Page 115 - 2019_02-Haematologica-web

Acute Lymphoblastic Leukemia
Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcεRI and FcγRIII
Ferrata Storti Foundation
Haematologica 2019 Volume 104(2):319-329
Sanjay Rathod,1 Manda Ramsey,1 Mary V. Relling,2 Fred D. Finkelman3 and Christian A. Fernandez1
1Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, PA; 2Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN; 3Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine and the Division of Immunobiology, Cincinnati Children's Hospital Medical Center,
OH, USA.
ABSTRACT
Asparaginase is an important drug for the treatment of leukemias. However, anti-asparaginase antibodies often develop, which can decrease asparaginase drug levels and increase the risk of relapse. The aim of this study is to identify the immunoglobulin iso- types and receptors responsible for asparaginase hypersensitivities. Mice immunized with asparaginase developed anti-asparaginase IgG1 and IgE antibodies, and challenging the sensitized mice with asparagi- nase induced severe hypersensitivity reactions. Flow cytometry analy- sis indicated that macrophages/monocytes, neutrophils, and basophils bind asparaginase ex vivo through FcγRIII. In contrast, asparaginase binding to basophils was dependent on FcγRIII and IgE. Consistent with the asparaginase binding data, basophil activation by asparagi- nase occurred via both IgG/FcγRIII and IgE/FcεRI. Depleting >95% of B cells suppressed IgG but not IgE-dependent hypersensitivity, while depleting CD4+ T cells provided complete protection. Combined treat- ment with either anti-IgE mAb plus a platelet-activating factor receptor antagonist or anti-FcγRIII mAb plus a H1 receptor antagonist sup- pressed asparaginase hypersensitivity. The observations indicate that asparaginase hypersensitivity is mediated by antigen-specific IgG and/or IgE through the immunoglobulin receptors FcγRIII and FcεRI, respectively. Provided that these results apply to humans, they empha- size the importance of monitoring both IgE- and IgG-mediated asparaginase hypersensitivities in patients receiving this agent.
Introduction
L-Asparaginase (ASNase) is given repeatedly during treatment regimens for acute lymphoblastic leukemia (ALL). The non-human enzyme is derived from bacteria and inhibits leukemic cell proliferation by depleting asparagine.1 The most common adverse reaction of ASNase in children results from the production of anti-ASNase antibodies (seen in up to 70% of patients) and the onset of clinical hypersensitivity reactions during treatment.2-7 ASNase-mediated hypersensitivity can occur in 30- 75% of patients receiving native E. coli ASNase3,8-10 and typically manifest as urticaria, angioedema, bronchospasm, dyspnea, and anaphylaxis.11 Typically, if a patient develops a hypersensitivity reaction to first-line PEG-ASNase, a substitution with Erwinia ASNase is recommended; a subsequent reaction to Erwinia ASNase may necessitate discontinuing ASNase therapy.12 In addition, the development of anti- ASNase antibodies can increase the risk of relapse by neutralizing ASNase in vivo.13
ASNase-mediated hypersensitivity during ALL treatment is most common upon drug re-exposure,2 this suggests that patients are sensitized to the agent earlier in therapy. However, the mechanism of ASNase hypersensitivity is not clear, as some patients develop reactions in the absence of detectable anti-ASNase IgG antibody. Moreover, many patients who have circulating anti-ASNase IgG never develop a
Correspondence:
chf63@pitt.edu
Received: June 8, 2018.
Accepted: September 20, 2018. Pre-published: September 20, 2018.
doi:10.3324/haematol.2018.199448
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/319
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(2)
319
ARTICLE