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Current Hematologic Malignancy Reports

, Volume 14, Issue 2, pp 94–105 | Cite as

Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia

  • Pietro Merli
  • Mattia Algeri
  • Francesca Del Bufalo
  • Franco LocatelliEmail author
Acute Lymphocytic Leukemias (K Ballen and M Keng, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Acute Lymphocytic Leukemias

Abstract

Purpose of Review

The remarkable improvement in the prognosis of children with acute lymphoblastic leukemia (ALL) has been mainly achieved through the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). This paper reviews the current indications to HSCT in ALL children, as well as the type of donor and conditioning regimens commonly used. Finally, it will focus on future challenges in immunotherapy.

Recent Findings

As our comprehension of disease-specific risk factors improves, indications to HSCT continue to evolve. Future studies will answer the year-old question on the best conditioning regimen to be used in this setting, while a recent randomized controlled study fixed the optimal anti-thymocyte globulin dose in unrelated donor HSCT.

Summary

HSCT, the oldest immunotherapy used in clinical practice, still represents the gold standard consolidation treatment for a number of pediatric patients with high-risk/relapsed ALL. New immunotherapies hold the promise of further improving outcomes in this setting.

Keywords

Acute lymphoblastic leukemia Children Hematopoietic stem cell transplantation Relapsed/refractory ALL 

Notes

Acknowledgments

The authors would like to thank P.D.S. and F.M. for the critical revision of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30(14):1663–9.  https://doi.org/10.1200/JCO.2011.37.8018.CrossRefGoogle Scholar
  2. 2.
    Moorman AV. New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2016;101(4):407–16.  https://doi.org/10.3324/haematol.2015.141101.CrossRefGoogle Scholar
  3. 3.
    Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. J Clin Oncol. 2017;35(9):975–83.  https://doi.org/10.1200/JCO.2016.70.7836.CrossRefGoogle Scholar
  4. 4.
    Algeri M, Del Bufalo F, Galaverna F, Locatelli F. Current and future role of bispecific T-cell engagers in pediatric acute lymphoblastic leukemia. Expert Rev Hematol. 2018;11(12):945–56.  https://doi.org/10.1080/17474086.2018.1540928.CrossRefGoogle Scholar
  5. 5.
    Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625–35.  https://doi.org/10.1182/blood-2013-11-492231.CrossRefGoogle Scholar
  6. 6.
    Jabbour E, O’Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010–6.  https://doi.org/10.1182/blood-2014-08-596403.CrossRefGoogle Scholar
  7. 7.
    Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366(15):1371–81.  https://doi.org/10.1056/NEJMoa1110169.CrossRefGoogle Scholar
  8. 8.
    • Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood. 2008;111(12):5477–85.  https://doi.org/10.1182/blood-2008-01-132837 First demonstration that end-induction MRD appears to predict disease relapse and long-term outcome in a multivariate analysis. CrossRefGoogle Scholar
  9. 9.
    van Dongen JJ, van der Velden VH, Bruggemann M, Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125(26):3996–4009.  https://doi.org/10.1182/blood-2015-03-580027.CrossRefGoogle Scholar
  10. 10.
    • Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115(16):3206–14.  https://doi.org/10.1182/blood-2009-10-248146 Demonstration that PCR-MRD at the end of consolidation therapy is the major determinant of relapse risk. CrossRefGoogle Scholar
  11. 11.
    Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8):2077–84.  https://doi.org/10.1182/blood-2011-03-338707.CrossRefGoogle Scholar
  12. 12.
    Nachman JB, Heerema NA, Sather H, Camitta B, Forestier E, Harrison CJ, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110(4):1112–5.  https://doi.org/10.1182/blood-2006-07-038299.CrossRefGoogle Scholar
  13. 13.
    Mullighan CG, Jeha S, Pei D, Payne-Turner D, Coustan-Smith E, Roberts KG, et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood. 2015;126(26):2896–9.  https://doi.org/10.1182/blood-2015-09-671131.CrossRefGoogle Scholar
  14. 14.
    McNeer J, Meenakshi D, Dai Y, Carroll AJ, Heerema NA, Gastier-Foster JM, et al. Hematopoietic stem cell transplantation does not improve the poor outcome of children with Hypodiploid Acute Lymphoblastic Leukemia: A report from Children's Oncology Group. J Clin Oncol. 2019. Epub ahead of print.Google Scholar
  15. 15.
    Biondi A, Cimino G, Pieters R, Pui CH. Biological and therapeutic aspects of infant leukemia. Blood. 2000;96(1):24–33.Google Scholar
  16. 16.
    Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370(9583):240–50.  https://doi.org/10.1016/S0140-6736(07)61126-X.CrossRefGoogle Scholar
  17. 17.
    Hilden JM, Dinndorf PA, Meerbaum SO, Sather H, Villaluna D, Heerema NA, et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood. 2006;108(2):441–51.  https://doi.org/10.1182/blood-2005-07-3011.CrossRefGoogle Scholar
  18. 18.
    Dreyer ZE, Dinndorf PA, Camitta B, Sather H, La MK, Devidas M, et al. Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children’s Oncology Group. J Clin Oncol. 2011;29(2):214–22.  https://doi.org/10.1200/JCO.2009.26.8938.CrossRefGoogle Scholar
  19. 19.
    • Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood. 2010;116(15):2644–50.  https://doi.org/10.1182/blood-2010-03-273532 Demonstration that HSCT in CR1 is superior to chemotherapy in infant MLL+ ALL carrying additional poor prognostic factors. CrossRefGoogle Scholar
  20. 20.
    Heerema NA, Carroll AJ, Devidas M, Loh ML, Borowitz MJ, Gastier-Foster JM, et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: a report from the children’s oncology group. J Clin Oncol. 2013;31(27):3397–402.  https://doi.org/10.1200/JCO.2013.49.1308.CrossRefGoogle Scholar
  21. 21.
    Moorman AV, Robinson H, Schwab C, Richards SM, Hancock J, Mitchell CD, et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol. 2013;31(27):3389–96.  https://doi.org/10.1200/JCO.2013.48.9377.CrossRefGoogle Scholar
  22. 22.
    Fischer U, Forster M, Rinaldi A, Risch T, Sungalee S, Warnatz HJ, et al. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet. 2015;47(9):1020–9.  https://doi.org/10.1038/ng.3362.CrossRefGoogle Scholar
  23. 23.
    Locatelli F, Zugmaier G, Vora A, Rossig C, Peters C, Brethon B, et al. Blinatumomab use in pediatric patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from an open-label, multicenter, expanded access study. J Clin Oncol. 2017;35:10530.  https://doi.org/10.1200/JCO.2017.35.15_suppl.10530.CrossRefGoogle Scholar
  24. 24.
    • Locatelli F, Schrappe M, Bernardo ME, Rutella S. How I treat relapsed childhood acute lymphoblastic leukemia. Blood. 2012;120(14):2807–16.  https://doi.org/10.1182/blood-2012-02-265884 This is a comprehensive review on the pathophysiology and management of relapsed pediatric ALL. CrossRefGoogle Scholar
  25. 25.
    Bailey LC, Lange BJ, Rheingold SR, Bunin NJ. Bone-marrow relapse in paediatric acute lymphoblastic leukaemia. Lancet Oncol. 2008;9(9):873–83.  https://doi.org/10.1016/S1470-2045(08)70229-8.CrossRefGoogle Scholar
  26. 26.
    Einsiedel HG, von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G, et al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J Clin Oncol. 2005;23(31):7942–50.  https://doi.org/10.1200/JCO.2005.01.1031.CrossRefGoogle Scholar
  27. 27.
    Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB, et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol. 2000;108(3):531–43.CrossRefGoogle Scholar
  28. 28.
    Borgmann A, von Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C, et al. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood. 2003;101(10):3835–9.  https://doi.org/10.1182/blood.V101.10.3835.CrossRefGoogle Scholar
  29. 29.
    Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376(9757):2009–17.  https://doi.org/10.1016/S0140-6736(10)62002-8.CrossRefGoogle Scholar
  30. 30.
    Paganin M, Zecca M, Fabbri G, Polato K, Biondi A, Rizzari C, et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed ‘high-risk’ acute lymphoblastic leukemia. Leukemia. 2008;22(12):2193–200.  https://doi.org/10.1038/leu.2008.227.CrossRefGoogle Scholar
  31. 31.
    Eckert C, Biondi A, Seeger K, Cazzaniga G, Hartmann R, Beyermann B, et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet. 2001;358(9289):1239–41.  https://doi.org/10.1016/S0140-6736(01)06355-3.CrossRefGoogle Scholar
  32. 32.
    Coustan-Smith E, Gajjar A, Hijiya N, Razzouk BI, Ribeiro RC, Rivera GK, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia. 2004;18(3):499–504.  https://doi.org/10.1038/sj.leu.2403283.CrossRefGoogle Scholar
  33. 33.
    Eckert C, von Stackelberg A, Seeger K, Groeneveld TW, Peters C, Klingebiel T, et al. Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia—long-term results of trial ALL-REZ BFM P95/96. Eur J Cancer. 2013;49(6):1346–55.  https://doi.org/10.1016/j.ejca.2012.11.010.CrossRefGoogle Scholar
  34. 34.
    Krentz S, Hof J, Mendioroz A, Vaggopoulou R, Dorge P, Lottaz C, et al. Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia. 2013;27(2):295–304.  https://doi.org/10.1038/leu.2012.155.CrossRefGoogle Scholar
  35. 35.
    Besse K, Maiers M, Confer D, Albrecht M. On modeling human leukocyte antigen-identical sibling match probability for allogeneic hematopoietic cell transplantation: estimating the need for an unrelated donor source. Biol Blood Marrow Transplant. 2016;22(3):410–7.  https://doi.org/10.1016/j.bbmt.2015.09.012.CrossRefGoogle Scholar
  36. 36.
    Locatelli F, Zecca M, Messina C, Rondelli R, Lanino E, Sacchi N, et al. Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors. Leukemia. 2002;16(11):2228–37.  https://doi.org/10.1038/sj.leu.2402690.CrossRefGoogle Scholar
  37. 37.
    Zhang MJ, Davies SM, Camitta BM, Logan B, Tiedemann K, Eapen M, et al. Comparison of outcomes after HLA-matched sibling and unrelated donor transplantation for children with high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2012;18(8):1204–10.  https://doi.org/10.1016/j.bbmt.2012.01.007.CrossRefGoogle Scholar
  38. 38.
    • Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015;33(11):1265–74.  https://doi.org/10.1200/JCO.2014.58.9747 The first prospective study to compare HSCT from unrelated donors and matched family donors in well-defined cohorts of children with high-risk ALL. CrossRefGoogle Scholar
  39. 39.
    Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339–48.  https://doi.org/10.1056/NEJMsa1311707.CrossRefGoogle Scholar
  40. 40.
    • Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. Blood. 2017;130(5):677–85.  https://doi.org/10.1182/blood-2017-04-779769 A large single-center study on TCRαβ-depleted haploidentical HSCT demonstrating similar outcomes when haploidentical, unrelated and matched-family donors were used. CrossRefGoogle Scholar
  41. 41.
    Bertaina A, Zecca M, Buldini B, Sacchi N, Algeri M, Saglio F, et al. Unrelated donor vs HLA-haploidentical alpha/beta T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood. 2018;132(24):2594–607.  https://doi.org/10.1182/blood-2018-07-861575.CrossRefGoogle Scholar
  42. 42.
    Bashey A, Solomon SR. T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor. Bone Marrow Transplant. 2014;49(8):999–1008.  https://doi.org/10.1038/bmt.2014.62.CrossRefGoogle Scholar
  43. 43.
    Srour SA, Milton DR, Bashey A, Karduss-Urueta A, Al Malki MM, Romee R, et al. Haploidentical transplantation with post-transplantation cyclophosphamide for high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2017;23(2):318–24.  https://doi.org/10.1016/j.bbmt.2016.11.008.CrossRefGoogle Scholar
  44. 44.
    Santoro N, Ruggeri A, Labopin M, Bacigalupo A, Ciceri F, Gulbas Z, et al. Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. J Hematol Oncol. 2017;10(1):113.  https://doi.org/10.1186/s13045-017-0480-5.CrossRefGoogle Scholar
  45. 45.
    Berger M, Lanino E, Cesaro S, Zecca M, Vassallo E, Faraci M, et al. Feasibility and outcome of haploidentical hematopoietic stem cell transplantation with post-transplant high-dose cyclophosphamide for children and adolescents with hematologic malignancies: an AIEOP-GITMO retrospective multicenter study. Biol Blood Marrow Transplant. 2016;22(5):902–9.  https://doi.org/10.1016/j.bbmt.2016.02.002.CrossRefGoogle Scholar
  46. 46.
    Hong KT, Kang HJ, Choi JY, Hong CR, Cheon JE, Park JD, et al. Favorable outcome of post-transplantation cyclophosphamide haploidentical peripheral blood stem cell transplantation with targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring in pediatric patients. Biol Blood Marrow Transplant. 2018;24(11):2239–44.  https://doi.org/10.1016/j.bbmt.2018.06.034.CrossRefGoogle Scholar
  47. 47.
    Rocha V, Cornish J, Sievers EL, Filipovich A, Locatelli F, Peters C, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood. 2001;97(10):2962–71.CrossRefGoogle Scholar
  48. 48.
    Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369(9577):1947–54.  https://doi.org/10.1016/S0140-6736(07)60915-5.CrossRefGoogle Scholar
  49. 49.
    Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53(9):1139–48.  https://doi.org/10.1038/s41409-018-0153-1.CrossRefGoogle Scholar
  50. 50.
    Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344–53.  https://doi.org/10.1182/blood-2014-02-514778.CrossRefGoogle Scholar
  51. 51.
    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(2):340–7.  https://doi.org/10.1200/JCO.2000.18.2.340.CrossRefGoogle Scholar
  52. 52.
    Shi-Xia X, Xian-Hua T, Hai-Qin X, Bo F, Xiang-Feng T. Total body irradiation plus cyclophosphamide versus busulphan with cyclophosphamide as conditioning regimen for patients with leukemia undergoing allogeneic stem cell transplantation: a meta-analysis. Leuk Lymphoma. 2010;51(1):50–60.  https://doi.org/10.3109/10428190903419130.CrossRefGoogle Scholar
  53. 53.
    Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, et al. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987;317(26):1618–24.  https://doi.org/10.1056/NEJM198712243172602.CrossRefGoogle Scholar
  54. 54.
    Kato M, Ishida H, Koh K, Inagaki J, Kato K, Goto H, et al. Comparison of chemotherapeutic agents as a myeloablative conditioning with total body irradiation for pediatric acute lymphoblastic leukemia: a study from the pediatric ALL working group of the Japan Society for Hematopoietic Cell Transplantation. Pediatr Blood Cancer. 2015;62(10):1844–50.  https://doi.org/10.1002/pbc.25602.CrossRefGoogle Scholar
  55. 55.
    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(6):1838–46.  https://doi.org/10.1200/JCO.1999.17.6.1838.CrossRefGoogle Scholar
  56. 56.
    Blume KG, Forman SJ, O’Donnell MR, Doroshow JH, Krance RA, Nademanee AP, et al. Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood. 1987;69(4):1015–20.Google Scholar
  57. 57.
    Snyder DS, Chao NJ, Amylon MD, Taguchi J, Long GD, Negrin RS, et al. Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission. Blood. 1993;82(9):2920–8.Google Scholar
  58. 58.
    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(4):438–53.  https://doi.org/10.1016/j.bbmt.2005.12.029.CrossRefGoogle Scholar
  59. 59.
    Giorgiani G, Bozzola M, Locatelli F, Picco P, Zecca M, Cisternino M, et al. Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood. 1995;86(2):825–31.Google Scholar
  60. 60.
    Willard VW, Leung W, Huang Q, Zhang H, Phipps S. Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation. J Clin Oncol. 2014;32(35):3982–8.  https://doi.org/10.1200/JCO.2014.56.2223.CrossRefGoogle Scholar
  61. 61.
    Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant. 2003;32(6):543–8.  https://doi.org/10.1038/sj.bmt.1704198.CrossRefGoogle Scholar
  62. 62.
    Pulsipher MA, Boucher KM, Wall D, Frangoul H, Duval M, Goyal RK, et al. Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood. 2009;114(7):1429–36.  https://doi.org/10.1182/blood-2009-01-196303.CrossRefGoogle Scholar
  63. 63.
    Locatelli F, Merli P, Bertaina A. Rabbit anti-human T-lymphocyte globulin and hematopoietic transplantation. Oncotarget. 2017;8(57):96460–1.  https://doi.org/10.18632/oncotarget.20878.CrossRefGoogle Scholar
  64. 64.
    Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated Myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35(36):4003–11.  https://doi.org/10.1200/JCO.2017.75.8177.CrossRefGoogle Scholar
  65. 65.
    •• Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A, et al. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(8):1126–36.  https://doi.org/10.1016/S1470-2045(17)30417-5 Multicenter randomized-controlled study demonstrating that a lower dose of ATLG determines a better outcome as compared to the use of an higher dose. This was due to a lower incidence of infectious complications, while the incidence of acute and chronic GvHD, as well as that of recurrence of the original disease was not significantly affected. CrossRefGoogle Scholar
  66. 66.
    Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll W, et al. Risk factors and timing of relapse after allogeneic transplantation in pediatric ALL: for whom and when should interventions be tested? Bone Marrow Transplant. 2015;50(9):1173–9.  https://doi.org/10.1038/bmt.2015.103.CrossRefGoogle Scholar
  67. 67.
    Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, et al. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children’s Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014;123(13):2017–25.  https://doi.org/10.1182/blood-2013-10-534297.CrossRefGoogle Scholar
  68. 68.
    Lucarelli B, Merli P, Bertaina V, Locatelli F. Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation. Expert Rev Clin Immunol. 2016;12(3):343–58.  https://doi.org/10.1586/1744666X.2016.1123091.CrossRefGoogle Scholar
  69. 69.
    Zecca M, Prete A, Rondelli R, Lanino E, Balduzzi A, Messina C, et al. Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood. 2002;100(4):1192–200.  https://doi.org/10.1182/blood-2001-11-0059.CrossRefGoogle Scholar
  70. 70.
    Bosi A, Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E, et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol. 2001;19(16):3675–84.  https://doi.org/10.1200/JCO.2001.19.16.3675.CrossRefGoogle Scholar
  71. 71.
    Yaniv I, Krauss AC, Beohou E, Dalissier A, Corbacioglu S, Zecca M, et al. Second hematopoietic stem cell transplantation for post-transplantation relapsed acute leukemia in children: a retrospective EBMT-PDWP study. Biol Blood Marrow Transplant. 2018;24(8):1629–42.  https://doi.org/10.1016/j.bbmt.2018.03.002.CrossRefGoogle Scholar
  72. 72.
    Willasch AM, Salzmann-Manrique E, Krenn T, Duerken M, Faber J, Opper J, et al. Treatment of relapse after allogeneic stem cell transplantation in children and adolescents with ALL: the Frankfurt experience. Bone Marrow Transplant. 2017;52(2):201–8.  https://doi.org/10.1038/bmt.2016.224.CrossRefGoogle Scholar
  73. 73.
    Maloney KW, Carroll WL, Carroll AJ, Devidas M, Borowitz MJ, Martin PL, et al. Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children’s Oncology Group. Blood. 2010;116(7):1045–50.  https://doi.org/10.1182/blood-2009-07-235291.CrossRefGoogle Scholar
  74. 74.
    Ragab AH, Abdel-Mageed A, Shuster JJ, Frankel LS, Pullen J, van Eys J, et al. Clinical characteristics and treatment outcome of children with acute lymphocytic leukemia and Down’s syndrome. A Pediatric Oncology Group study. Cancer. 1991;67(4):1057–63.CrossRefGoogle Scholar
  75. 75.
    Rubin CM, Mick R, Johnson FL. Bone marrow transplantation for the treatment of haematological disorders in Down’s syndrome: toxicity and outcome. Bone Marrow Transplant. 1996;18(3):533–40.Google Scholar
  76. 76.
    Goto H, Kaneko T, Shioda Y, Kajiwara M, Sakashita K, Kitoh T, et al. Hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia and down syndrome. Pediatr Blood Cancer. 2015;62(1):148–52.  https://doi.org/10.1002/pbc.25245.CrossRefGoogle Scholar
  77. 77.
    Meissner B, Borkhardt A, Dilloo D, Fuchs D, Friedrich W, Handgretinger R, et al. Relapse, not regimen-related toxicity, was the major cause of treatment failure in 11 children with Down syndrome undergoing haematopoietic stem cell transplantation for acute leukaemia. Bone Marrow Transplant. 2007;40(10):945–9.  https://doi.org/10.1038/sj.bmt.1705844.CrossRefGoogle Scholar
  78. 78.
    Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan KW, et al. Outcome of transplantation for acute lymphoblastic leukemia in children with Down syndrome. Pediatr Blood Cancer. 2014;61(6):1126–8.  https://doi.org/10.1002/pbc.24918.CrossRefGoogle Scholar
  79. 79.
    Duncan CN, Clark JJ, Silverman LB. Hematopoietic stem cell transplantation in unique pediatric populations: adolescents, infants, and children with down syndrome. Biol Blood Marrow Transplant. 2013;19(1 Suppl):S52–7.  https://doi.org/10.1016/j.bbmt.2012.10.018.CrossRefGoogle Scholar
  80. 80.
    Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175–81.  https://doi.org/10.1200/JCO.2008.21.2514.CrossRefGoogle Scholar
  81. 81.
    Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13(9):936–45.  https://doi.org/10.1016/S1470-2045(12)70377-7.CrossRefGoogle Scholar
  82. 82.
    Rives S, Estella J, Gomez P, Lopez-Duarte M, de Miguel PG, Verdeguer A, et al. Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005. Br J Haematol. 2011;154(5):600–11.  https://doi.org/10.1111/j.1365-2141.2011.08783.x.CrossRefGoogle Scholar
  83. 83.
    Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia. 2014;28(7):1467–71.  https://doi.org/10.1038/leu.2014.30.CrossRefGoogle Scholar
  84. 84.
    Slayton WB, Schultz KR, Kairalla JA, Devidas M, Mi X, Pulsipher MA, et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: results of Children’s Oncology Group Trial AALL0622. J Clin Oncol. 2018;36(22):2306–14.  https://doi.org/10.1200/JCO.2017.76.7228.CrossRefGoogle Scholar
  85. 85.
    Litzow MR. Allogeneic transplantation for patients with Philadelphia chromosome positive acute lymphoblastic leukemia: is it imperative in the tyrosine kinase inhibitor era? Best Pract Res Clin Haematol. 2018;31(4):357–60.  https://doi.org/10.1016/j.beha.2018.09.004.CrossRefGoogle Scholar
  86. 86.
    Akahoshi Y, Mizuta S, Shimizu H, Uchida N, Fukuda T, Kanamori H, et al. Additional cytogenetic abnormalities with Philadelphia chromosome-positive acute lymphoblastic leukemia on allogeneic stem cell transplantation in the tyrosine kinase inhibitor era. Biol Blood Marrow Transplant. 2018;24(10):2009–16.  https://doi.org/10.1016/j.bbmt.2018.06.006.CrossRefGoogle Scholar
  87. 87.
    Pfeifer H, Raum K, Markovic S, Nowak V, Fey S, Oblander J, et al. Genomic CDKN2A/2B deletions in adult Ph(+) ALL are adverse despite allogeneic stem cell transplantation. Blood. 2018;131(13):1464–75.  https://doi.org/10.1182/blood-2017-07-796862.CrossRefGoogle Scholar
  88. 88.
    Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, et al. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a propensity score analysis. Cancer. 2016;122(23):3650–6.  https://doi.org/10.1002/cncr.30231.CrossRefGoogle Scholar
  89. 89.
    Jabbour E, DerSarkissian M, Duh MS, McCormick N, Cheng WY, McGarry LJ, et al. Efficacy of ponatinib versus earlier generation tyrosine kinase inhibitors for front-line treatment of newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2018;18(4):257–65.  https://doi.org/10.1016/j.clml.2018.02.010.CrossRefGoogle Scholar
  90. 90.
    •• von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381–9.  https://doi.org/10.1200/JCO.2016.67.3301 This study reports the results of a large phase I/phase II trial of blinatumomab in pediatric patients with relapsed/refractory ALL. CrossRefGoogle Scholar
  91. 91.
    Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2018.  https://doi.org/10.1038/s41375-018-0265-z.
  92. 92.
    •• Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.  https://doi.org/10.1056/NEJMoa1709866 Large, updated, multicenter, phase II study proving the efficacy of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory CD19+−ALL. CrossRefGoogle Scholar
  93. 93.
    Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.  https://doi.org/10.1056/NEJMoa1709919.CrossRefGoogle Scholar
  94. 94.
    • Kansagra AJ, Frey NV, Bar M, Laetsch TW, Carpenter PA, Savani BN, et al. Clinical utilization of chimeric antigen receptors T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)—an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT). Biol Blood Marrow Transplant. 2018.  https://doi.org/10.1016/j.bbmt.2018.12.068 A comprehensive expert opinion on the use of CD19 CAR T cells for ALL, including a commentary on the role of HSCT.
  95. 95.
    Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med. 2018;24(10):1504–6.  https://doi.org/10.1038/s41591-018-0146-z.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Pietro Merli
    • 1
  • Mattia Algeri
    • 1
  • Francesca Del Bufalo
    • 1
  • Franco Locatelli
    • 1
    • 2
    Email author
  1. 1.Department of Pediatric Hematology and OncologyBambino Gesù Children’s HospitalRomeItaly
  2. 2.Sapienza University of RomeRomeItaly

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