Iranian Journal of Immunology

Rescue of HLH with T and B Lymphocyte Involvement Due to Epstein-Barr Virus by PD-1 Inhibitor/Ruxolitinib and Rituximab Combination Regimens: A Case Report

Document Type : Case Report

Authors

Miao Zhu 1, 2
Jun Zhang 2
Qingqing Shi 2
Xing Sun 2
Haibo Wang 1
Mei Sun 2
Yanqing Liu 1

1 The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu, China.

2 Clinical Medical College, Yangzhou University, Yangzhou 225001, China.

https://doi.org/10.22034/iji.2023.99254.2629
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a fatal clinical syndrome. The most common cause of secondary HLH is Epstein-Barr virus (EBV) infection. EBV-HLH is a common clinical disease with high mortality, easy relapse, and poor prognosis. Therefore, treating EBV-HLH with T and B lymphocyte involvement is challenging, and selecting an appropriate treatment regimen is critical. Moreover, research on how to evaluate the recurrence index after remission is scarce. In this study, we reported a case of EBV-HLH successfully treated with programmed cell death protein-1 (PD-1) inhibitor in combination with rituximab. The regimen had a good curative effect, and we successfully detected the trend of early recurrence. Our findings indicated that PD-1 inhibitor in combination with rituximab may help to treat EBV-HLH and maintain EBV-infected T and B whole-line lymphocytes.

Keywords

CD20 Monoclonal Antibody
Epstein-Barr Virus
Hemophagocytic Lymphohistiocytosis
Programmed Cell Death Protein-1
Salvage Therapy
  1. Imashuku S, Morimoto A, Ishii E. Virus-triggered secondary hemophagocytic lymphohistiocytosis. Acta Paediatr. 2021;110(10):2729-2736.
  2. Maakaroun NR, Moanna A, Albrecht H. Viral infections associated with haemophagocytic syndrome. Rev Med Virol. 2010;20(2):93-105.
  3. Mottaghipisheh H, Kalantar K, Amanati A, et al. Comparison of the clinical features and outcome of children with hemophagocytic lymphohistiocytosis (HLH) secondary to visceral leishmaniasis and primary HLH: a single-center study. BMC Infect Dis. 2021;21(1):732.
  4. Cui X, Snapper CM. Epstein Barr Virus: Development of Vaccines and Immune Cell Therapy for EBV-Associated Diseases. Front Immunol. 2021;12:734471.
  5. Ressing ME, van Gent M, Gram AM, et al. Immune Evasion by Epstein-Barr Virus. Curr Top Microbiol Immunol. 2015;391:355-81.
  6. JankaGE, LehmbergK. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program, 2013, 2013:605-611. 
  7. Maakaroun NR, Moanna A, Jacob JT. Viral infections associated with haemophagocytic syndrome. Rev Med Virol. 2010;20(2):93-105.
  8. Ohga S, Nomura A, Hara T. Immunological aspects of Epstein-Barr virus infection. Crit Rev Oncol Hematol. 2002;44(3):203-15.
  9. Diao B, Huang X, Guo S,et al. MAGT1-mediated disturbance of Mg2+ homeostasis lead to exhausted of HBV-infected NK and CD8+ T cells. Sci Rep. 2017;7(1):13594.
  10. Elmore JP, McGee MC, Nidetz NF,et al. Tuning T helper cell differentiation by ITK. Biochem Soc Trans. 2020;48(1):179–185.
  11. Ghosh S, Bienemann K, Borkhardt A. Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects. J Clin Immunol. 2014;34(8):892–9.
  12. Moore EK, Strazza M, Mor A. Combination Approaches to Target PD-1 Signaling in Cancer. Front Immunol. 2022;13:927265.
  13. Henter JI, Aricò M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28(5):342-7.
  14. J Henter , Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31.
  15. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738.
  16. Johnson TS, Terrell CE, Millen SH, et al. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014;192(1):84-91.
  17. Keenan C, Nichols KE, Albeituni S. Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis. Front Immunol. 2021;12:614704.
  18. Wang H, Gu J, Liang X, et al. Low dose ruxolitinib plus HLH-94 protocol: A potential choice for secondary HLH. Semin Hematol. 2020;57(1):26-30.
  19. Zhang Q, Wei A, Ma HH, et al. A pilot study of ruxolitinib as a front-line therapy for 12 children with secondary hemophagocytic lymphohistiocytosis. Haematologica. 2021;106(7):1892-1901.
  20. Wang Y, Huang W, Hu L, et al. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015;126(19):2186-92.
  21. Lai W, Wang Y, Wang J, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents-a life-threatening disease: analysis of 133 cases from a single center. Hematology. 2018;23(10):810-816.
  22. Chatterjee B, Deng Y, Holler A, et al. CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo. PLoS Pathog. 2019;15(5):e1007748.
  23. Kim ST, Cristescu R, Bass AJ, et al.Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449-1458.
  24. Meng GQ, Wang JS, Wang YN, et al. Rituximab-containing immuno-chemotherapy regimens are effective for the elimination of EBV for EBV-HLH with only and mainly B lymphocytes of EBV infection. Int Immunopharmacol. 2021;96:107606.
  25. Latour S, Fischer A. Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases. Immunol Rev. 2019;291(1):174-189.
  26. Liu P , Pan X , Chen C, et al. Nivolumab treatment for relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistocytosis in adults. Blood. 2020;135 (11):826–833.
  27. Young LS, Yap LF, Murray PG. Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer. 2016;16(12):789-802.
  28. Kerr JR. Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors. J Clin Pathol. 2019;72(10):651-658.
  29. Fournier B, Boutboul D, Latour S, et al. Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection. J Exp Med. 2020;217(11):e20192262.
  30. Shokripour M, Mokhtari M, Samizadeh B. Association of soluble interleukin-2 receptor alpha with laboratory parameters and clinical findings of hemophagocytic lymphohistiocytosis patients: The first report from South of Iran. J Educ Health Promot. 2020;9:48.
Iranian Journal of Immunology
Volume 20, Issue 4
Autumn 2023
Pages 466-472

Home

Guide for Authors

Submit Manuscript

Guide for Reviewers

Contact Us