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Mutations in PIGA cause a CD52-/GPI-anchor-deficient phenotype complicating alemtuzumab treatment in T-cell prolymphocytic leukemia.

Authors :
Johansson P
Klein-Hitpass L
Röth A
Möllmann M
Reinhardt HC
Dührsen U
Dürig J
Source :
European journal of haematology [Eur J Haematol] 2020 Dec; Vol. 105 (6), pp. 786-796. Date of Electronic Publication: 2020 Sep 28.
Publication Year :
2020

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.<br />Methods: We performed flow cytometry and real-time-PCR for CD52-expression and next generation sequencing for PIGA mutational analyses.<br />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.<br />Conclusion: These data indicate that PIGA mutations were acquired during or after completion of alemtuzumab treatment.<br /> (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Details

Language :
English
ISSN :
1600-0609
Volume :
105
Issue :
6
Database :
MEDLINE
Journal :
European journal of haematology
Publication Type :
Academic Journal
Accession number :
32875608
Full Text :
https://doi.org/10.1111/ejh.13511