Skip to main content

Advertisement

SpringerLink
Log in

Long-term outcomes of 172 children with severe aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

This article has been updated

Abstract

This study retrospectively analyzed the clinical outcome of 172 children with newly diagnosed severe aplastic anemia (SAA) between January 2008 and April 2018, who received rabbit antithymocyte globulin (ATG) and cyclosporine (CsA) as first-line treatment. The median age at diagnosis was 5 years (range, 1–14). The overall response rates were 22.7%, 45.3%, and 61% at 40 days, 3 months, and 6 months, respectively, after rabbit ATG. In multivariate analysis, mild disease severity was the only predictor of favorable response at 6 months (P = 0.006). In the present study, median follow-up period was 63 months (range, 1–135). The 5-year overall survival (OS) and failure-free survival (FFS) rates were 90.5% and 70.4%. Multivariate analysis showed that erythroid burst-forming units (BFU-E) > 2/105 bone marrow mononuclear cell (BMMNC) (P = 0.037) and time interval before IST ≤ 30 days (P = 0.017) were independent positive predictors for OS, meanwhile BFU-E > 2/105BMMNC (P = 0.029) was the only favorable prognostic factor for FFS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

  • 07 November 2020

    This article was revised because of the track changes present in the supplementary file.

Abbreviations

IST:

Immunosuppressive therapy

ATG:

Antithymocyte globulin

CsA:

Cyclosporine

SAA:

Severe aplastic anemia

HLA:

Human leukocyte antigen

vSAA:

Very severe aplastic anemia

OS:

Overall survival

FFS:

Failure-free survival

BFU-E:

Erythroid burst-forming units

BMMNC:

Bone marrow mononuclear cell

PB:

Peripheral blood

BM:

Bone marrow

aAA:

Acquired aplastic anemia

HSCs:

Hematopoietic stem cells

HSCT:

Hematopoietic stem cell transplantation

ALG:

Antilymphocyte globulin

AA:

Aplastic anemia

ANC:

Absolute neutrophil count

PLT:

Platelet

ARC:

Absolute reticulocyte count

CR:

Complete response

HGB:

Hemoglobin

NR:

Nonresponse

PR:

Partial response

IMDM:

Iscove’s Modified Dulbecco’s Medium

FBS:

Fetal bovine serum

PNH:

Paroxysmal nocturnal hemoglobinuria

CFU-GM:

Granulocyte-macrophage colony-forming units

AML:

Acute myelogenous leukemia

MDS:

Myelodysplastic syndrome

CFU-E:

Erythroid colony-forming units

NIH:

National Institutes of Health

WBC:

White blood cell

ALC:

Absolute lymphocyte count

CFU-GEMM:

Granulocyte erythrocyte macrophage megakaryocyte colony-forming units

References

  1. Scheinberg P, Young NS (2012) How I treat acquired aplastic anemia. Blood 120(6):1185–1196. https://doi.org/10.1182/blood-2011-12-274019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Young NS, Calado RT, Scheinberg P (2006) Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 108(8):2509–2519. https://doi.org/10.1182/blood-2006-03-010777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H (2003) Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 101(4):1236–1242. https://doi.org/10.1182/blood-2002-04-1134

    Article  CAS  PubMed  Google Scholar 

  4. Peslak SA, Olson T, Babushok DV (2017) Diagnosis and treatment of aplastic anemia. Curr Treat Options in Oncol 18(12):70. https://doi.org/10.1007/s11864-017-0511-z

    Article  Google Scholar 

  5. Luzzatto L, Risitano AM (2018) Advances in understanding the pathogenesis of acquired aplastic anaemia. Br J Haematol 182(6):758–776. https://doi.org/10.1111/bjh.15443

    Article  PubMed  Google Scholar 

  6. Liu LP, Chen XJ, Yang WY, Yi MH, Zhou K, Ruan M, Liu F, Chen X, Chang LX, Liu TF, Zhang L, Zou Y, Chen YM, Zhang FK, Zhu XF, Guo Y (2019) Predicting response to porcine antilymphocyte globulin plus cyclosporine A in children with acquired severe aplastic anemia. Pediatr Res 86(3):360–364. https://doi.org/10.1038/s41390-019-0437-1

    Article  CAS  PubMed  Google Scholar 

  7. Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, Young NS (2011) Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med 365(5):430–438. https://doi.org/10.1056/NEJMoa1103975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Atta EH, Dias DS, Marra VL, de Azevedo AM (2010) Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a single-center retrospective study. Ann Hematol 89(9):851–859. https://doi.org/10.1007/s00277-010-0944-y

    Article  CAS  PubMed  Google Scholar 

  9. Jeong DC, Chung NG, Cho B, Zou Y, Ruan M, Takahashi Y, Muramatsu H, Ohara A, Kosaka Y, Yang W, Kim HK, Zhu X, Kojima S (2014) Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children. Haematologica 99(4):664–671. https://doi.org/10.3324/haematol.2013.089268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Camitta BM, Rappeport JM, Parkman R, Nathan DG (1975) Selection of patients for bone marrow transplantation in severe aplastic anemia. Blood 45(3):355–363

    Article  CAS  PubMed  Google Scholar 

  11. Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT, Congiu M, De Planque MM, Ernst P, McCann S et al (1988) Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol 70(2):177–182. https://doi.org/10.1111/j.1365-2141.1988.tb02460.x

    Article  CAS  PubMed  Google Scholar 

  12. Subspecialty Group of H, Society of P, Chinese Medical Association The Editorial B, Chinese Journal of P (2014) Recommendations for diagnosis and treatment of acquired aplastic anemia in children. Zhonghua Er Ke Za Zhi 52(2):103–106

    Google Scholar 

  13. Camitta BM (2000) What is the definition of cure for aplastic anemia? Acta Haematol 103(1):16–18. https://doi.org/10.1159/000040999

    Article  CAS  PubMed  Google Scholar 

  14. Scheinberg P, Wu CO, Nunez O, Scheinberg P, Boss C, Sloand EM, Young NS (2009) Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica 94(3):348–354. https://doi.org/10.3324/haematol.13829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nishikawa E, Yagasaki H, Hama A, Yabe H, Ohara A, Kosaka Y, Kudo K, Kobayashi R, Ohga S, Morimoto A, Watanabe KI, Yoshida N, Muramatsu H, Takahashi Y, Kojima S (2017) Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine. Pediatr Blood Cancer 64(5). https://doi.org/10.1002/pbc.26305

  16. Tichelli A, Schrezenmeier H, Socie G, Marsh J, Bacigalupo A, Duhrsen U, Franzke A, Hallek M, Thiel E, Wilhelm M, Hochsmann B, Barrois A, Champion K, Passweg JR (2011) A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood 117(17):4434–4441. https://doi.org/10.1182/blood-2010-08-304071

    Article  CAS  PubMed  Google Scholar 

  17. Chen C, Xue HM, Xu HG, Li Y, Huang K, Zhou DH, Guo HX, Fang JP, Huang SL (2012) Rabbit-antithymocyte globulin combined with cyclosporin A as a first-line therapy: improved, effective, and safe for children with acquired severe aplastic anemia. J Cancer Res Clin Oncol 138(7):1105–1111. https://doi.org/10.1007/s00432-012-1184-4

    Article  CAS  PubMed  Google Scholar 

  18. Rogers ZR, Nakano TA, Olson TS, Bertuch AA, Wang W, Gillio A, Coates TD, Chawla A, Castillo P, Kurre P, Gamper C, Bennett CM, Joshi S, Geddis AE, Boklan J, Nalepa G, Rothman JA, Huang JN, Kupfer GM, Cada M, Glader B, Walkovich KJ, Thompson AA, Hanna R, Vlachos A, Malsch M, Weller EA, Williams DA, Shimamura A (2019) Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study. Haematologica 104(10):1974–1983. https://doi.org/10.3324/haematol.2018.206540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tutelman PR, Aubert G, Milner RA, Dalal BI, Schultz KR, Deyell RJ (2014) Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia. Br J Haematol 164(5):717–721. https://doi.org/10.1111/bjh.12656

    Article  CAS  PubMed  Google Scholar 

  20. Kulagin A, Lisukov I, Ivanova M, Golubovskaya I, Kruchkova I, Bondarenko S, Vavilov V, Stancheva N, Babenko E, Sipol A, Pronkina N, Kozlov V, Afanasyev B (2014) Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-Centre prospective study. Br J Haematol 164(4):546–554. https://doi.org/10.1111/bjh.12661

    Article  CAS  PubMed  Google Scholar 

  21. Scheinberg P, Marte M, Nunez O, Young NS (2010) Paroxysmal nocturnal hemoglobinuria clones in severe aplastic anemia patients treated with horse anti-thymocyte globulin plus cyclosporine. Haematologica 95(7):1075–1080. https://doi.org/10.3324/haematol.2009.017889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yoshida N, Yagasaki H, Takahashi Y, Yamamoto T, Liang J, Wang Y, Tanaka M, Hama A, Nishio N, Kobayashi R, Hotta N, Asami K, Kikuta A, Fukushima T, Hirano N, Kojima S (2008) Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia. Br J Haematol 142(3):427–435. https://doi.org/10.1111/j.1365-2141.2008.07182.x

    Article  CAS  PubMed  Google Scholar 

  23. Bacigalupo A (2017) How I treat acquired aplastic anemia. Blood 129(11):1428–1436. https://doi.org/10.1182/blood-2016-08-693481

    Article  CAS  PubMed  Google Scholar 

  24. Yoshida N, Yagasaki H, Hama A, Takahashi Y, Kosaka Y, Kobayashi R, Yabe H, Kaneko T, Tsuchida M, Ohara A, Nakahata T, Kojima S (2011) Predicting response to immunosuppressive therapy in childhood aplastic anemia. Haematologica 96(5):771–774. https://doi.org/10.3324/haematol.2010.032805

    Article  PubMed  PubMed Central  Google Scholar 

  25. Scheinberg P, Wu CO, Nunez O, Young NS (2009) Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 144(2):206–216. https://doi.org/10.1111/j.1365-2141.2008.07450.x

    Article  CAS  PubMed  Google Scholar 

  26. Fuhrer M, Rampf U, Baumann I, Faldum A, Niemeyer C, Janka-Schaub G, Friedrich W, Ebell W, Borkhardt A, Bender-Goetze C (2005) Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood 106(6):2102–2104. https://doi.org/10.1182/blood-2005-03-0874

    Article  CAS  PubMed  Google Scholar 

  27. Chang MH, Kim KH, Kim HS, Jun HJ, Kim DH, Jang JH, Kim K, Jung CW (2010) Predictors of response to immunosuppressive therapy with antithymocyte globulin and cyclosporine and prognostic factors for survival in patients with severe aplastic anemia. Eur J Haematol 84(2):154–159. https://doi.org/10.1111/j.1600-0609.2009.01378.x

    Article  CAS  PubMed  Google Scholar 

  28. Marsh JC, Hows JM, Bryett KA, Al-Hashimi S, Fairhead SM, Gordon-Smith EC (1987) Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease severity. Blood 70(4):1046–1052

    Article  CAS  PubMed  Google Scholar 

  29. Bacigalupo A, Oneto R, Schrezenmeier H, Hochsmann B, Dufour C, Kojima S, Zhu X, Chen X, Issaragrisil S, Chuncharunee S, Jeong DC, Giammarco S, Van Lint MT, Zheng Y, Vallejo C (2018) First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: outcome of 955 patients treated 2001-2012. Am J Hematol 93(5):643–648. https://doi.org/10.1002/ajh.25081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Saracco P, Quarello P, Iori AP, Zecca M, Longoni D, Svahn J, Varotto S, Del Vecchio GC, Dufour C, Ramenghi U, Bacigalupo A, Locasciulli A (2008) Cyclosporin A response and dependence in children with acquired aplastic anaemia: a multicentre retrospective study with long-term observation follow-up. Br J Haematol 140(2):197–205. https://doi.org/10.1111/j.1365-2141.2007.06903.x

    Article  CAS  PubMed  Google Scholar 

  31. Calado RT, Cooper JN, Padilla-Nash HM, Sloand EM, Wu CO, Scheinberg P, Ried T, Young NS (2012) Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia. Leukemia 26(4):700–707. https://doi.org/10.1038/leu.2011.272

    Article  CAS  PubMed  Google Scholar 

  32. Jeong D-C, Chung NG, Lee JW, P-s J, Cho B, Kim H-K (2011) Long-term outcome of immunosuppressive therapy with rabbit antithymocyte globulin (rATG) for childhood severe aplastic anemia for 15 years. Blood 118(21):1346–1346. https://doi.org/10.1182/blood.V118.21.1346.1346

    Article  Google Scholar 

  33. Jain R, Trehan A, Bansal D, Varma N (2019) Aplastic anemia in children: how good is immunosuppressive therapy? Pediatr Hematol Oncol 36(4):211–221. https://doi.org/10.1080/08880018.2019.1621970

    Article  PubMed  Google Scholar 

  34. Issaragrisil S, Up Y, Yimyam M, Pakdeesuwan K, Khuhapinant A, Muangsup W, Pattanapanyasat K (1998) Hematopoietic progenitor cells in the blood and bone marrow in various hematologic disorders. Stem Cells 16(Suppl 1):123–128. https://doi.org/10.1002/stem.5530160815

    Article  PubMed  Google Scholar 

  35. Rosenfeld S, Follmann D, Nunez O, Young NS (2003) Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. Jama 289(9):1130–1135. https://doi.org/10.1001/jama.289.9.1130

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to sincerely thank the patients that participated in the follow-up and the support of AiYou Foundation.

Funding

This study was funded by the National Key Research and Development Program of China (grant No.2016YFC0901503).

Author information

Authors and Affiliations

  1. Division of Pediatric Blood Diseases Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Heping District, Tianjin, 300020, China

    Yang Lan, Lixian Chang, Meihui Yi, Yuli Cai, Jing Feng, Yuanyuan Ren, Chao Liu, Xiaoyan Chen, Shuchun Wang, Ye Guo, Aoli Zhang, Lipeng Liu, Jingliao Zhang & Xiaofan Zhu

Authors
  1. Yang Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lixian Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meihui Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuli Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuanyuan Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shuchun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ye Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aoli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lipeng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jingliao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiaofan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Yang Lan designed the study, collected and analyzed the data, and wrote the article; Lixian Chang designed the study, collected the data, and reviewed the article; Meihui Yi, Yuli Cai, and Jing Feng collected and analyzed the data; Chao Liu, Xiaoyan Chen, Aoli Zhang, and Lipeng Liu analyzed the data; Yuanyuan Ren, Shuchun Wang, Ye Guo, and Jingliao Zhang collected the data; Xiaofan Zhu designed the study and reviewed the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaofan Zhu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics Committee and Institutional Review Board of Chinese Academy of Medical Sciences and Peking Union Medical College.

Consent to participate

Informed consent was obtained from legal guardians.

Consent for publication

Patients signed informed consent regarding publishing their data.

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 24.3 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lan, Y., Chang, L., Yi, M. et al. Long-term outcomes of 172 children with severe aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine. Ann Hematol 100, 53–61 (2021). https://doi.org/10.1007/s00277-020-04296-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-020-04296-9

Keywords

Search

Navigation