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Review
. 2014 Apr 9:3:79-89.
doi: 10.2147/ITT.S37292. eCollection 2014.

Antigen-based immunotherapy for the treatment of acute lymphoblastic leukemia: the emerging role of blinatumomab

Affiliations
Review

Antigen-based immunotherapy for the treatment of acute lymphoblastic leukemia: the emerging role of blinatumomab

Mark R Litzow. Immunotargets Ther. .

Abstract

Acute lymphoblastic leukemia (ALL) arises from immature B and T lymphoblasts. An increasing array of cytogenetic and molecular markers have been identified in ALL, which allows for increasingly sophisticated prognostication, as well as identification of potential new targets for therapy. The treatment of ALL in children has shown astounding success in the last 50 years, with more than 90% of children now able to be cured of their ALL. In adults, these success rates have not been duplicated. However, the use of pediatric-intensive regimens in young adults has shown increasing success. The use of monoclonal antibodies conjugated to drugs, immunotoxins, and cells also has shown early success and promises to enhance the outcome of newly diagnosed patients. Blinatumomab, a bispecific T-cell engager antibody, brings a malignant B cell in proximity to a T cell with redirected lysis. This antibody construct has shown promising results in patients with relapsed and refractory disease and is entering randomized clinical trials in newly diagnosed patients. The addition of monoclonal antibody therapy to chemotherapy in adults promises to enhance outcomes while hopefully not increasing toxicity. After many years of stagnation, it appears that the therapy of adults with ALL is showing significant improvement.

Keywords: CD19; acute lymphoblastic leukemia; blinatumomab; chemotherapy; monoclonal antibodies.

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Figures

Figure 1
Figure 1
Frequency of cytogenetic abnormalities in adult B-ALL. Notes: There may be an overlap between different chromosomal alterations in adult ALL. Copyright © 2013. Reprinted with permission from Dove Medical Press. Kenderian SS, Litzow MR. Acute lymphoblastic leukemia in adolescents and young adults – from genomics to the clinics. Clin Oncol Adolesc Young Adults. 2013;3:49–62. Abbreviations: ALL, acute lymphoblastic leukemia; B-ALL, B-cell acute lymphoblastic leukemia; CRLF2, cytokine receptor-like factor 2; iAMP-21, intrachromosomal amplifications of chromosome 21; MLL, myeloid lymphoid or mixed lineage leukemia; MYC, myelocytomatosis; PAX-5, paired box-5; JAK, janus kinase.
Figure 2
Figure 2
A 50-year journey to cure childhood ALL. Notes: Roman numerals refer to successive trials carried out at St Judes Childrens Hospital. Reprinted from Seminars in Hematology, Vol 50, Pui CH, Evans WE, A 50-year journey to cure childhood acute lymphoblastic leukemia, Pages 185–196, Copyright © 2013, with permission from Elsevier. Abbreviation: ALL, acute lymphoblastic leukemia.
Figure 3
Figure 3
CD19 molecular structure. Notes: CD19 is a type I one-pass transmembrane protein. The two extracellular C2 immunoglobulin-like domains are separated by a small helical nonimmunoglobulin domain with possible disulfide links. The highly conserved, 242 amino acid cytoplasmic domain includes multiple tyrosine residues. Three key tyrosine residues are shown with their associated signaling kinases and molecules. Reprinted from Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1(1):36. Copyright © 2012 Wang et al; licensee BioMed Central Ltd.
Figure 4
Figure 4
Generation and structure of blinatumomab. Notes: Variable domains (variable heavy chain [VH] and variable light chain [VL]) of a CD19-specific monoclonal antibody and a CD3-specific mAb were converted into single-chain antibodies (circle) recombinantly joined by nonimmunogenic linker sequences. Reprinted from Pharmacology and Therapeutics, Vol 136, Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: a historical perspective, Pages 334–342, Copyright © 2012, with permission from Elsevier. Abbreviations: CD, cluster of differentiation; mAb, monoclonal antibody.

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