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- Title
Mutations in PIGA cause a CD52‐/GPI‐anchor‐deficient phenotype complicating alemtuzumab treatment in T‐cell prolymphocytic leukemia.
- Authors
Johansson, Patricia; Klein‐Hitpass, Ludger; Röth, Alexander; Möllmann, Michael; Reinhardt, Hans Christian; Dührsen, Ulrich; Dürig, Jan
- Abstract
Objective: Infusional alemtuzumab followed by consolidating allogeneic hematopoietic stem cell transplantation in eligible patients is considered a standard of care in T‐cell prolymphocytic leukemia (T‐PLL). Antibody selection against CD52 has been associated with the development of CD52‐negative leukemic T cells at time of relapse. Clinical implications and molecular mechanisms underlying this phenotypic switch are unknown. Methods: We performed flow cytometry and real‐time‐PCR for CD52‐expression and next generation sequencing for PIGA mutational analyses. Results: We identified loss of CD52 expression after alemtuzumab treatment in two of 21 T‐PLL patients resulting from loss of GPI‐anchor expression caused by inactivating mutations of the PIGA gene. One patient with relapsed T‐PLL exhibited a single PIGA mutation, causing a CD52‐negative escape variant of the initial leukemic cell clone, preventing alemtuzumab‐retreatment. The second patient with continued complete remission after alemtuzumab treatment harbored three different PIGA mutations that affected either the non‐neoplastic T cell or the mononuclear cell compartment and resulted in symptomatic paroxysmal nocturnal hemoglobinuria. Next generation sequencing of T‐PLL cells collected before the initiation of treatment revealed PIGA wild‐type sequence reads in all 16 patients with samples available for testing. Conclusion: These data indicate that PIGA mutations were acquired during or after completion of alemtuzumab treatment.
- Subjects
PAROXYSMAL hemoglobinuria; HEMATOPOIETIC stem cell transplantation; GENETIC mutation; LYMPHOCYTOSIS; CLONE cells; LEUKEMIA; ALEMTUZUMAB
- Publication
European Journal of Haematology, 2020, Vol 105, Issue 6, p786
- ISSN
0902-4441
- Publication type
Article
- DOI
10.1111/ejh.13511