Introduction

Depending on the disease in question as well as the stem cell source, two goals need to be attained by the preparative regimen prior to hematopoietic stem cell transplantation. With the majority of allogeneic transplants being performed on patients with a malignant disease, one of the key goals of conditioning is a reduction of the malignant cell mass, ideally down to disease eradication. In the allogeneic setting, the preparative regimen also needs to be immunosuppressive enough to secure engraftment without graft rejection. Most preparative regimens employed have initially been designed for adult recipients with a hematologic malignancy.

Acute lymphoblastic leukemia

TBI, fractionated (fTBI) in most cases and combined with CY, has been extensively employed due to its substantial immunosuppressive potential, lack of cross-reactivity with other modalities and sanctuary sparing as well as effective antileukemic potential as the backbone of the conditioning regimen in transplants performed for pediatric ALL^{1, 2, 3, 4, 5, 6, 7} in the matched related, matched unrelated and mismatched settings. Cumulative doses up to 10–14 Gy have been used with many groups reducing the pulmonary cumulative dose down to 8–9 Gy and the use of fTBI to patients above the age of 2 years.

fTBI continues to be employed in the pre-transplant conditioning of pediatric patients with ALL by most groups with many currently combining it with etoposide (60 mg/kg) for patients above the age of 2–3 years.^{8, 9, 10, 11, 12} Yet, the use of fTBI in conjunction with CY also continues.¹³ The clinical efficacy of chemotherapy-only regimens over fTBI-containing regimens in the conditioning of patients with ALL and over the age of 2 years has not been established.⁷

For patients above the age of 2–3 years but not eligible for fTBI (for example, those with a history of high-dose irradiation), chemotherapy-only regimens (for example, BU/CY/melphalan (Mel)) are employed.¹²

fTBI-based regimens have been employed also among patients under the age of 18 months, particularly in the unrelated setting.¹⁴ Yet, to avoid the long-term toxic effects of fTBI, most groups currently employ chemotherapy-only regimens for the youngest patients under the age of 2–3 years as is also the recommendation of the Interfant-group for those under the age of 1 year. Variable drug combinations are used in this group with most having a BU+CY backbone in combination with, for example, Mel, thiotepa, etoposide or alemtuzumab.

Acute myeloid leukemia

Non-fTBI-based regimens are currently employed by most groups for patients transplanted for AML in either first or subsequent remission. Regimens with a BU+CY backbone are mostly used and supplemented in most cases with Mel.¹⁵ Yet, fTBI-containing regimens are also being employed by some groups, particularly in advance cases.¹⁶ No data comparing these two approaches in the treatment of pediatric AML are available. The International-BFM-Study Group presents the two key preparative regimens (that is, BU+CY+Mel vs fTBI+CY) as optional in their ongoing trial on relapsed AML.

MDS and juvenile myelomonocytic leukemia

In the pretransplant conditioning of this challenging group of pediatric patients, both chemotherapy-only (BU+CY+Mel) and fTBI-contaning regimens have been employed, with the former rendering a seemingly lower incidence of non-relapse mortality.^{17, 18}

Fanconi anemia

In this toxicity-prone group of patients, convincing data are available on the use of low-dose CY (20 mg/kg) and thoraco-abdominal irradiation (5 Gy) as conditioning, when sibling donors are employed.¹⁹ Data on the use of CY-only regimens are also available, but only on more limited numbers of patients.²⁰

In the unrelated donor setting, medium-dose CY (40–45 mg/kg) in combination with either thoraco-abdominal or fTBI and anti-T serotherapy has been successfully employed.²¹ More recently, a reduction in treatment-related toxicity has been reported, when fludarabine-containing regimens (mostly also containing fTBI (4.5 Gy) with CY) were used.²²

Severe aplastic anemia

For severe aplastic anemia, and again to reduce TBI-related long-term sequelae, most groups currently employ non-fTBI-containing regimens, CY with or without ATG in the sibling donor setting²³ and fludarabine plus cyclo plus ATG in the unrelated setting.²⁴ Some employ fludarabine-containing regimens also in the sibling setting as an essentially non-myeloablative approach. TBI (2–6 Gy) with cyclofludarabine and ATG are also being used by some groups in the unrelated donor setting. Even in the face of an increased risk of graft rejection in stem cell transplantation for pediatric severe aplastic anemia, encouraging data on the use of partial T-cell depletion have been reported.²⁵

Additional indications

For patients with primary immunodeficiencies, both data and the recommendations of both The European Group for Blood & Marrow Transplantation and the European Society for Immunodeficiency support the use of BU and CY with effective T-cell depletion particularly in the mismatch setting.²⁶

In stem cell transplantation for inborn errors of metabolism, a variety of preparative regimens have been employed, but no preferred regimen has been identified.²⁷ The feasibility of standard BU+CY regimen has been demonstrated in transplantations in the case of, for example, mucopolysaccharidosis type 1H (Hurler).²⁸

Haploidentical transplants

In haploidentical transplantation for pediatric acute leukemia, both standard fTBI-based regimens and BU with CY and thiotepa have been successfully employed in conjunction with the obligatory high dose of CD34+ cells and low dose of CD34+ cells.^{29, 30}

Specific issues

While the benefits of in vivo and/or ex vivo T-cell depletion in reducing the incidence and severity of both acute and chronic GvHD³¹ as well as in increasing the number of potential donors^{1, 25} have been well established, the use of T-cell depletion in the matched unrelated donor setting of pediatric stem cell transplantation remains controversial with data on both an increased risk of relapse³² and viral infections³³ having been published. Most European groups employ ATG or alemtuzumab (Campath) in matched unrelated transplantation for pediatric ALL and AML.

With cord blood transplantation, mostly standard fTBI-based regimens have been employed.³⁴

Future perspectives

Several key developments are underway that will affect the structure and composition of future conditioning regimens. These include accumulating data on the role of minimal residual disease prior to transplant in defining the risk of relapse post transplant, data on the effects of advanced HLA-genotyping on our perception of HLA compatibility, the increasing use of peripheral blood as the stem cell source also in the pediatric setting, the use of haploidentical donors and accumulating data on the pathophysiology of both acute and chronic GvHD as well as those on the process of immunoreconstitution post transplant. The result will, in all likelihood, be an ever more 'tailored' approach on conditioning based on the biological and disease characteristics of a given patient.

Notes

Conflict of interest

The author declared no financial interests.

References

1. Green A, Clarke E, Hunt L, Canterbury A, Lankester A, Hale G et al. Children with acute lymphoblastic leukemia who receive T-cell-depleted HLA mismatched marrow allografts from unrelated donors have an increased incidence of primary graft failure but a similar overall transplant outcome. Blood 1999; 94: 2236–2246. | PubMed | ISI | ChemPort |
2. Balduzzi A, Gooley T, Anasetti C, Sanders JE, Martin PJ, Petersdorf EW et al. Unrelated donor marrow transplantation in children. Blood 1995; 86: 3247–3256. | PubMed | ISI | ChemPort |
3. Woolfrey AE, Anasetti C, Storer B, Doney K, Milner LA, Sievers EL et al. Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood 2002; 99: 2002–2008. | Article | PubMed | ISI | ChemPort |
4. Zecca M, Pession A, Messina C, Bonetti F, Favre C, Prete A et al. Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings. J Clin Oncol 1999; 17: 1838–1846. | PubMed | ISI | ChemPort |
5. Bleakley M, Shaw PJ, Nielsen JM. Allogeneic bone marrow transplantation for childhood relapsed acute lymphoblastic leukemia: comparison of outcome in patients with and without a matched family donor. Bone Marrow Transplant 2002; 30: 1–7. | Article | PubMed | ChemPort |
6. Bunin N, Carston M, Wall D, Adams R, Casper J, Kamani N et al. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood 2002; 99: 3151–3157. | Article | PubMed | ISI | ChemPort |
7. Davies SM, Ramsay NK, Klein JP, Weisdorf DJ, Bolwell B, Cahn JY et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol 2000; 18: 340–347. | PubMed | ISI | ChemPort |
8. Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B et al. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 2006; 24: 5742–5749. | Article | PubMed |
9. Marks DI, Forman SJ, Blume KG, Perez WS, Weisdorf DJ, Keating A et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 2006; 12: 438–453. | Article | PubMed | ISI | ChemPort |
10. Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C et al. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 2005; 366: 635–642. | Article | PubMed | ISI |
11. Gaynon PS, Harris RE, Altman AJ, Bostrom BC, Breneman JC, Hawks R et al. Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 2006; 24: 3150–3156. | Article | PubMed |
12. Peters C, Schrauder A, Schrappe M, von Stackelberg A, Stary J, Yaniv I, et al., BFM Study Group, the IBFM-Study Group and the Paediatric Disease Working Party of the EBMT. Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: the BFM/IBFM/EBMT concepts. Bone Marrow Transplant 2005; 35 (Suppl 1): S9–11. | Article | PubMed |
13. Eapen M, Raetz E, Zhang MJ, Muehlenbein C, Devidas M, Abshire T et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 2006; 107: 4961–4967. | Article | PubMed | ChemPort |
14. Eapen M, Rubinstein P, Zhang MJ, Camitta BM, Stevens C, Cairo MS et al. Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol 2006; 24: 145–151. | Article | PubMed |
15. Neudorf S, Sanders J, Kobrinsky N, Alonzo TA, Buxton AB, Gold S et al. Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood 2004; 103: 3655–3661. | Article | PubMed | ISI | ChemPort |
16. Nemecek ER, Gooley TA, Woolfrey AE, Carpenter PA, Matthews DC, Sanders JE. Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia. Bone Marrow Transplant 2004; 34: 799–806. | Article | PubMed | ISI | ChemPort |
17. Locatelli F, Nollke P, Zecca M, Korthof E, Lanino E, Peters C et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005; 105: 410–419. | Article | PubMed | ISI | ChemPort |
18. Yusuf U, Frangoul HA, Gooley TA, Woolfrey AE, Carpenter PA, Andrews RG et al. Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant 2004; 33: 805–814. | Article | PubMed | ISI | ChemPort |
19. Socie G, Devergie A, Girinski T, Piel G, Ribaud P, Esperou H et al. Transplantation for Fanconi's anaemia: long-term follow-up of fifty patients transplanted from a sibling donor after low-dose cyclophosphamide and thoraco-abdominal irradiation for conditioning. Br J Haematol 1998; 103: 249–255. | Article | PubMed | ISI | ChemPort |
20. Flowers ME, Zanis J, Pasquini R, Deeg HJ, Ribeiro R, Longton G et al. Marrow transplantation for Fanconi anaemia: conditioning with reduced doses of cyclophosphamide without radiation.see comment. Br J Haematol 1996; 92: 699–706. | Article | PubMed | ISI | ChemPort |
21. Guardiola P, Pasquini R, Dokal I, Ortega JJ, van Weel-Sipman M, Marsh JC et al. Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation. Blood 2000; 95: 422–429. | PubMed | ISI | ChemPort |
22. Wagner JE, Eapen M, MacMillan ML, Harris RE, Pasquini R, Boulad F et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007; 109: 2256–2262. | Article | PubMed | ChemPort |
23. Kroger N, Zabelina T, Renges H, Kruger W, Kordes U, Rischewski J et al. Long-term follow-up of allogeneic stem cell transplantation in patients with severe aplastic anemia after conditioning with cyclophosphamide plus antithymocyte globulin. Ann Hematol 2002; 81: 627–631. | Article | PubMed | ChemPort |
24. Urban C, Benesch M, Sykora KW, Schwinger W, Lackner H. Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Bone Marrow Transplant 2005; 35: 591–594. | Article | PubMed | ChemPort |
25. Bunin N, Aplenc R, Iannone R, Leahey A, Grupp S, Monos D et al. Unrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T cell depletion. Bone Marrow Transplant 2005; 35: 369–373. | Article | PubMed | ChemPort |
26. Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–1999.see comment. Lancet 2003; 361: 553–560. | Article | PubMed | ISI |
27. Peters C, Steward CG. National Marrow Donor Program. International Bone Marrow Transplant Registry. Working Party on Inborn Errors, European Bone Marrow Transplant Group. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003; 31: 229–239. | Article | PubMed | ISI | ChemPort |
28. Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F et al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant 2003; 31: 1105–1117. | Article | PubMed | ISI | ChemPort |
29. Klingebiel T, Handgretinger R, Lang P, Bader P, Niethammer D. Haploidentical transplantation for acute lymphoblastic leukemia in childhood. Blood Rev 2004; 18: 181–192. | Article | PubMed |
30. Marks DI, Khattry N, Cummins M, Goulden N, Green A, Harvey J et al. Haploidentical stem cell transplantation for children with acute leukaemia. Br J Haematol 2006; 134: 196–201. | Article | PubMed |
31. Bacigalupo A. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant 2005; 35: 225–231. | Article | PubMed | ISI | ChemPort |
32. Vettenranta K, Saarinen-Pihkala UM, Cornish J, Steward C, Pamphilon D, Hovi L et al. Pediatric marrow transplantation for acute leukemia using unrelated donors and T-replete or -depleted grafts: a case-matched analysis. Bone Marrow Transplant 2000; 25: 395–399. | Article | PubMed | ISI | ChemPort |
33. Myers GD, Krance RA, Weiss H, Kuehnle I, Demmler G, Heslop HE et al. Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (Campath). Bone Marrow Transplant 2005; 36: 1001–1008. | Article | PubMed | ChemPort |
34. Rocha V, Sanz G, Gluckman E, Eurocord and European Blood and Marrow Transplant group. Umbilical cord blood transplantation. Curr Opin Hematol 2004; 11: 375–385. | Article | PubMed |

Acknowledgements

I thank the members of the Board of the Paediatric Diseases Working Party of the EBMT as well as Drs Carsten Heilmann (Rigshospitalet, Copenhagen, Denmark) and Jacek Winiarski (Karolinska Sjukhuset, Stockhlm, Sweden) for their valuable contribution in the preparation of this paper.