Abstract
The interleukin-3 receptor alpha chain (IL-3Rα), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 is expressed at both the level of leukemic stem cells (LSCs) and more differentiated leukemic blasts, which makes CD123 an attractive therapeutic target. Various agents have been developed as drugs able to target CD123 on malignant leukemic cells and on the normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed of a truncated diphtheria toxin payload fused to IL-3, was approved for use in patients with BPDCN in December of 2018 and showed some clinical activity in AML. Different monoclonal antibodies directed against CD123 are under evaluation as antileukemic drugs, showing promising results either for the treatment of AML minimal residual disease or of relapsing/refractory AML or BPDCN. Finally, recent studies are exploring T cell expressing CD123 chimeric antigen receptor-modified T-cells (CAR T) as a new immunotherapy for the treatment of refractory/relapsing AML and BPDCN. In December of 2018, MB-102 CD123 CAR T developed by Mustang Bio Inc. received the Orphan Drug Designation for the treatment of BPDCN. In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.
Highlights
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are heterogeneous disorders originated from hematopoietic stem cells (HSCs) through the progressive and sequential acquisition of genetic and epigenetic alterations that cause a clonal expansion of myeloid progenitors/precursors in the bone marrow and peripheral blood, exhibiting disease-specific phenotypes mainly represented by impaired cell differentiation and increased proliferation [1]
Of patients Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplications (ITD)-positive at diagnosis lost FLT3-ITD mutation [21]. These observations suggest that in NMP1-mutated acute myeloid leukemia (AML), relapse often originates from persistent leukemic clones; NPM1mut loss occurring in a minority of cases suggests a second “de novo” or treatment-associated AML [21]. These findings were in line with a recent study carried out in sequentially inducible mouse models showing that NPM1 mutation causes leukemic transformation and evolution of DNA methyltransferase 3A (DNMT3A)-mutant clonal hematopoiesis; interestingly, the rate of disease progression is accelerated with longer latency of clonal hematopoiesis [22]
The results of this study provided the basis for a targeted therapy option for patients with blastic plasmacytoid dendritic neoplasm (BPDCN)
Summary
There are three different approaches to try to improve the treatment of acute leukemia:. These observations suggest that in NMP1-mutated AMLs, relapse often originates from persistent leukemic clones; NPM1mut loss occurring in a minority of cases suggests a second “de novo” or treatment-associated AML [21] These findings were in line with a recent study carried out in sequentially inducible mouse models showing that NPM1 mutation causes leukemic transformation and evolution of DNMT3A-mutant clonal hematopoiesis; interestingly, the rate of disease progression is accelerated with longer latency of clonal hematopoiesis [22]. MacMahon and coworkers recently showed through a single-cell DNA sequencing that different patterns of clonal selection and evolution occur in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expression of alternative WT-FLT3 subclones (or both patterns simultaneously), secondary FLT3-F619L gatekeeper mutations or BCR-ABL1 fusions [23] These observations strongly support the need for the development of combinatorial targeted therapeutic approaches for advanced AML [23]. These observations support the view that pre-existing MDS stem cells drive disease progression and transformation to sAML
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