title: Immunoconjugates in the management of hairy cell leukemia.
abstract: Hairy cell leukemia (HCL) is an indolent B-cell malignancy effectively treated but not often cured by purine analog therapy; after multiple courses of purine analogs, patients can become purine analog resistant and in need of alternative therapies. Complete remission to single-agent purine analog is often accompanied by minimal residual disease (MRD), residual HCL cells detectable by immunologic methods, considered a risk factor for eventual relapse. Several different non-chemotherapy approaches are being used to target relapsed and refractory HCL, including inhibitors of BRAF, but so far only monoclonal antibody (MAb)-based approaches have been reported to eliminate MRD in a high percentage of patients. One of the MAb-based options for HCL currently under clinical investigation involves recombinant immunotoxins, containing a fragment of a MAb and a bacterial toxin. The bacterial toxin, a highly potent fragment from Pseudomonas exotoxin, catalytically ADP-ribosylates elongation factor 2 (EF2), resulting in protein synthesis inhibition and apoptotic cell death. Recombinant immunotoxins tested in HCL patients include LMB-2, targeting CD25, and BL22, targeting CD22. An affinity matured version of BL22, termed moxetumomab pasudotox (formerly HA22 or CAT-8015) achieved high CR rates in phase I, and is currently undergoing multicenter Phase 3 testing. Phase I testing was without dose-limiting toxicity, although 2 patients had grade 2 hemolytic uremic syndrome (HUS) with transient grade 1 abnormalities in platelets and creatinine. Preclinical work is underway to identify residues on moxetumomab pasudotox leading to immunogenicity. Moxetumomab pasudotox is undergoing pivotal testing for relapsed and refractory HCL.
authors.affiliation: The Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37/5124b, 9000 Rockville Pike Bethesda, MD 20892-4255, USA. Electronic address: kreitmar@mail.nih.gov.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
authors.affiliation: The Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37/5124b, 9000 Rockville Pike Bethesda, MD 20892-4255, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000627:therapeutic use*; D017338:Cladribine / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D005098:Exotoxins / Q000627:therapeutic use*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007943:Leukemia, Hairy Cell / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D009154:Mutation; D018365:Neoplasm, Residual; D015649:Pentostatin / Q000627:therapeutic use; D020652:Peptide Elongation Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D012074:Remission Induction; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D001427:Bacterial Toxins; D005098:Exotoxins; D018796:Immunoconjugates; D020652:Peptide Elongation Factor 2; C541974:immunotoxin HA22; D015649:Pentostatin; D017338:Cladribine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BL22; CD22; CD25; Moxetumomab pasudotox; Pseudomonas exotoxin; Recombinant immunotoxin