The current treatment approach for myeloid malignancies is heavily dependent on intensive chemotherapy regimens that follow the old strategy of “one size fits all”. Novel targeted agents are emerging in clinical practice and clinical trials. Data on their efficacy and tolerability are promising, although no treatment has produced a cure thus far [1]. Intensive chemotherapy treatments are designed to induce hypocellular marrow and allow hematopoietic stem cells to recover and resume normal production of blood cell components. The durability and duration of remission by this kind of therapy can vary and will depend primarily on the mutational signature of the disease and epigenetic aberration. In addition, the planned consolidation strategy, whether it is allogeneic stem cell transplantation or further consolidative chemotherapy, has an effect on leukemia-free survival and how deeply we can eradicate leukemic stem cells. New agents that target actionable mutations, such as FLT3 and IDH, have been approved for clinical practice [2,3]. However, they have not had a significant enough effect on overall survival rates to replace chemotherapy, partly because of the diversity of cytogenetic abnormalities and the clonal evolution of new mutations. Nevertheless, it is important to assess the performance status and comorbidities of these treatments before exploring which treatment approach is the most appropriate in terms of toxicity and survival. Unfortunately, even with the most intensive treatment, the risk of relapse is high in the first two years, especially in patients with adverse cytogenetic profiles [4]. Extensive time and effort were spent in clinical trials optimizing the sequence of well-known acute leukemia chemotherapy protocols. There is a need to revolutionize the treatment of acute leukemia.

Unlike traditional chemotherapy, the specificity of the target on the tumor cells is the focus of the new era in cancer treatment. Various examples have been investigated in clinical trials, and many agents have been approved and are available in clinical practice. These include, for example, tyrosine kinase inhibitors to target the FLT3 mutation, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T cell therapies. The ideal target, for example, in acute myeloid and lymphoid leukemia, is highly expressed in leukemic blasts, with minimal or no expression on normal hematopoietic cells, to induce deeper remission. Targets that have been studied in acute myeloid leukemia include CD33, CD135, FLT3, CXCR4, and vascular endothelial growth factor [5]. This article focuses on the diphtheria toxin-interleukin 3 fusion protein as a targeted therapy to leukemic blasts.

Hematopoiesis is a complex process with multiple factors, undertaken to avoid the production of clones and leukemic stem cells. Interleukin 3 (IL-3) is one of the growth factors and cytokines that participate in this process at the level of granulocytic and monocytic lineage [6]. Expression of the interleukin 3 receptor (IL-3R) starts at the CD34⁺ hematopoietic cell and is maintained during all stages of development for granulocytes and monocyte precursors. Multiple investigators have targeted this receptor for the treatment of different types of myeloid leukemia [7]. Most recently, experiments have used chimeric antigen receptor T cell technology to target CD123 in Hodgkin lymphoma in an effort to overcome the immunosuppressed microenvironment and allow the patient’s T lymphocytes to attack tumor cells [8]. The structure of IL-3R consists of an α subunit, which is the site of ligand attachment and represents the specificity of the receptor, and a β subunit, which is shared with the granulocyte-macrophage colony-stimulating factor and is important for signal transduction, internalization of the ligand–receptor complexes, and activation through phosphorylation of the Ras pathway [9].

The development of monoclonal antibodies and cytokines was a major advance in cancer treatment because of their ability to deliver cancer therapies, such as cytotoxic drugs, isotopes, and toxins. Toxins are powerful pro-apoptosis agents, and they achieve their cellular effect by various pathways. One of them is by shutting down protein synthesis [10]. After removal of the natural binding domain of the toxins, they are conjugated to a monoclonal antibody or cytokine as their ligand [11]. One toxin that has been used in cancer therapy is the diphtheria toxin, which is an exotoxin secreted by Corynebacterium diphtheriae [12]. This toxin inhibits protein synthesis in the host, which is the underlying pathophysiology of diphtheria infection [8]. Previously, the diphtheria toxin was engineered to target interleukin-2 and was approved by the Food and Drug Administration (FDA) in 2002 for the treatment of cutaneous T cell lymphoma [13]. However, because of the side effects, marketing of this drug was discontinued by the manufacturer.

Diphtheria toxin consists of three domains and several linkers elements: The C terminus binding domain, the N terminus catalytic domain, and the translocation domain [14]. IL-3 is a cytokine that promotes the differentiation of hematopoietic stem cells into various myeloid cells [12]. IL-3R is composed of two subunits (α and β). The α subunit (CD123) directly binds to IL-3, whereas the β subunit (CDw131) functions as the signaling subunit (see Figure 1) [10]. The idea is to remove the diphtheria toxin binding domain and replace it with IL-3 to target leukemic stem cells that express CD123 and CDw131 by inhibiting intracellular protein synthesis and therefore inducing cell death.

2. Clinical Trials