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Efficacy of nivolumab as checkpoint inhibitor drug on survival rate of patients with relapsed/refractory classical Hodgkin lymphoma: a meta-analysis of prospective clinical study

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Abstract

Aims

The primary standard treatment for classic Hodgkin's lymphoma (cHL) is chemotherapy and radiation therapy. However, some patients get relapsed, or their diseases become resistant. PD1 blocking antibodies have been used to increase the response of treatment in solid tumors, and led to potentially stable responses that are acceptable. Our purpose in this study is to investigate the effect of nivolumab as a PD1 blocking antibody on the survival rate of patients with Hodgkin's cancer.

Methods

Databases were found in International Medical Sciences, Web of Science, Medline, Scopus, Index Copernicus, PubMed, DOAJ, Google Scholar, EBSCO-CINAHL, and Persian databases containing SID and Magiran using keywords such as: “checkpoint inhibitor”, “nivolumab”, “Hodgkin lymphoma”, and “PD1 Blockade”. The risk of bias was determined by two external observers using the Cochrane checklists. After the search, the data provided in 51 documents was independently evaluated. Duplicate papers were excluded. Assessing the full texts of the remaining papers, 7 papers were approved.

Results

Pooled data of these seven studies revealed that the overall objective response rate was 68% (CI 64.1% to 72.1%; heterogeneity; I2 = 40.19%; p = 0.123) with partial remission (52%; CI 46.5% to 57.6%; heterogeneity; I2 = 28.36%; p = 0.212). In the pooled analysis, complete remission was 16.8 (CI 11.1% to 26.4%). Pooled data of six studies showed that stable disease was averaged to 19% (CI 16% to 23%; heterogeneity; I2 = 30%; p = 0.209; fixed-effect model).

Conclusions

The results of the study indicate that nivolumab as a PD1 pathway inhibitor can be effective in treating relapsed and refractory cHL patients compared to other therapies, and lead to more effective treatment over the long term. Furthermore, the adverse effects of nivolumab are controllable and have a good safety profile.

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References

  1. Makita S, Maruyama D, Maeshima AM, et al. Clinical features and outcomes of 139 Japanese patients with Hodgkin lymphoma. Int J Hematol. 2016;104(2):233–44.

    Article  Google Scholar 

  2. Ogura M, Itoh K, Kinoshita T, et al. Phase II study of ABVd therapy for newly diagnosed clinical stage II–IV Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG 9305). Int J Hematol. 2010;92(5):713–24.

    Article  CAS  PubMed  Google Scholar 

  3. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  Google Scholar 

  4. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer—preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37(5):430–9.

    Article  CAS  PubMed  Google Scholar 

  5. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 anti-body in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013;19(2):462–8.

    Article  CAS  PubMed  Google Scholar 

  8. Taube JM, Klein AP, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17(13):4232–44.

    Article  CAS  PubMed  Google Scholar 

  10. Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31(33):4199–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51.

    Article  CAS  PubMed  Google Scholar 

  12. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15(1):69–77.

    Article  CAS  PubMed  Google Scholar 

  13. Wilcox RA, Feldman AL, Wada DA, et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood. 2009;114(10):2149–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang ZZ, Novak AJ, Stenson MJ, et al. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 2006;107(9):3639–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Keytruda (pembrolizumab). White-house Station, NJ: Merck (package insert). http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.

  16. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Juszczynski P, Ouyang J, Monti S, et al. The AP1-dependent secretion of galectin-1 by Reed–Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA. 2007;104(32):13134–9.

    Article  CAS  PubMed  Google Scholar 

  18. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471(7338):377–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and post transplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaufman D, Longo L. Hodgkin’s disease. In: Lenhord ER, Osteen R, Gansler T, editors. Clinical oncology. 2nd ed. Livingstone: Churchill; 2000. p. 2620–48.

    Google Scholar 

  21. Horning S. Hodgkin lymphoma. In: Beutler E, Lichtman M, Coller R, Kipps T, Seligsohn U, editors. Williams hematolog. 6th ed. New York: McGraw-Hill; 2001. p. 1215–28.

    Google Scholar 

  22. Fung HC, Nademanee AP. Approach to Hodgkin’s lymphoma in the new millennium. Hematol Oncol. 2002;20(1):1–15.

    Article  PubMed  Google Scholar 

  23. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  CAS  PubMed  Google Scholar 

  24. Abdi F, Roozbeh N. The effects of Humulus lupulus L.) hops) on menopausal vasomotor symptoms: a systematic review and meta-analysis. Iran J Obstetrics Gynecol Infer. 2016;19(26):9–17.

    Google Scholar 

  25. Maruyama D, Hatake K, Kinoshita T, et al. Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Cancer Sci. 2017;108(5):1007–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beköz H, Karadurmus N, Paydas S, et al. Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience. Ann Oncol. 2017;28(10):2496–502.

    Article  PubMed  Google Scholar 

  28. Kasamon YL, de Claro RA, Wang Y, et al. FDA approval summary: nivolumab for the treatment of relapsed or progressive classical hodgkin lymphoma. Oncologist. 2017;22(5):585–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow up of the multicohort single-arm phase II Check Mate 205 trial. J Clin Oncol. 2018;36(14):1428–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Herbaux C, Gauthier J, Brice P, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkinlymphoma. Blood. 2017;129(18):2471–8.

    Article  CAS  PubMed  Google Scholar 

  31. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Geneva: World Health Organization; 2008.

    Google Scholar 

  32. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323):2065–71.

    Article  CAS  PubMed  Google Scholar 

  33. Salihoglu A, Elverdi T, Karadogan I, et al. Brentuximab vedotin for relapsed or refractory Hodgkin lymphoma: experience in Turkey. Ann Hematol. 2015;94(3):415–20.

    Article  CAS  PubMed  Google Scholar 

  34. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cheah CY, Chihara D, Horowitz S, et al. Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes. Ann Oncol. 2016;27(7):1317–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martin-Liberal J, Furness AJ, Joshi K, et al. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother. 2015;64(6):765–7.

    Article  PubMed  Google Scholar 

  37. Hughes J, Vudattu N, Sznol M, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38(4):e55–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Okamoto M, Okamoto M, Gotoh K, et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig. 2016;7(6):915–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Miyoshi Y, Ogawa O, Oyama Y. Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku J Exp Med. 2016;239(2):155–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank to Dr. Ramin Sadeghi from Mashhad University Department of Nuclear Medicine for his advice in the meta-analysis.

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Correspondence to L. Darvish.

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Amraee, A., Evazi, M.R., Shakeri, M. et al. Efficacy of nivolumab as checkpoint inhibitor drug on survival rate of patients with relapsed/refractory classical Hodgkin lymphoma: a meta-analysis of prospective clinical study. Clin Transl Oncol 21, 1093–1103 (2019). https://doi.org/10.1007/s12094-018-02032-4

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