that post-hoc analysis showed that this type of immunotherapy with histamine and IL-2 appears to work better in patients with monocytic forms of AML (FAB class M4 and M5), where malignant cells express histamine type 2 receptors and are capable of producing oxygen radicals, and outlines in vitro results showing that histamine can inhibit the formation of oxygen radicals by these malignant monocytes. This inhibition facilitates the killing of malignant cells by NK cells. She argues that the expression on myeloid cells of histamine type 2 receptors and the NOX-2 enzyme, which produces oxygen radicals, could be used as biomarkers for AML.

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