Review Article | Published:

Current status and future clinical directions in the prevention and treatment of relapse following hematopoietic transplantation for acute myeloid and lymphoblastic leukemia

Bone Marrow Transplantation (2018) | Download Citation

Abstract

In recent years we have seen a dramatic evolution of therapeutic approaches in the management of acute leukemia with hematopoietic stem cell transplantation (HCT). For both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), alloHCT provides the best chance of long-term disease-free survival for significant subsets of patients. During this interval, we have witnessed an evolution of HCT from a therapy based on high-dose conditioning to our current understanding that its success depends both on cytoreduction and graft-versus-leukemia (GVL) effects mediated by adoptively transferred donor immune cells. Improvements in conditioning, infectious disease monitoring and management, histocompatibility testing and graft selection have successively improved outcomes, primarily due to a reduction in non-relapse mortality. Unfortunately, disease relapse remains a significant cause of treatment failure in both AML and ALL. Here, two distinguished experts, Prof. Charles Craddock and Prof. Dieter Hoelzer, reflect on the significant challenge of disease relapse following allogeneic HCT for AML and ALL, respectively. This is a review of the biology, current approaches, and future directions in the field and reflects concepts that were presented at the Third International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation held in Hamburg, Germany in November 2016 under the auspices of the EBMT and the ASBMT.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Ossenkoppele GJ, Janssen JJ, van de Loosdrecht AA. Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia. Haematologica. 2016;101:20–25. https://doi.org/10.3324/haematol.2015.139105.

  2. 2.

    Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016;127:62–70. https://doi.org/10.1182/blood-2015-07-604546.

  3. 3.

    de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I. et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129:1753–62. https://doi.org/10.1182/blood-2016-06-724500.

  4. 4.

    Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012;119:1599–606. https://doi.org/10.1182/blood-2011-08-375840. e-pub ahead of print 2011/12/15

  5. 5.

    Christopeit M, Kuss O, Finke J, Bacher U, Beelen DW, Bornhauser M, et al. Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31:3259–71. https://doi.org/10.1200/JCO.2012.44.7961

  6. 6.

    Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM, et al. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood. 2007;110:409–17.

  7. 7.

    Craddock C, Labopin M, Pillai S, Finke J, Bunjes D, Greinix H, et al. Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia. Leuk: Off J Leuk Soc Am, Leuk Res Fund, UK. 2011;25:808–13. https://doi.org/10.1038/leu.2011.13. e-pub ahead of print 2011/02/23

  8. 8.

    Bacigalupo A, Van Lint MT, Occhini D, Gualandi F, Lamparelli T, Sogno G, et al. Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood. 1991;77:1423–8.

  9. 9.

    Craddock C, Nagra S, Peniket A, Brookes C, Buckley L, Nikolousis E, et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2010;95:989–95. https://doi.org/10.3324/haematol.2009.013920. e-pub ahead of print 2009/12/03

  10. 10.

    Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006;108:836–46.

  11. 11.

    Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol: Off J Am Soc Clin Oncol. 2017;35:1154–61. https://doi.org/10.1200/JCO.2016.70.7091

  12. 12.

    Kroger N, Iacobelli S, Franke GN, Platzbecker U, Uddin R, Hubel K, et al. Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized phase III study of the EBMT (RICMAC Trial). J Clin Oncol: Off J Am Soc Clin Oncol 2017: JCO2016707349. https://doi.org/10.1200/JCO.2016.70.7349

  13. 13.

    Bornhauser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3trial. Lancet Oncol. 2012;13:1035–44. https://doi.org/10.1016/S1470-2045(12)70349-2

  14. 14.

    Blaise D, Tabrizi R, Boher JM, Le Corroller-Soriano AG, Bay JO, Fegueux N, et al. Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation. Cancer. 2013;119:602–11. https://doi.org/10.1002/cncr.27786

  15. 15.

    Rambaldi A, Grassi A, Masciulli A, Boschini C, Mico MC, Busca A, et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3trial. Lancet Oncol. 2015;16:1525–36. https://doi.org/10.1016/S1470-2045(15)00200-4

  16. 16.

    Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:1190–7. https://doi.org/10.1200/JCO.2010.31.8121

  17. 17.

    Bradbury C, Houlton AE, Akiki S, Gregg R, Rindl M, Khan J, et al. Prognostic value of monitoring a candidate immunophenotypic leukaemic stem/progenitor cell population in patients allografted for acute myeloid leukaemia. Leuk: Off J Leuk Soc Am, Leuk Res Fund, UK. 2015;29:988–91. https://doi.org/10.1038/leu.2014.327

  18. 18.

    Cornelissen JJ, Breems D, van Putten WL, Gratwohl AA, Passweg JR, Pabst T, et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30:2140–6. https://doi.org/10.1200/JCO.2011.39.6499

  19. 19.

    Middeke JM, Fang M, Cornelissen JJ, Mohr B, Appelbaum FR, Stadler M, et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood. 2014;123:2960–7. https://doi.org/10.1182/blood-2013-12-544957

  20. 20.

    Schmid C, Labopin M, Socie G, Daguindau E, Volin L, Huynh A, et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015;126:2062–9. https://doi.org/10.1182/blood-2015-06-651562

  21. 21.

    Quek LFP, Metzner M, et al. Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia. Blood Adv. 2017;1:193–204.

  22. 22.

    Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47. https://doi.org/10.1056/NEJMoa1611604

  23. 23.

    Yoshizato T, Nannya Y, Atsuta Y, Shiozawa Y, Iijima-Yamashita Y, Yoshida K, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129:2347–58. https://doi.org/10.1182/blood-2016-12-754796

  24. 24.

    Tallman MS, Rowlings PA, Milone G, Zhang MJ, Perez WS, Weisdorf D, et al. Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood. 2000;96:1254–8.

  25. 25.

    Warlick ED, Paulson K, Brazauskas R, Zhong X, Miller AM, Camitta BM, et al. Effect of postremission therapy before reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2014;20:202–8. https://doi.org/10.1016/j.bbmt.2013.10.023

  26. 26.

    Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:1867–71.

  27. 27.

    Clift RA, Buckner CD, Appelbaum FR, Bryant E, Bearman SI, Petersen FB, et al. Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood. 1991;77:1660–5.

  28. 28.

    Martino R, de Wreede L, Fiocco M, van Biezen A, von dem Borne PA, Hamladji RM, et al. Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with 10% BM blasts: a report from EBMT. Bone Marrow Transplant. 2013;48:761–70. https://doi.org/10.1038/bmt.2012.236. e-pub ahead of print 2012/12/05

  29. 29.

    Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23:5675–87.

  30. 30.

    Malard F, Labopin M, Stuhler G, Bittenbring J, Ganser A, Tischer J, et al. Sequential intensified conditioning regimen allogeneic hematopoietic stem cell transplantation in adult patients with intermediate- or high-risk acute myeloid leukemia in complete remission: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2017;23:278–84. https://doi.org/10.1016/j.bbmt.2016.11.002

  31. 31.

    Olavarria E, Siddique S, Griffiths MJ, Avery S, Byrne JL, Piper KP, et al. Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia. Blood. 2007;110:4614–7. https://doi.org/10.1182/blood-2007-04-082990. e-pub ahead of print 2007/09/21

  32. 32.

    Brunner AM, Fathi AT, Chen YB. Life after transplant: are we becoming high maintenance in AML? Bone Marrow Transplant. 2016;51:1423–30. https://doi.org/10.1038/bmt.2016.160

  33. 33.

    Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012;119:3361–9. https://doi.org/10.1182/blood-2011-09-377044. e-pub ahead of print 2012/01/12

  34. 34.

    Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. 2010;116:129–39. https://doi.org/10.1182/blood-2009-12-257253

  35. 35.

    Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:2042–8. https://doi.org/10.1016/j.bbmt.2014.09.007

  36. 36.

    Battipaglia G, Ruggeri A, Massoud R, El Cheikh J, Jestin M, Antar A, et al. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia. Cancer. 2017;123:2867–74. https://doi.org/10.1002/cncr.30680

  37. 37.

    Brunner AM, Li S, Fathi AT, Wadleigh M, Ho VT, Collier K, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175:496–504. https://doi.org/10.1111/bjh.14260

  38. 38.

    Cruijsen M, Hobo W, van der Velden WJ, Bremmers ME, Woestenenk R, Bar B, et al. Addition of 10-day decitabine to fludarabine/total body irradiation conditioning is feasible and induces tumor-associated antigen-specific T cell responses. Biol Blood Marrow Transplant. 2016;22:1000–8. https://doi.org/10.1016/j.bbmt.2016.02.003

  39. 39.

    Pusic I, Choi J, Fiala MA, Gao F, Holt M, Cashen AF, et al. Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2015;21:1761–9. https://doi.org/10.1016/j.bbmt.2015.05.026

  40. 40.

    Craddock C, Jilani N, Siddique S, Yap C, Khan J, Nagra S, et al. Tolerability and clinical activity of post-transplantation azacitidine in patients allografted for acute myeloid leukemia treated on the RICAZA Trial. Biol Blood Marrow Transplant. 2016;22:385–90. https://doi.org/10.1016/j.bbmt.2015.09.004

  41. 41.

    Haverkos BM, Abbott D, Hamadani M, Armand P, Flowers ME, Merryman R, et al. PD-1 blockade for relapsed lymphoma post allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130:221–8. https://doi.org/10.1182/blood-2017-01-761346

  42. 42.

    Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143–53. https://doi.org/10.1056/NEJMoa1601202

  43. 43.

    Network SCotBaMTCT. The Blood and Marrow Transplant Clinical Trials Network: an effective infrastructure for addressing important issues in hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:1747–57.

  44. 44.

    Thomas DA, Kantarjian H, Smith TL, Koller C, Cortes J, O’Brien S, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer. 1999;86:1216–30. e-pub ahead of print 1999/10/03

  45. 45.

    Tavernier E, Boiron JM, Huguet F, Bradstock K, Vey N, Kovacsovics T, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leuk: Off J Leuk Soc Am, Leuk Res Fund, UK. 2007;21:1907–14. https://doi.org/10.1038/sj.leu.2404824. e-pub ahead of print2007/07/06

  46. 46.

    Oriol A, Vives S, Hernandez-Rivas JM, Tormo M, Heras I, Rivas C, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica. 2010;95:589–96. https://doi.org/10.3324/haematol.2009.014274. e-pub ahead of print 2010/02/11

  47. 47.

    Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50. https://doi.org/10.1182/blood-2006-05-018192. e-pub ahead of print 2006/10/13

  48. 48.

    Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:532–43. https://doi.org/10.1200/JCO.2010.30.1382. e-pub ahead of print 2011/01/12

  49. 49.

    Gokbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Huttmann A, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120:2032–41. https://doi.org/10.1182/blood-2011-12-399287. e-pub ahead of print 2012/04/12

  50. 50.

    Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015;126:589–96. https://doi.org/10.1182/blood-2014-09-551937. e-pub ahead of print 2015/05/15

  51. 51.

    Gokbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101:1524–33. https://doi.org/10.3324/haematol.2016.144311. e-pub ahead of print 2016/09/03

  52. 52.

    van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731–8. https://doi.org/10.1016/S0140-6736(98)04058-6. e-pub ahead of print 1998/12/16

  53. 53.

    Bruggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107:1116–23. https://doi.org/10.1182/blood-2005-07-2708. e-pub ahead of print 2005/10/01

  54. 54.

    Gokbuget N, Kneba M, Raff T, Trautmann H, Bartram CR, Arnold R, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120:1868–76. https://doi.org/10.1182/blood-2011-09-377713. e-pub ahead of print 2012/03/24

  55. 55.

    Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C, et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v69–v82. https://doi.org/10.1093/annonc/mdw025. e-pub ahead of print 2016/04/09

  56. 56.

    Hoelzer D. Novel antibody-based therapies for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:243–9.

  57. 57.

    Hoelzer D, Walewski J, Dohner H, Viardot A, Hiddemann W, Spiekermann K, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood. 2014;124:3870–9. https://doi.org/10.1182/blood-2014-03-563627. e-pub ahead of print 2014/11/02

  58. 58.

    Thomas DA, O’Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28:3880–9. https://doi.org/10.1200/JCO.2009.26.9456. e-pub ahead of print 2010/07/28

  59. 59.

    Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, et al. Addition of rituxmab improves the outcome of adult patients with CD20-positive, Ph-negative, B-cell precursor acute lymphoblastic leukemia (BCP-ALL): results of the randomized Graali-R 2005 study. American Society of Hematology Annual Meeting, Orlando, FL, 2015;126:1.

  60. 60.

    DeAngelo, DJ, Jabbour E, Stelljes M, Liedtke M, Stock W, Gokbuget N, et al. Inotuzumab ozogamicin (InO) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the phase III INO-VATE trial: efficacy and safety by prior therapy. American Society of Clinical Oncology Annual Meeting, Chicago, IL USA, DOI: 10.1200/JCO.2016.34.15_suppl.7028 2016.

  61. 61.

    Kantarjian HM, Vandendries E, Advani AS. Inotuzumab ozogamicin for acute lymphoblastic leukemia. N Engl J Med. 2016;375:2100–1. https://doi.org/10.1056/NEJMc1612040. e-pub ahead of print 2016/12/14

  62. 62.

    Jabbour E, O'Brien S, Thomas D, Sasaki K, Garcia-Manero G, Konopleva M, et al. Inotuzumab Ozogamicin versus standard therapy in combination with low-intensity chemotherapy (mini-Hyper-CVAD) for the frontline therapy in elderly patients (60 years) with acute lymphoblastic leukemia (ALL). European Hematology Association Annual Meeting. Vienna, Austria, 2015.

  63. 63.

    Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974–7. https://doi.org/10.1126/science.1158545. e-pub ahead of print 2008/08/16

  64. 64.

    Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A. Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leuk: Off J Leuk Soc Am, Leuk Res Fund, UK. 2011;25:181–4. https://doi.org/10.1038/leu.2010.239. e-pub ahead of print 2010/10/15

  65. 65.

    Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:2493–8. https://doi.org/10.1200/JCO.2010.32.7270. e-pub ahead of print 2011/05/18

  66. 66.

    Topp MS, Gokbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120:5185–7. https://doi.org/10.1182/blood-2012-07-441030. e-pub ahead of print 2012/10/02

  67. 67.

    Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Long-Term outcomes after blinatumomab treatment: follow-up of a phase 2 study in patients (Pts) with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL). Blood. 2015;126:680–680.

  68. 68.

    Topp MS, Gokbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66. https://doi.org/10.1016/S1470-2045(14)71170-2. e-pub ahead of print 2014/12/20

  69. 69.

    Martinelli G, Boissel N, Chevallier P, Ottmann O, Gokbuget N, Topp MS, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol: Off J Am Soc Clin Oncol. 2017;35:1795–802. https://doi.org/10.1200/JCO.2016.69.3531. e-pub ahead of print 2017/03/30

  70. 70.

    Gokbuget N, Kelsh M, Chia V, Advani A, Bassan R, Dombret H, et al. Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia. Blood Cancer J. 2016;6:e473 https://doi.org/10.1038/bcj.2016.84. e-pub ahead of print 2016/09/24

  71. 71.

    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28. https://doi.org/10.1016/S0140-6736(14)61403-3. e-pub ahead of print 2014/10/17

  72. 72.

    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17. https://doi.org/10.1056/NEJMoa1407222. e-pub ahead of print 2014/10/16

  73. 73.

    Park JH, Riviere I, Wang X, Bernal YJ, Yoo S, Purdon T, et al. CD19-targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL. Blood. 2014;124:382–382.

  74. 74.

    Park JH, Riviere I, Wang X, Senechal B, Wang Y, Mead E, et al. Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy. J Clin Oncol. 2017;35(15_suppl):7008–7008. https://doi.org/10.1200/JCO.2017.35.15_suppl.7008

  75. 75.

    Frey N, Porter DL. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Am Soc Hematol Educ Program. 2016;1:567–72.

  76. 76.

    Lee DW, Stetler-Stevenson M, Yuan CM, Shah NN, Delbrook C, Yates B, et al. Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood. 2016;128:218–218.

  77. 77.

    Mayer S, van Besien K. Second allogeneic transplantation: ever? never? or sometimes. Leuk Lymphoma. 2017;58:1279–80. https://doi.org/10.1080/10428194.2016.1253839. e-pub ahead of print 2016/11/16

Download references

Author information

Affiliations

  1. Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK

    • Charles Craddock
  2. ONKOLOGIKUM Frankfurt|am Museumsufer, Gartenstr. 134, 60596, Frankfurt, Germany

    • Dieter Hoelzer
  3. Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Suite 916, Miami, FL, 33157, USA

    • Krishna V. Komanduri

Authors

  1. Search for Charles Craddock in:

  2. Search for Dieter Hoelzer in:

  3. Search for Krishna V. Komanduri in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Charles Craddock.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41409-018-0203-8