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Efficacy and steroid-sparing effect of tacrolimus in patients with autoimmune cytopenia

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Abstract

The aim of this study was to evaluate the efficacy, safety, and steroid-sparing effect of tacrolimus in patients with autoimmune cytopenia, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES). Patients in the tacrolimus group were treated with tacrolimus in combination with steroids, and the control group received only steroids. Of the 318 patients finally enrolled, 87 (27.4%) were males, with a median age of 45 (14–90) years. The tacrolimus group comprised 144 patients, including 120 ITP, 19 AIHA, and 5 ES patients, and the control group comprised 174 patients, including 141 ITP, 25 AIHA, and 8 ES patients. The optimal ORR of the tacrolimus group was comparable to that of the control group, and the optimal CRR was higher (p < 0.05). Patients receiving tacrolimus had a decreased relapse rate and prolonged relapse-free survival (p < 0.05) compared with the controls for both the whole cohort and the ITP and AIHA subgroups. Compared with the control group, the tacrolimus group had a lower cumulative steroid dosage and earlier discontinuation of steroids (p < 0.05), which resulted in a decreased incidence of steroid-related adverse events (p < 0.05) although the total side effects were similar between the two groups. Similar drug expenses were observed between the tacrolimus and control groups at the 18-month follow-up. In conclusion, the early addition of tacrolimus had a similar ORR, better CRR, lower relapse rate, and prolonged relapse-free survival compared to steroids alone, with reduced steroid-related adverse events.

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References

  1. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kühne T, Ruggeri M, George JN (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113(11):2386–2393

    Article  CAS  PubMed  Google Scholar 

  2. Jager U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, Jilma B, Kuter DJ, Michel M, Montillo M, Roth A, Zeerleder SS, Berentsen S (2020) Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev 41:100648

    Article  PubMed  Google Scholar 

  3. Norton A, Roberts I (2006) Management of Evans syndrome. Br J Haematol 132(2):125–137

  4. Takase K, Nagai H, Kadono M, Yoshioka T, Yoshio N, Hirabayashi Y, Ito T, Sawamura M, Yokoyama A, Yoshida S, Tsutsumi I, Otsuka M, Suehiro Y, Hidaka M, Yoshida I, Yokoyama H, Inoue H, Iida H, Nakayama M, Hishita T, Iwasaki H, Kada A, Saito AM, Kuroda Y (2020) High-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura. Int J Hematol 111(3):388–395

    Article  CAS  PubMed  Google Scholar 

  5. Wang L, Xu L, Hao H, Jansen AJG, Liu G, Li H, Liu X, Zhao Y, Peng J, Hou M (2020) First line treatment of adult patients with primary immune thrombocytopenia: a real-world study. Platelets 31(1):55–61

    Article  CAS  PubMed  Google Scholar 

  6. Pamuk GE, Pamuk ON, Başlar Z, Ongören S, Soysal T, Ferhanoğlu B, Aydin Y, Ulkü B, Aktuğlu G, Akman N (2002) Overview of 321 patients with idiopathic thrombocytopenic purpura Retrospective analysis of the clinical features and response to therapy. Ann Hematol 81(8):436–40

    Article  CAS  PubMed  Google Scholar 

  7. González-López TJ, Pascual C, Álvarez-Román MT, Fernández-Fuertes F, Sánchez-González B, Caparrós I, Jarque I, Mingot-Castellano ME, Hernández-Rivas JA, Martín-Salces M, Solán L, Beneit P, Jiménez R, Bernat S, Andrade MM, Cortés M, Cortti MJ, Pérez-Crespo S, Gómez-Núñez M, Olivera PE, Pérez-Rus G, Martínez-Robles V, Alonso R, Fernández-Rodríguez A, Arratibel MC, Perera M, Fernández-Miñano C, Fuertes-Palacio MA, Vázquez-Paganini JA, Gutierrez-Jomarrón I, Valcarce I, de Cabo E, Sainz A, Fisac R, Aguilar C, Paz Martínez-Badas M, Peñarrubia MJ, Calbacho M, de Cos C, González-Silva M, Coria E, Alonso A, Casaus A, Luaña A, Galán P, Fernández-Canal C, Garcia-Frade J, González-Porras JR (2015) Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol 90(3):E40–E43

    Article  PubMed  Google Scholar 

  8. Newland A, Godeau B, Priego V, Viallard JF, López Fernández MF, Orejudos A, Eisen M (2016) Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol 172(2):262–273

    Article  CAS  PubMed  Google Scholar 

  9. Tjønnfjord E, Holme PA, Darne B, Khelif A, Waage A, Michel M, Ben Romdhan N, Ghanima W (2020) Long-term outcomes of patients treated with rituximab as second-line treatment for adult immune thrombocytopenia - follow-up of the RITP study. Br J Haematol 191(3):460–465

    Article  PubMed  Google Scholar 

  10. Vianelli N, Palandri F, Polverelli N, Stasi R, Joelsson J, Johansson E, Ruggeri M, Zaja F, Cantoni S, Catucci AE, Candoni A, Morra E, Björkholm M, Baccarani M, Rodeghiero F (2013) Splenectomy as a curative treatment for immune thrombocytopenia: a retrospective analysis of 233 patients with a minimum follow up of 10 years. Haematologica 98(6):875–880

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rodeghiero F (2018) A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol 181(2):183–195

    Article  CAS  PubMed  Google Scholar 

  12. Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, George JN, Grace RF, Kühne T, Kuter DJ, Lim W, McCrae KR, Pruitt B, Shimanek H, Vesely SK (2019) American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 3(23):3829–3866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ (2019) Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 3(22):3780–3817

    Article  PubMed  PubMed Central  Google Scholar 

  14. Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S, Michallet AS, Vital-Durand D, Lega JC (2015) Efficacy and safety of rituximab in auto-immune hemolytic anemia: a meta-analysis of 21 studies. Autoimmun Rev 14(4):304–313

    Article  CAS  PubMed  Google Scholar 

  15. Jäger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, Jilma B, Kuter DJ, Michel M, Montillo M, Röth A, Zeerleder SS, Berentsen S (2020) Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev 41:100648

    Article  PubMed  Google Scholar 

  16. Audia S, Grienay N, Mounier M, Michel M, Bonnotte B (2020) Evans’ syndrome: from diagnosis to treatment. J Clin Med 9(12):3851

  17. Yoon KH (2010) Efficacy and cytokine modulating effects of tacrolimus in systemic lupus erythematosus: a review. J Biomed Biotechnol 2010:686480

    Article  PubMed  PubMed Central  Google Scholar 

  18. Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB (2013) PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet Genomics 23(10):563–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yagasaki H, Kojima S, Yabe H, Kato K, Kigasawa H, Sakamaki H, Tsuchida M, Kato S, Kawase T, Muramatsu H, Morishima Y, Kodera Y (2009) Tacrolimus/methotrexate versus cyclosporine/methotrexate as graft-versus-host disease prophylaxis in patients with severe aplastic anemia who received bone marrow transplantation from unrelated donors: results of matched pair analysis. Biol Blood Marrow Transplant 15(12):1603–1608

    Article  CAS  PubMed  Google Scholar 

  20. Du Y, Huang Y, Zhou W, Liu X, Chen F, Yang C, Chen M, Ruan J, Han B (2020) Effective tacrolimus treatment for patients with non-severe aplastic anemia that is refractory/intolerant to cyclosporine A: a retrospective study. Drug Des Devel Ther 14:5711–5719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zufferey A, Kapur R, Semple JW (2017) Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J Clin Med 6(2):16

  22. Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, Yazdanbakhsh K (2010) Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood 116(22):4639–4645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mqadmi A, Zheng X, Yazdanbakhsh K (2005) CD4+CD25+ regulatory T cells control induction of autoimmune hemolytic anemia. Blood 105(9):3746–3748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Khodadi E, Asnafi AA, Shahrabi S, Shahjahani M, Saki N (2016) Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis. Ann Hematol 95(11):1765–1776

    Article  CAS  PubMed  Google Scholar 

  25. Zeng DF, Chen F, Wang S, Chen SL, Xu Y, Shen MQ, Du CH, Wang C, Kong PY, Cheng TM, Su YP, Wang JP (2018) Autoantibody against integrin α(v) β(3) contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes. J Thromb Haemost 16(9):1843–1856

    Article  CAS  PubMed  Google Scholar 

  26. Wang X, Lu J, Wei G, Tong H, Zhou J, Ding Y, Zhang S, Xu X, Lai R, Luo Q, Ju W, Yan Z, Zeng L, Xu K, Qiao J (2020) Tacrolimus ameliorates thrombocytopenia in an ITP mouse model. Ann Hematol 99(10):2315–2322

    Article  CAS  PubMed  Google Scholar 

  27. Debska-Slizień A, Chamienia A, Król E, Zdrojewski Z, Pirski I, Zadrozny D, Sledziński Z, Rutkowski B (2003) Hemolytic anemia after renal transplantation: analysis of case reports. Transplant Proc 35(6):2233–2237

    Article  PubMed  Google Scholar 

  28. Gergis U, Ibrahim M, Al-Kazaz M, Parkash S, Gergis E, Desancho M (2012) Successful treatment with tacrolimus of a patient with severe idiopathic thrombocytopenic purpura after allogeneic bone marrow transplantation. J Clin Oncol 30(26):e241–e242

    Article  PubMed  Google Scholar 

  29. Tabchi S, Hanna C, Kourie HR, Aftimos P, El Osta L, Ghosn M (2015) Successful treatment of Evans syndrome with tacrolimus. Invest New Drugs 33(1):254–256

    Article  PubMed  Google Scholar 

  30. Bennett CM, de Jong JL, Neufeld EJ (2006) Targeted ITP strategies: do they elucidate the biology of ITP and related disorders? Pediatr Blood Cancer 47(5 Suppl):706–709

    Article  PubMed  Google Scholar 

  31. Du Y, Yang C, Chen M, Ruan J, Huang Y, Chen F, Han B (2020) Tacrolimus is effective in relapsed/refractory autoimmune cytopenias: results of a single-center retrospective study. Hematol 25(1):478–483

    Article  CAS  Google Scholar 

  32. Suzuki K, Kameda H, Amano K, Nagasawa H, Takei H, Nishi E, Okuyama A, Tsuzaka K, Takeuchi T (2011) Single center prospective study of tacrolimus efficacy and safety in the treatment of various manifestations in systemic lupus erythematosus. Rheumatol Int 31(6):757–763

    Article  CAS  PubMed  Google Scholar 

  33. Li H, Zhang X, Chen J (2011) Successful treatment of steroid-refractory systemic lupus erythematosus-associated protein-losing enteropathy using combination therapy with tacrolimus and steroid. Lupus 20(10):1109–1111

    Article  CAS  PubMed  Google Scholar 

  34. Chin HJ, Chae DW, Kim YC, An WS, Ihm C, Jin DC, Kim SG, Kim YL, Kim YS, Kim YG, Koo HS, Lee JE, Lee KW, Oh J, Park JH, Jiang H, Lee H, Lee SK (2021) Comparison of the efficacy and safety of tacrolimus and low-dose corticosteroid with high-dose corticosteroid for minimal change nephrotic syndrome in adults. J Am Soc Nephrol 32(1):199–210

    Article  CAS  PubMed  Google Scholar 

  35. Westhoff TH, Schmidt S, Zidek W, Beige J, van der Giet M (2006) Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome. Clin Nephrol 65(6):393–400

    Article  CAS  PubMed  Google Scholar 

  36. Yoshikawa H, Kiuchi T, Saida T, Takamori M (2011) Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 82(9):970–977

    Article  PubMed  Google Scholar 

  37. Borrows R, Loucaidou M, Van Tromp J, Cairns T, Griffith M, Hakim N, McLean A, Palmer A, Papalois V, Taube D (2004) Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. Am J Transplant 4(11):1845–1851

    Article  CAS  PubMed  Google Scholar 

  38. McMillan R, Bussel JB, George JN, Lalla D, Nichol JL (2008) Self-reported health-related quality of life in adults with chronic immune thrombocytopenic purpura. Am J Hematol 83(2):150–154

    Article  PubMed  Google Scholar 

  39. Zimmer J, Andrès E, Noel E, Koumarianou A, Blicklé JF, Maloisel F (2004) Current management of adult idiopathic thrombocytopenic purpura in practice: a cohort study of 201 patients from a single center. Clin Lab Haematol 26(2):137–142

    Article  CAS  PubMed  Google Scholar 

  40. Stasi R, Stipa E, Masi M, Cecconi M, Scimò MT, Oliva F, Sciarra A, Perrotti AP, Adomo G, Amadori S et al (1995) Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 98(5):436–442

    Article  CAS  PubMed  Google Scholar 

  41. Seale JPMRC (1986) Side-effects of corticosteroid agents. Med J Aust 144(3):139–142

    Article  CAS  PubMed  Google Scholar 

  42. Sestøl HG, Trangbæk SM, Bussel JB, Frederiksen H (2018) Health-related quality of life in adult primary immune thrombocytopenia. Expert Rev Hematol 11(12):975–985

    Article  PubMed  Google Scholar 

  43. Terrell DR, Neunert CE, Cooper N, Heitink-Pollé KM, Kruse C, Imbach P, Kühne T, Ghanima W (2020) Immune thrombocytopenia (ITP): current limitations in patient management. Medicina (Kaunas) 56(12):667

  44. Liu D, Yang Y, Kuang F, Qing S, Hu B, Yu X (2019) Risk of infection with different immunosuppressive drugs combined with glucocorticoids for the treatment of idiopathic membranous nephropathy: a pairwise and network meta-analysis. Int Immunopharmacol 70:354–361

    Article  CAS  PubMed  Google Scholar 

  45. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA (2011) The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117(16):4190–4207

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all patients who consented to disclose their medical records and answered our review calls. Their cooperation and helpful comments throw light upon our data collection and statistical analysis.

Funding

This study was supported by the CAMS innovation fund for medical sciences (CIFMS 2021-I2M-1-003), Peking Union Medical Colleague Hospital Youth Research Foundation (pumch201912367), and National Natural Science Foundation of China (81970106).

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Authors and Affiliations

  1. Department of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital, Beijing, 100730, China

    Ruoxi Zhang, Miao Chen, Chen Yang & Bing Han

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Contributions

R.Z. and B.H. designed the study and wrote the manuscript. R.Z. and M.C. collected and analyzed the clinical data. C.Y. helped to analyze the date and provide critical suggestions. All authors reviewed the manuscript finally and approved the final submission of the manuscript.

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Correspondence to Bing Han.

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Ethics approval

This study was approved by the ethics committee of Peking Union Medical College Hospital and was conducted in accordance with the Declaration of Helsinki.

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Informed consent was obtained from all patients for being included in the study.

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The authors declare no competing interests.

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Zhang, R., Chen, M., Yang, C. et al. Efficacy and steroid-sparing effect of tacrolimus in patients with autoimmune cytopenia. Ann Hematol 101, 2421–2431 (2022). https://doi.org/10.1007/s00277-022-04967-9

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  • DOI: https://doi.org/10.1007/s00277-022-04967-9

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