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.

Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia

“…Previously published data on T-LGL describe lowered expression of CD52 on the cell surface but not complete absence. 43 In contrast to this report and others on B-cell lymphoma, [39][40][41][42] we demonstrated here that CD52 is decreased in a subset of patients with LGL as a distinct immunophenotypic feature independent of alemtuzumab therapy. Moreover, we found that patients with CD52-negative LGL are refractory to alemtuzumab treatment and that the proportion of deficient cells increases during therapy, likely due to a selection process.…”

“…Based on reports of the emergence of lymphocytes deficient in the expression of GPI-anchored proteins mimicking a PNH phenotype after treatment with alemtuzumab, [39][40][41][42] we investigated whether down-modulated expression of GPI-anchored CD52 may be responsible for the incomplete response rate documented in our LGL patients. Our observation of CD52-negative LGL in the context of alemtuzumab therapy parallels earlier findings in B-cell lymphoma treated with alemtuzumab: decreased membrane expression of CD52 was accompanied by decreased expression of other otherwise constitutively expressed GPI-deficient proteins, including CD55 and CD59.…”

Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG)

“…Similar immunophenotypic changes were described for patients with rheumatoid arthritis and refractory B-NHL including B-CLL receiving alemtuzumab. 30,36,37 PIG-AP-deficient cells were not only observed in T cells and monocytes, 30 but also in granulocytes and erythrocytes which showed diminished expression of CD52. It is hypothesized that alemtuzumab, which targets the PIG-AP CD52, leads to the expansion of a PIG-anchor-deficient cell clone with the phenotypic characteristics of PNH cells.…”

High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H

“…Studies in CLL have shown that, in some individuals, there is emergence of a paroxysmal nocturnal hemoglobinuria, CD52 Ϫ clone following treatment with CAMPATH-1H. 20 This clone was probably present at a very low level prior to treatment and is selected out after elimination of CD52 ϩ cells. Another possibility is the acquisition of new somatic mutations in the PIGA gene.…”