Clinical Characteristics and Outcome Analysis for HLA Loss Patients Following Partially Mismatched Related Donor Transplantation Using HLA Chimerism for Loss of Heterozygosity Analysis by Next-Generation Sequencing

Andi Wang; Wenjun Li; Fei Zhao; Zhongzheng Zheng; Ting Yang; Sanbin Wang; Jinsong Yan; Jianpin Lan; Shengjin Fan; Mingfeng Zhao; Jianpin Shen; Xin Li; Tonghua Yang; Quanyi Lu; Ying Lu; Hai Bai; Haiyan Zhang; Dali Cai; Ling Wang; Zhiyang Yuan; Erlie Jiang; Fang Zhou; Xianmin Song

doi:10.1177/09636897221102902

Clinical Characteristics and Outcome Analysis for HLA Loss Patients Following Partially Mismatched Related Donor Transplantation Using HLA Chimerism for Loss of Heterozygosity Analysis by Next-Generation Sequencing

Cell Transplant. 2022 Jan-Dec:31:9636897221102902. doi: 10.1177/09636897221102902.

Authors

Andi Wang¹, Wenjun Li², Fei Zhao³, Zhongzheng Zheng⁴, Ting Yang⁵, Sanbin Wang⁶, Jinsong Yan⁷, Jianpin Lan⁸, Shengjin Fan⁹, Mingfeng Zhao¹⁰, Jianpin Shen¹¹, Xin Li¹², Tonghua Yang¹³, Quanyi Lu¹⁴, Ying Lu¹⁵, Hai Bai¹⁶, Haiyan Zhang¹⁷, Dali Cai¹⁸, Ling Wang¹⁹, Zhiyang Yuan⁴, Erlie Jiang³, Fang Zhou², Xianmin Song^{1

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Affiliations

¹ Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Hematology, No. 960 Hospital of People's Liberation Army, Jinan, China.
³ Department of Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
⁴ Tissuebank Biotechnology Co., Ltd, Shanghai, China.
⁵ Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
⁶ Department of Hematology, 920th Hospital of Joint Logistics Support Force, Kunming, China.
⁷ Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Second Hospital of Dalian Medical University, Dalian, China.
⁸ Department of Hematology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
⁹ Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
¹⁰ Department of Hematology, Tianjin First Central Hospital, Tianjin, China.
¹¹ Department of Hematology, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China.
¹² Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha, China.
¹³ Department of Hematology, First People's Hospital of Yunnan Province, Kunming University of Science and Technology Affiliated Kun Hua Hospital, Kunming, China.
¹⁴ Department of Hematology, Zhongshan Hospital of Xiamen University, Xiamen, China.
¹⁵ Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China.
¹⁶ Department of Hematology, The 940th Hospital of the Joint Logistic Support Force of PLA, Lanzhou, China.
¹⁷ Department of Hematology, Linyi People's Hospital, Linyi, China.
¹⁸ Department of Hematology, The First Hospital of China Medical University, Shenyang, China.
¹⁹ Department of Hematology, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, China.
²⁰ Engineering Technology Research Center of Cell Therapy and Clinical Translation, Shanghai Science and Technology Committee, Shanghai, China.

Abstract

Genomic loss of mismatched human leukocyte antigen (HLA loss) is one of the most vital immune escape mechanisms of leukemic cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the methods currently used for HLA loss analysis have some shortcomings. Limited literature has been published, especially in lymphoid malignancies. This study aims to evaluate the incidences, risk factors of HLA loss, and clinical outcomes of HLA loss patients. In all, 160 patients undergoing partially mismatched related donor (MMRD) transplantation from 18 centers in China were selected for HLA loss analysis with the next-generation sequencing (NGS)-based method, which was validated by HLA-KMR. Variables of the prognostic risk factors for HLA loss or HLA loss-related relapse were identified with the logistic regression or the Fine and Gray regression model. An HLA loss detection system, HLA-CLN [HLA chimerism for loss of heterozygosity (LOH) analysis by NGS], was successfully developed. Forty (25.0%) patients with HLA loss were reported, including 27 with myeloid and 13 with lymphoid malignancies. Surprisingly, 6 of those 40 patients did not relapse. The 2-year cumulative incidences of HLA loss (22.7% vs 22.0%, P = 0.731) and HLA loss-related relapse (18.4% vs 20.0%, P = 0.616) were similar between patients with myeloid and lymphoid malignancies. The number of HLA mismatches (5/10 vs <5/10) was significantly associated with HLA loss in the whole cohort [odds ratio (OR): 3.15, P = 0.021] and patients with myeloid malignancies (OR: 3.94, P = 0.021). A higher refined-disease risk index (OR: 6.91, P = 0.033) and donor-recipient ABO incompatibility (OR: 4.58, P = 0.057) contributed to HLA loss in lymphoid malignancies. To sum up, HLA-CLN could overcome the limitations of HLA-KMR and achieve a better HLA coverage for more patients. The clinical characteristics and outcomes were similar in patients with HLA loss between myeloid and lymphoid malignancies. In addition, the results suggested that a patient with HLA loss might not always relapse.

Keywords: HLA loss; hematopoietic stem cell transplantation (HSCT); human leukocyte antigen (HLA); next-generation sequencing (NGS).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chimerism
Graft vs Host Disease* / etiology
HLA Antigens / genetics
Hematopoietic Stem Cell Transplantation* / methods
High-Throughput Nucleotide Sequencing
Humans
Loss of Heterozygosity / genetics
Neoplasms*
Recurrence

Substances

HLA Antigens