title: The PNH phenotype cells that emerge in most patients after CAMPATH-1H therapy are present prior to treatment.
abstract: Paroxysmal nocturnal haemoglobinuria (PNH) cells are deficient in glycosylphosphatidylinositol (GPI) linked antigens due to a somatic mutation of the PIG-A gene in a haemopoietic stem cell. It appears that a PNH clone reaches detectable proportions only when there is selection in its favour. GPI-deficient T lymphocytes have been identified in patients treated with CAMPATH-1H, a monoclonal antibody against the GPI-linked CD52 molecule. CAMPATH-1H selects for cells that are deficient in CD52 (such as PNH-like cells) promoting the development of a PNH-like clone (analogous to PNH). We report that 10/15 patients with chronic lymphocytic leukaemia developed PNH-like lymphocytes after therapy with CAMPATH-1H. The remaining five patients developed no PNH-like cells at any stage, including one patient who received 12 weeks of therapy. The inactivating PIG-A mutation has been identified in one patient. This mutation was detectable by an extremely sensitive mutation-specific PCR-based analysis in the patient's mononuclear cells prior to CAMPATH-1H therapy. The frequency and phenotype of GPI-deficient lymphocytes after CAMPATH-1H and the detection of a PIG-A mutation in the lymphocytes prior to CAMPATH-1H therapy indicated that such mutations were present in a very small proportion of cells prior to selection in their favour by CAMPATH-1H. This suggests that a large proportion of individuals have cells with PIG-A mutations that are not detectable by flow cytometry and thus may have the potential to develop PNH.
authors.affiliation: Department of Haematology, University of Leeds, Leeds General Infirmary.
authors.forename: A C
authors.initials: AC
authors.lastname: Rawstron
authors.forename: S J
authors.initials: SJ
authors.lastname: Rollinson
authors.forename: S
authors.initials: S
authors.lastname: Richards
authors.forename: M A
authors.initials: MA
authors.lastname: Short
authors.forename: A
authors.initials: A
authors.lastname: English
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: G
authors.initials: G
authors.lastname: Hale
authors.forename: P
authors.initials: P
authors.lastname: Hillmen
mesh_terms: D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D017261:Glycosylphosphatidylinositols / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D012680:Sensitivity and Specificity
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D017261:Glycosylphosphatidylinositols; D000074323:Alemtuzumab