Post‐consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin‐2 in AML

Abstract

The initial chemotherapy in acute myeloid leukaemia (AML) comprises a first phase of induction and a second phase of consolidation. In the majority of patients, the induction treatment leads to complete remission (CR), defined as microscopic disappearance of leukaemic disease along with the return of normal haematopoiesis. However, despite the introduction of more efficacious consolidation regimens, a worryingly large proportion of AML patients in CR will subsequently experience relapses with poor prospects of long‐term survival. A relapse is assumed to be the result of expansion of residual leukaemic cells that have escaped the initial chemotherapy. The anti‐leukaemic functions of T cells and natural killer (NK) cells has formed the background to the use of interleukin‐2 (IL‐2), a T‐ and NK cell‐activating cytokine, with the aim to eliminate residual leukaemia and hence reduce the relapse rate in AML, but the clinical trials using IL‐2 monotherapy have yielded disappointment. A recent phase III study has demonstrated that post‐consolidation treatment with the combination of histamine dihydrochloride (HDC) and IL‐2 significantly prevents relapse in AML patients. Here we account for the preclinical background to the use of HDC/IL‐2 in AML along with a review of clinical results.

Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia

“…Therefore, the suggestion that IL-2 has the potential to improve LFS and OS in AML may be valid, but for IL-2 to exert a significant clinical effect on relapse prevention in this disease, its activity on T and NK cells may need to be protected from interference by ROS. 2 In conclusion, this meta-analysis confirms that IL-2, when given as monotherapy, is not effective as a remission maintenance therapy for AML patients in CR1, a conclusion also reached by others based on data extracted from the literature. 49 However, the optimism that clinicians once held for immunotherapy to prevent relapse in AML should not be discounted, because it may be possible to protect the activity of IL-2 on T and NK cells from ROS-mediated destruction in the tumor microenvironment.…”

“…Second, it has been proposed that the efficacy of IL-2 monotherapy could be hampered by the activity of other immune cells that prevent the activation and proliferation of cytotoxic lymphocytes (ie, the effector cells of IL-2). 2 Reactive oxygen species (ROS) or "oxygen radicals" derived from adjacent phagocytic cells have been shown to inhibit the ability of IL-2 to effectively activate T and NK cells. 42 Reactive oxygen species also reduce the expression of the CD3 antigen that is critical to signal transduction in lymphocytes [43][44][45] and trigger apoptosis of cytotoxic lymphocytes.…”

“…2,3 One of the only interventions known to improve relapse rates in patients with AML is allogeneic hematopoietic stem cell transplantation (allo-HCT) used as consolidation or intensification therapy. In contrast, maintenance regimens used after consolidation that are aimed at preventing relapse have not been widely used in AML.…”

Enhancement of ionizing radiation response by histamine in vitro and in vivo in human breast cancer

“…Histamine dihydrochloride is currently safely used in clinical trials as an adjuvant for the potential treatment of different cancers, exhibiting no unexpected or irreversible side effects, 37 and therefore could be an attractive candidate to be used as adjuvant for breast cancer radiotherapy.…”

Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists

“…26,27 It is assumed that histamine inhibits oxygen radical formation via H 2 R mediated inhibition of NADPH oxidase, resulting in the protection of T cells and NK cells. 26 Since histamine activates all four histamine receptor subtypes, the treatment is accompanied by serious side effects like itch, erythema, decrease in blood pressure and gastrointestinal problems. 26,27 Patients could benefit from selective H 2 R stimulation due to reduction of side effects mediated by the other histamine receptor subtypes.…”