Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4-10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6-11.4, p < 0.01) were significantly associated with L-asparaginase hypersensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3-10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6-13.3, p < 0.01)]

Chan, GCF

Chan, YS

Cheuk, DKL

Chiang, AKS

Chu, WK

Chua, GT

Ha, SY

Ho, MHK

Ip, P

Kwan, MYW

Kwok, J

Lau, YL

Lee, PPW

Leung, AWK

Leung, WH

Li, CK

Ling, ASC

Liu, APY

Luk, CW

Rosa Duque, JS

Wong, ICK

Wong, WHS

Yiu, OKF

English

UCL Discovery

Chua et al. J Hematol Oncol          (2021) 14:182  https://doi.org/10.1186/s13045-021-01201-3LETTER TO THE EDITORHLA alleles associated with asparaginase hypersensitivity in Chinese childrenGilbert T. Chua1,2†, Jaime S. Rosa Duque1,2†, Daniel Ka Leung Cheuk1,2, Alex Wing Kwan Leung2,3, Wilfred Hing Sang Wong1, Anthony Pak Yin Liu1,2, Pamela P. W. Lee1,2, Shau Yin Ha1,2, Alan Kwok Shing Chiang1,2, Marco Hok Kung Ho1, Wai Keung Chu4, Yuk Sing Chan4, Chun Wing Luk2, Alvin Siu Cheung Ling2, Mike Yat Wah Kwan5, Oscar Kuen Fong Yiu1, Ian Chi Kei Wong6,7,8, Yu Lung Lau1,2, Chi Kong Li2,3, Wing Hang Leung1,2, Godfrey Chi Fung Chan1,2, Patrick Ip1,2* and Janette Kwok4* Abstract Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4–10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6–11.4, p < 0.01) were significantly associated with l-asparaginase hyper-sensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3–10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6–13.3, p < 0.01)].Keywords: Human leukocyte antigens, Asparaginase, Hypersensitivity, Allergy, Chinese, Children© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.To the editor:Asparaginase is one of the essential drugs for the curative treatment of acute lymphoblastic leukaemia (ALL) [1]. About 30–75% of patients receiving native Escherichia coli asparaginase experience hypersensitivity reactions [1, 2]. Furthermore, patients who were inadequately treated with asparaginase because of hypersensitivity reactions have worse outcomes compared with patients with fewer reactions that can tolerate more asparaginase doses [3]. Recent studies involving patients with European ances-try showed that the rs6021191 variant in NFATC2 and the rs17885382 in HLA-DRB1 were associated with an increased risk of asparaginase hypersensitivity [4, 5]. Nevertheless, data from the Chinese populations are lacking.Between 1 January 2009 and 31 December 2019, 107 Chinese patients with ALL, mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received aspar-aginases with HLA typing performed were analysed. The detailed study methodology is described in Additional file  1. There were no significant differences in terms of the demographics, primary diagnoses and outcomes of the patients with and without asparaginase hypersensitiv-ity (Table  1). The distribution of asparaginase exposure, hypersensitivity and anaphylaxis to l-asparaginase, peg-asparaginase and erwinase is illustrated in Additional Open Access*Correspondence:  patricip@hku.hk; kwoksy@ha.org.hk†Gilbert T. Chua and Jaime S. Rosa Duque co-first authors1 Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, 1/F, New Clinical Building, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China4 Division of Transplantation and Immunogenetics, Department of Pathology, Queen Mary Hospital, 15/F, Block T102 Pokfulam Road, Pokfulam, Hong Kong SAR, ChinaFull list of author information is available at the end of the articlePage 2 of 4Chua et al. J Hematol Oncol          (2021) 14:182 file 1: Table S1. None of them developed the reactions on the first dose of injection.HLA-B*51:01 was enriched among children with at least one asparaginase hypersensitivity, and HLA-B*46:01, DRB1*09:01 and B*51:01 were enriched among children l-asparaginase allergies (Additional file  1). HLA-B*46:01 (OR 3.8, 95% CI 1.4–10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6–11.4, p < 0.01) were significantly associated with l-asparaginase hypersen-sitivity. Multiple logistic regression showed that HLA-B*46:01 (adjusted OR 3.5, 95% CI 1.3–10.5, p = 0.02) and DRB1*09:01 (adjusted OR 4.4, 95% CI 1.6–13.3, p < 0.01) remained significantly associated with l-asparaginase allergy after adjusting for age, gender and the diagno-sis of B cell ALL. HLA-B*51:01 was not associated with any asparaginase hypersensitivities (Table  2). Of note, Table 1 Comparison of demographics, diagnoses and outcomes between patients with and without asparaginase hypersensitivity to at least one form of asparaginaseALL, acute lymphoblastic leukaemia; BMT, bone marrow transplantation; Ph + , Philadelphia chromosome# Some patients have multiple allergic conditionsAsparaginase hypersensitivityN = 71No asparaginase hypersensitivityN = 36p valuesDemographicsMedian age at diagnosis (years, interquartile ranges) 4.6 (2.2–12.0) 6.1 (2.1–14.1) 0.53Male (%) 47 (66.2) 22 (61.1) 0.67Other  allergies# 10 (14.8) 1 (2.8) 0.09Drug hypersensitivity 6 1 –Asthma 2 0 –Eczema 2 0 –Allergic rhinitis 2 0 –Food allergy 1 0 –DiagnosesB lineage ALL (%) 54 (76.1) 23 (63.9) 0.25B cell ALL (%) 46 (64.8) 16 (44.4) 0.06Infant ALL (%) 5 (7.0) 5 (13.9) 0.30Ph + ALL (%) 3 (4.2) 2 (5.6) 0.99T cell ALL (%) 10 (14.1) 7 (19.4) 0.58Mixed phenotype acute leukaemia (%) 2 (2.8) 4 (11.1) 0.18T cell lymphoma (%) 5 (7.0) 2 (5.6) 0.99OutcomesDisease relapse (%) 37 (52.1) 18 (50.0) 0.84BMT (%) 34 (47.9) 16 (44.4) 0.84Death (%) 22 (31.0) 13 (36.1) 0.66Table 2 HLA alleles associated with asparaginase hypersensitivityCI, confidence interval; HLA, human leukocyte antigen; NA, not applicable; and OR, odds ratio* p < 0.05# Adjusted for, age, gender and the diagnosis of B cell acute lymphoblastic leukaemiaHLA alleles OR (95% CI) p value Adjusted  OR# (95% CI) Adjusted p  value#HLA allele associated with at least one asparaginase hypersensitivityB*51:01 1.2 (0.5–3.1) 0.81 NA NAHLA alleles associated with  l-aspara-ginase hypersensitivityB*46:01 3.8 (1.4–10.1)  < 0.01* 3.5 (1.3–10.5) 0.02*B*51:01 1.3 (0.5–3.4) 0.81 NA NADRB1*09:01 4.3 (1.6–11.4)  < 0.01* 4.4 (1.6–13.3)  < 0.01*Page 3 of 4Chua et al. J Hematol Oncol          (2021) 14:182  19 patients carried both HLA-B*46:01 and DRB1*09:01. 18 of them (94.7%) had l-asparaginase hypersensitiv-ity, and 10 of them (52.6%) also had peg-asparaginase hypersensitivity.This is the first study that explores the association between HLA genotypes and asparaginase hypersensi-tivity among Han Chinese children. HLA-B*46:01 and DRB1*09:01 were significantly associated with l-aspar-aginase hypersensitivity. A previous study involving patients with European ancestry showed that HLA-DRB1*07:01 was a high-risk allele associated with aspar-aginase hypersensitivity [5]. However, a subsequent study did not reproduce the same association in the Asian ancestry, probably due to the smaller Asian sam-ple size [4]. We identified another HLA class II allele, HLA-DRB1*09:01, being associated with l-asparaginase hypersensitivity. HLA class II molecule was implicated in various IgE-mediated allergies, including asthma, food and drug hypersensitivities [6, 7], and different HLA alleles have also been implicated in allergic dis-eases among different ethnic populations [8]. Our study also demonstrated that HLA-B*46:01, a class I allele, was associated with immediate-type l-asparaginase hyper-sensitivity. Conventionally, HLA class I alleles were known to be associated with severe cutaneous adverse reactions (SCAR), such as the association between HLA-B*15:02 and carbamazepine-induced SJS [9]. However, a recent study in children and adults has demonstrated the role of allergen-specific CD8 + T cells with IgE-mediated peanut hypersensitivity and was associated with HLA-A*02:01 [10], therefore, indicating the IgE-mediated immediate-type reactions are not limited to be associated with HLA class II alleles, but also class I alleles.The management of l-asparaginase hypersensitiv-ity varies between centres, mainly depending on the availability of expertise and alternative drugs, includ-ing peg-asparaginase and Erwinase. In centres where access to peg-asparaginase and Erwinase is limited, an alternative approach using steroid and anti-his-tamines as pre-medications followed by desensitisa-tion if needed [11]. Evaluation of polyethylene glycol (PEG) hypersensitivity may be warranted in patients with exclusive peg-asparaginase allergies or a history of allergic reactions to drugs containing PEG as excipi-ents. 80% of our patients with exclusive peg-asparagi-nase hypersensitivity carry HLA-A*11:01. This group of patients is possibly allergic to the PEG molecule rather than the asparaginases. PEGs are used widely in drugs, cosmetics and laxatives, and hypersensitivity to PEGs can be severe but rare [12]. Patients who are allergic to PEGs usually reacted against PEGs of higher molecu-lar weights and higher concentrations. Skin prick and intradermal skin tests are possible ways to investigate PEGs allergies [12]. The identification and addition of pre-treatment HLA typing may provide a guide for individualised treatment design in choosing aspara-ginase preparations to minimise the risk of allergic reactions.This study has to be interpreted with several cave-ats. First, only patients who had higher risk or relapsed diseases had HLA genotyping performed in anticipa-tion to receive bone marrow transplantation. There is a possibility that the relapsed cases may have a higher chance of developing asparaginase hypersensitivity as they have a higher exposure to asparaginases. Never-theless, there were no significant differences between our patients with and without asparaginase hypersensi-tivity in their clinical outcomes. Second, these patients identified as having asparaginase hypersensitivities were based on clinical observations. Additional inves-tigations such as serum tryptase level and drug pro-vocative test were not performed. Nevertheless, these allergic reactions were all being evaluated and clearly documented by their physicians-in-charge. Therefore, the labelling of asparaginase allergy can be considered as reliable.The identification of ethnic-specific high-risk HLA alleles may help guide choosing which preparations of asparaginase to use and possibly the early involvement of allergists in managing these at-risk patients. A large-scale, prospective, Chinese studies will be warranted to confirm the findings.AbbreviationsALL: Acute lymphoblastic leukaemia; BMT: Bone marrow transplantation; CI: Confidence intervals; HLA: Human leukocyte antigen; IgE: Immunoglobulin E; NHL: Non-Hodgkin lymphoma; OR: Odds ratio; PEG: Polyethylene glycol.Supplementary InformationThe online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13045- 021- 01201-3.Additional file 1. The Additional File contains the details of the study methodology and results of the enrichment analysis, including data retrieval, HLA typing, identification of HLA alleles enriched and associated with asparaginase hypersensitivity, and statistical analysis.AcknowledgementsNone.Authors’ contributionsJK and PI have assessed and verified the data. GTC, JSRD, PI and JK contributed to concept and design. DKLC, AWKL, APYL, PPWL, SYH, AKSC, MHKH, WKC, YSC, CWL, ASCL, MYWK, YLL, CKL, LWH and GCFC were involved in acquisition of data. WHSW, GTC, DKLC, OKFY and ICKW contributed to statistical analysis. All authors were involved in interpretation of data. GTC, JSRD, AWKL and APYL contributed to literature review. GC and JSRD were involved in drafting of the manuscript. All authors contributed to critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.Page 4 of 4Chua et al. J Hematol Oncol          (2021) 14:182 • fast, convenient online submission •  thorough peer review by experienced researchers in your field•  rapid publication on acceptance•  support for research data, including large and complex data types•  gold Open Access which fosters wider collaboration and increased citations  maximum visibility for your research: over 100M website views per year •  At BMC, research is always in progress.Learn more biomedcentral.com/submissionsReady to submit your research ?  Choose BMC and benefit from: FundingNone.Availability of data and materialsThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.DeclarationsEthics approval and consent to participateThe University of Hong Kong/Hospital Authority Hong Kong West Cluster Institutional Review Board (Reference number: UW 21-208) and the Hong Kong Children’s Hospital Research Ethics Committee (Reference number: HKCH-REC-2021-22) approved the study.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Author details1 Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, 1/F, New Clinical Building, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China. 2 Depart-ment of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Kowloon, Hong Kong SAR, China. 3 Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. 4 Division of Trans-plantation and Immunogenetics, Department of Pathology, Queen Mary Hospital, 15/F, Block T102 Pokfulam Road, Pokfulam, Hong Kong SAR, China. 5 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Kwai Chung, Hong Kong SAR, China. 6 Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Shatin, Hong Kong SAR, China. 7 Centre for Safe Medication Practice and Research, Depart-ment of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. 8 Research Department of Practice and Policy, UCL School of Pharmacy, University College, London, UK. Received: 23 August 2021   Accepted: 25 October 2021References 1. Appel IM, Kazemier KM, Boos J, et al. Pharmacokinetic, pharmacody-namic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008;22(9):1665–79. https:// doi. org/ 10. 1038/ leu. 2008. 165. 2. Bowman WP, Larsen EL, Devidas M, et al. Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children’s Oncology Group trial P9906. Pediatr Blood Cancer. 2011;57(4):569–77. https:// doi. org/ 10. 1002/ pbc. 22944. 3. Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana–Farber Consortium Protocol 91–01. Blood. 2001;97(5):1211–8. https:// doi. org/ 10. 1182/ blood. v97.5. 1211. 4. Fernandez CA, Smith C, Yang W, et al. Genome-wide analysis links NFATC2 with asparaginase hypersensitivity. 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HLA alleles associated with asparaginase hypersensitivity in Chinese children

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HLA alleles associated with asparaginase hypersensitivity in Chinese children

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