title: Immunoconjugates and new molecular targets in hairy cell leukemia.
abstract: Hairy cell leukemia (HCL) is a B-cell malignancy that in its classic form is exquisitely sensitive to single-agent purine analog therapy, but that is associated in many patients with late relapse and eventual purine analog resistance. Minimal residual disease, which is present in most patients achieving complete remission with purine analogs, retains Ags that are ideal for targeted therapy. Rituximab, which targets CD20, is active as a single agent, particularly if combined with purine analogs. Recombinant immunotoxins targeting either CD25 or CD22 and containing truncated Pseudomonas exotoxin have achieved major responses in relapsed/refractory HCL. Moxetumomab pasudotox in phase 1 testing achieved responses in 86% of such patients (complete in 46%) without dose limiting toxicity and often without MRD. Soluble CD22 has been used for improved detection and monitoring of HCL, particularly the poor-prognosis variant that lacks CD25. Ig rearrangements unique for each HCL patient have been cloned, sequenced, and followed by real-time quantitative PCR using sequence-specific reagents. Analysis of these rearrangements has identified an unmutated IGVH4-34-expressing poor-prognosis variant with immunophenotypic characteristics of either classic or variant HCL. The BRAF V600E mutation, reported in 50% of melanomas, is present in > 85% of HCL cases that are both classic and express rearrangements other than IGVH4-34, making HCL a potential target for specific inhibitors of BRAF V600E. Additional targets are being defined in both classic and variant HCL, which should improve both detection and therapy.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000378:metabolism; D001427:Bacterial Toxins / Q000627:therapeutic use; D005098:Exotoxins / Q000627:therapeutic use; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism*; D016130:Immunophenotyping / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007943:Leukemia, Hairy Cell / Q000276:immunology* / Q000628:therapy*; D008495:Medical Oncology / Q000379:methods*; D008954:Models, Biological; D009154:Mutation; D011379:Prognosis; D011687:Purines / Q000737:chemistry; D000069283:Rituximab; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000096:biosynthesis; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001427:Bacterial Toxins; D005098:Exotoxins; D018796:Immunoconjugates; D053645:Interleukin-2 Receptor alpha Subunit; D011687:Purines; D051918:Sialic Acid Binding Ig-like Lectin 2; C541974:immunotoxin HA22; D000069283:Rituximab; C030985:purine