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Thiotepa-based reduced toxicity conditioning in combination with post-transplant cyclophosphamide and mTOR inhibitor for heavily transfused acquired severe aplastic anemia in children and young adults: encouraging outcomes of a pilot study

Bone Marrow Transplantation volume 58, pages 233–236 (2023)Cite this article

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An estimated 8–12 cases/million population/year of SAA are reported in far eastern countries with lesser incidence in <18 years of age [1,2,3]. The standard of care for any patient who has HLA identical donor is hematopoietic stem cell transplant (HSCT) (related/unrelated) [2, 4, 5]. Various groups have reported encouraging outcomes for HLA identical donor transplants with success rates >90% [5,6,7,8,9]. A joint study by SAA WP and PDWP of EBMT showed that although the overall survival (OS) of MFD HSCT and immune suppressive therapy (IST) was not different 91% vs 87% (P: 0.18) but the event-free survival (EFS) was superior in HSCT (87% vs 33%, P: 0.001) [5, 9]. Our colleagues from India have previously reported that HSCT is superior to IST in Indian children with SAA (70% vs 37.1%) [10]. The same group reported that the addition of fludarabine to cyclophosphamide ± ATG reduces the graft failure (GF) 2.9% in their analysis in HLA identical settings but with increased risk of VOD (8.5%), acute and chronic GvHD (29% and 32%, respectively) [11]. For patients lacking suitable HLA identical donor, clear consensus is not available and IST using horse ATG ± eltrombopag is considered to be the second-best option but the limitation being poor response rates and risk of clonal evolution over a period of time which becomes more relevant in children and young adults [12,13,14,15]. The outcomes of cord blood transplants are also not very promising [16, 17]. This provides an opportunity to explore other alternative donor sources such as haploidentical family donor (HFD). Despite the wider increasing application HFD-HSCT, data on its use in SAA are still limited in children and young adults [15, 18].

Huang et al. reported encouraging results of HFD-HSCT in pediatric patients with SAA with an OS and EFS of 84.5 ± 5.0% and 82.7 ± 5.2% at a median follow-up of 744.5 days (range, 100–3294) [18]. Recently, EBMT published data of 33 patients (13 pediatric) who underwent HFD-HSCT for SAA between 2011 and 2017 with 2-year OS and FFS 78 and 63% [15]. Jaiswal et al. in a small subset of 10 patients showed GvHD-free survival (GFS) and EFS of 80% using abatacept and sirolimus [19]. DeZern et al. reported 37 patients who underwent HFD-HSCT for SAA using the conventional John Hopkins approach with 11% of patients experiencing GF, majority of whom were treatment naïve warranting protocol amendment with TBI increased to 4 Gy [20]. Iftikhar et al. used a TBI-free regimen for patients undergoing HFD HCT for SAA and reported an OS and EFS of 80% in a cohort of 10 patients but possibly did not include donor-specific antibody (DSA)-positive patients in their analysis [21]. Arcuri et al. reported that 32 of the 87 patients of relapsed/refractory SAA who received intensified conditioning either by increasing the dose of cyclophosphamide to 50 mg/kg or by increasing TBI to 3–4 Gy led to improved EFS at 2 years 88% [22]. Recently Hashem et al. reported the outcomes of their cohort of 15 patients with SAA undergoing HFD-HSCT. The initial 6 were transplanted using the conventional JH approach which led to high GF rates; subsequently, the protocol was modified with the addition of TT and increasing the dose of TBI to 4 Gy which led to better OS/EFS 89% at 1 year with no reported GF [23].

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Fig. 1: Overall survival (N = 12).

Data availability

The Centre reports its data to EBMT with CIC No 464. Relevant patient-specific data can always be retrieved from EBMT database.

References

  1. Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2015;172:187–207.

    Article  Google Scholar 

  2. Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, Cesaro S, et al. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. 2015;55:40–7.

    Article  Google Scholar 

  3. Young NS, editor. Epidemiology of aplastic anemia. In: Bone marrow failure syndromes. 1st ed. Philadelphia: WB Saunders Company; 1996. p. 1–46.

  4. Peffault de Latour R. Transplantation for bone marrow failure: current issues. Hematology. 2016;2016:90–8.

  5. Dufour C, Veys P, Carraro E, Bhatnagar N, Pillon M, Samarasinghe S, et al. Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT. Br J Haematol. 2015;171:585–94.

    Article  CAS  Google Scholar 

  6. Chen J, Lee V, Luo CJ, Chiang AK, Hongeng S, Tan PL, et al. Allogeneic stem cell transplantation for children with acquired severe aplastic anaemia: a retrospective study by the Viva-Asia Blood and Marrow Transplantation Group. Br J Haematol. 2013;162:383–91.

    Article  Google Scholar 

  7. Szpecht D, Gorczynska E, Kalwak K, Owoc-Lempach J, Choma M, Styczynski J, et al. Matched sibling versus matched unrelated allogeneic hematopoietic stem cell transplantation in children with severe acquired aplastic anemia: experience of the polish pediatric group for hematopoietic stem cell transplantation. Arch Immunol Ther Exp. 2012;60:225–33.

    Article  Google Scholar 

  8. Chung NG, Lee JW, Jang PS, Jeong DC, Cho B, Kim HK. Reduced dose cyclophosphamide, fludarabine and antithymocyte globulin for sibling and unrelated transplant of children with severe and very severe aplastic anemia. Pediatr Transplant. 2013;17:387–93.

    Article  CAS  Google Scholar 

  9. Dufour C, Pillon M, Socie G, Rovo A, Carraro E, Bacigalupo A, et al. Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant. Br J Haematol. 2015;169:565–73. https://doi.org/10.1111/bjh.13297.

    Article  Google Scholar 

  10. George B, Mathew V, Viswabandya A, Lakshmi KM, Srivastava A, Chandy M. Allogenic stem cell transplant is superior to immunosuppressive therapy in Indian children with aplastic anemia—a single center analysis of 100 patients. Pediatr Hematol Oncol. 2010;27:122–31.

    Article  CAS  Google Scholar 

  11. George B, Mathew V, Viswabandya A, Kavitha ML, Srivastava A, Chandy M. Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduces rejection and improve outcomes in Indian patients undergoing allogenic stem cell transplantation for severe aplastic anemia. Bone Marrow Transplant. 2007;40:13–8.

    Article  CAS  Google Scholar 

  12. Young NS. Aplastic anemia. N Engl J Med. 2018;379:1643–56.

    Article  CAS  Google Scholar 

  13. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129:1428–36.

    Article  CAS  Google Scholar 

  14. Jeong DC, Chung NG, Cho B, Zou Y, Ruan M, Takahashi Y, et al. Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children. Haematologica. 2014;99:664–71.

    Article  CAS  Google Scholar 

  15. Prata PH, Eikema DJ, Afansyev V, Bosman P, Smiers F, Diez-Martin JL, et al. Haploidentical transplantation and post-transplant cyclophosphamide for treating aplastic anemia patients: a report from the EBMT severe aplastic anemia working party. Bone Marrow Transplant. 2020;55:1050–8.

    Article  CAS  Google Scholar 

  16. Yoshimi A, Kojima S, Taniguchi S, Hara J, Matsui T, Takahashi Y, et al. Unrelated cord blood transplantation for severe aplastic anemia. Biol Blood Marrow Transplant. 2008;14:1057–63.

    Article  CAS  Google Scholar 

  17. Peffault de Latour R, Purtill D, Ruggeri A, Sanz G, Michel G, Gandemer V, et al. Influence of nucleated cell dose on overall survival of unrelated cord blood transplantation for patients with severe acquired aplastic anemia: a study by eurocord and the aplastic anemia working party of the European group for blood and marrow transplantation. Biol Blood Marrow Transplant. 2011;17:78–85.

    Article  Google Scholar 

  18. Xu LP, Zhang XH, Huang XJ. Haploidentical transplantation for pediatric patients with acquired severe aplastic anemia. Bone Marrow Transplant. 2017;52:381–7.

    Article  CAS  Google Scholar 

  19. Jaiswal SR, Bhakuni P, Zaman S, Bansal S, Bharadwaj P, Bhargava S, et al. T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol. 2017;43–44:54–9. https://doi.org/10.1016/j.trim.2017.07.004.

  20. DeZern AE, Zahurak ML, Symons HJ, Cooke KR, Rosner GL, Gladstone DE, et al. Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide. Blood Adv. 2020;4:1770–9.

    Article  CAS  Google Scholar 

  21. Iftikhar R, Chaudhry QN, Mahmood SK, Ghafoor T, Shahbaz N, Khan MA, et al. A novel TBI free conditioning protocol for haploidentical transplant in acquired aplastic anemia: (FluCAB-Prime). Bone Marrow Transplant. 2021;56:2309–11.

    Article  Google Scholar 

  22. Arcuri LJ, Nabhan SK, Cunha R, Nichele S, Ribeiro AAF, Fernandes JF, et al. Impact of CD34 cell dose and conditioning regimen on outcomes after haploidentical donor hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for relapsed/refractory severe aplastic anemia. Biol Blood Marrow Transplant. 2020;26:2311–7.

    Article  CAS  Google Scholar 

  23. Hashem H, Rihani R, Shanap MA, Khattab E, Tbakhi A, Sultan I. Novel conditioning regimen for upfront haploidentical hematopoietic cell transplantation in children with severe aplastic anemia and donor-specific anti-HLA antibodies. Bone Marrow Transplant. 2022;57:304–5.

    Article  CAS  Google Scholar 

  24. Ciurea SO, Cao K, Fernandez-Vina M, Kongtim P, Malki MA, Fuchs E, et al. The European Society for Blood and Marrow Transplantation (EBMT) consensus guidelines for the detection and treatment of donor specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation. Bone Marrow Transplant. 2018;53:521–34.

    Article  CAS  Google Scholar 

  25. Rutella S, Filippini P, Bertania V, Pira GL, Altomare L, Ceccarelli S, et al. Mobilization of healthy donors with plerixafor affects the cellular composition of T-cell receptor (TCR)-αβ/Cd19-depleted haploidentical stem cell graft. J Transl Med. 2014;12:240.

    Article  Google Scholar 

  26. Kharya G, Bakane A, Agarwal S, Rauthan A. Pretransplant myeloid and immune suppression, upfront plerixafor mobilization and posttransplant cyclophosphamide: novel strategy for haploidentical transplant in sickle cell disease. Bone Marrow Transplant. 2021;56:492–504. https://doi.org/10.1038/s41409-020-01054-3.

  27. Kharya G, Bakane AN, Rauthan AM. Pre-transplant myeloid and immune suppression, reduced toxicity conditioning with posttransplant cyclophosphamide: initial outcomes of novel approach for matched unrelated donor hematopoietic stem cell transplant for hemoglobinopathies. Pediatr Blood Cancer. 2021;68:e28909. https://doi.org/10.1002/pbc.28909.

  28. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95.

    Article  CAS  Google Scholar 

  29. Sanders JE. Stem-cell transplant preparative regimens. Pediatr Transplant. 1999;3(Suppl 1):23–34. https://doi.org/10.1034/j.1399-3046.1999.00073.x.

    Article  Google Scholar 

  30. Rosales F, Peylan-Ramu N, Cividalli G, Varadi G, Or R, Naparstek E, et al. The role of thiotepa in allogeneic bone marrow transplantation for genetic diseases. Bone Marrow Transplant. 1999;23:861–5. https://doi.org/10.1038/sj.bmt.1701758.

    Article  CAS  Google Scholar 

  31. Pei XY, Zhao XY, Xu LP, Wang Y, Zhang XH, Huang XJ, et al. Immune reconstitution in patients with acquired severe aplastic anemia after haploidentical stem cell transplantation. Bone Marrow Transplant. 2017;52:1556–62.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Bone Marrow Transplant and Cellular Therapy, Indraprastha Apollo Hospital, New Delhi, 110076, India

    Gaurav Kharya, Sudhir Sapkota, Neeraj Teotia, K. K. Swathymon, Pema Chodan, Sherin Peters, Anju Anthony, Bharti Sharma, Himshikha Yadav, Atish Bakane & Manju Joseph

  2. Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Delhi, India

    Mohit Chaudhary

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The study was designed by GK, and all authors participated in the conduct of the study and reviewed and approved the paper.

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Correspondence to Gaurav Kharya.

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Kharya, G., Sapkota, S., Teotia, N. et al. Thiotepa-based reduced toxicity conditioning in combination with post-transplant cyclophosphamide and mTOR inhibitor for heavily transfused acquired severe aplastic anemia in children and young adults: encouraging outcomes of a pilot study. Bone Marrow Transplant 58, 233–236 (2023). https://doi.org/10.1038/s41409-022-01876-3

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