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Methods to prevent and treat relapse after hematopoietic stem cell transplantation with tyrosine kinase inhibitors, immunomodulating drugs, deacetylase inhibitors, and hypomethylating agents

Bone Marrow Transplantation volume 54, pages 497–507 (2019)Cite this article

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Abstract

Relapse is a major cause of treatment failure after stem cell transplantation. Novel agents given as maintenance or preemptive post transplant were discussed at the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation in Hamburg/Germany in November 2016 under the auspices of EBMT and ASBMT. Maintenance therapy is started after SCT without detectable disease, while preemptive therapy is triggered by the detection of minimal residual disease (MRD). The maintenance approach treats all patients, and overtreats a significant amount. Maintenance therapy requires an agent without significant off-target toxicity. The preemptive approach only initiates therapy upon detection of MRD, while sparing further therapy to those who remain in remission. Preemptive strategies require sensitive and clinically reliable assays to detect MRD. Here current development of tyrosine kinase inhibitors (TKIs) immunomodulating drugs (IMiDs), deacetylase inhibitors, and hypomethylating agents were reviewed.

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References

  1. Carpenter PA, Snyder DS, Flowers ME, Sanders JE, Gooley TA, Martin PJ, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007;109:2791–3. https://doi.org/10.1182/blood-2006-04-019836. e-pub ahead of print 2006/11/23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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

    Article  CAS  PubMed  Google Scholar 

  3. Ribera JM, Oriol A, Gonzalez M, Vidriales B, Brunet S, Esteve J, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010;95:87–95. https://doi.org/10.3324/haematol.2009.011221. e-pub ahead of print 2009/10/03

    Article  CAS  PubMed  Google Scholar 

  4. Caocci G, Vacca A, Ledda A, Murgia F, Piras E, Greco M, et al. Prophylactic and preemptive therapy with dasatinib after hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2012;18:652–4. https://doi.org/10.1016/j.bbmt.2011.12.587. e-pub ahead of print 2012/01/14

    Article  PubMed  Google Scholar 

  5. Teng CL, Yu JT, Chen HC, Hwang WL. Maintenance therapy with dasatinib after allogeneic hematopoietic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann Hematol. 2013;92:1137–9. https://doi.org/10.1007/s00277-012-1670-4. e-pub ahead of print 2013/01/12

    Article  PubMed  Google Scholar 

  6. Nishimoto M, Nakamae H, Koh KR, Kosaka S, Matsumoto K, Morita K, et al. Dasatinib maintenance therapy after allogeneic hematopoietic stem cell transplantation for an isolated central nervous system blast crisis in chronic myelogenous leukemia. Acta Haematol. 2013;130:111–4. https://doi.org/10.1159/000347158. e-pub ahead of print 2013/04/04

    Article  PubMed  Google Scholar 

  7. Shimoni A, Volchek Y, Koren-Michowitz M, Varda-Bloom N, Somech R, Shem-Tov N, et al. Phase 1/2 study of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121:863–71. https://doi.org/10.1002/cncr.29141. e-pub ahead of print 2014/11/13

    Article  CAS  PubMed  Google Scholar 

  8. Carpenter PA, Johnston L, Fernandez HF, Radich JP, Mauro MJ, Flowers ME, et al. A multicenter phase I/II study of relapse prophylaxis with nilotinib after hematopoietic cell transplantation (HCT) for high-risk philadelphia chromosome-positive (Ph+) leukemias. Biol Blood Marrow Transplant. 2015;21:S274–6.

    Article  Google Scholar 

  9. Bachanova V, Marks DI, Zhang MJ, Wang H, de Lima M, Aljurf MD, et al. Ph+ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia. 2014;28:658–65. https://doi.org/10.1038/leu.2013.253. e-pub ahead of print 2013/08/31

    Article  CAS  PubMed  Google Scholar 

  10. Brissot E, Labopin M, Beckers MM, Socie G, Rambaldi A, Volin L, et al. Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematologica. 2015;100:392–9. https://doi.org/10.3324/haematol.2014.116954. e-pub ahead of print 2014/12/21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G, Scheuring UJ, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD + Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2005;106:458–63. https://doi.org/10.1182/blood-2004-05-1746. e-pub ahead of print 2005/04/09

    Article  CAS  PubMed  Google Scholar 

  12. Chen H, Liu KY, Xu LP, Liu DH, Chen YH, Zhao XY, et al. Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. J Hematol & Oncol. 2012;5:29 https://doi.org/10.1186/1756-8722-5-29. e-pub ahead of print 2012/06/12

    Article  CAS  Google Scholar 

  13. Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhauser M, Stadler M, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia. 2013;27:1254–62. https://doi.org/10.1038/leu.2012.352. e-pub ahead of print 2012/12/06

    Article  CAS  PubMed  Google Scholar 

  14. Giebel S, Czyz A, Ottmann O, Baron F, Brissot E, Ciceri F, et al. Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2016;122:2941–51. https://doi.org/10.1002/cncr.30130

    Article  CAS  PubMed  Google Scholar 

  15. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Am Soc Hematol Am Soc Hematol Educ Program. 2013;2013:220–6. https://doi.org/10.1182/asheducation-2013.1.220. e-pub ahead of print2013/12/10

    Article  Google Scholar 

  16. Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30:735–41. https://doi.org/10.1200/JCO.2011.36.9868. e-pub ahead of print 2012/02/01

    Article  Google Scholar 

  17. Deol A, Sengsayadeth S, Ahn KW, Wang HL, Aljurf M, Antin JH, et al. Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Cancer. 2016;122:3005–14. https://doi.org/10.1002/cncr.30140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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. e-pub ahead of print 2014/09/23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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. British journal of haematology 2016. e-pub ahead of print 2016/07/20; https://doi.org/10.1111/bjh.14260

    Article  CAS  Google Scholar 

  20. Pratz KW, Gojo I, Karp JE, Luznik L, Smith BD, Jones RJ, et al. Prospective study of peri-transplant use of sorafenib as remission maintenance for FLT3-ITD patients undergoing allogeneic transplantation. Blood. 2015;126:3164–3164.

    Google Scholar 

  21. Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126:6–6.

    Article  Google Scholar 

  22. Sandmaier BM,Khaled SK,Oran B,Gammon G,Trone D,Frankfurt O, Results of a phase 1 study of quizartinib (AC220) as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic cell transplantation. Blood. 2014;124:428

    Google Scholar 

  23. Collins R,Kantarjian HM,Ravandi F,Chen J,Macaraeg M,Urity V, et al. Full doses of crenolanib, a type I FLT3 Inhibitor, can be safely administered in AML patients post allogeneic stem cell transplant. Blood. 2015;126:4359

    Google Scholar 

  24. Schlenk R,Doehner K,Salih H,Kondgen A,Fielder W,Salwender HJ, et al. Midostaurin in combination with intensive induction and as single agent maintenance therapy after consolidation therapy with allogeneic hematopoietic stem cell transplantation or high-dise cytarabine (NCT01477606). Blood. 2015;126:322

    Google Scholar 

  25. Kroger N,Abd Kadir SSS,Zabelina T,Wolschke C,Ayuk FA,Badbaran A, et al. Ruxolitinib during peritransplant period for myelofibrosis patients undergoing allogeneic stem cell transplantation reduces acute graft-versus-host disease. Blood. 2016;128:2242

    Google Scholar 

  26. McCarthy PL, Holstein SA. Role of stem cell transplant and maintenance therapy in plasma cell disorders. Hematol Am Soc Hematol Educ Program. 2016;2016:504–11. https://doi.org/10.1182/asheducation-2016.1.504

    Article  Google Scholar 

  27. Holstein SA, McCarthy PL. Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience. Drugs. 2017;77:505–20. https://doi.org/10.1007/s40265-017-0689-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71. https://doi.org/10.1056/NEJM199911183412102

    Article  CAS  PubMed  Google Scholar 

  29. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR, Eastern Cooperative Oncology G. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24:431–6. https://doi.org/10.1200/JCO.2005.03.0221

    Article  CAS  Google Scholar 

  30. Corral LG, Muller GW, Moreira AL, Chen Y, Wu M, Stirling D, et al. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med. 1996;2:506–15.

    Article  CAS  Google Scholar 

  31. Muller GW, Corral LG, Shire MG, Wang H, Moreira A, Kaplan G, et al. Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J Med Chem. 1996;39:3238–40. https://doi.org/10.1021/jm9603328

    Article  CAS  PubMed  Google Scholar 

  32. Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24:22–32. https://doi.org/10.1038/leu.2009.236

    Article  CAS  PubMed  Google Scholar 

  33. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289–94. https://doi.org/10.1182/blood-2006-05-022962

    Article  CAS  PubMed  Google Scholar 

  34. Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112:3115–21. https://doi.org/10.1182/blood-2008-03-145235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113–20. https://doi.org/10.1182/blood-2009-05-222539

    Article  CAS  PubMed  Google Scholar 

  36. Morgan GJ, Davies FE, Gregory WM, Szubert AJ, Bell SE, Drayson MT, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood. 2012;119:5374–83. https://doi.org/10.1182/blood-2011-11-392522

    Article  CAS  PubMed  Google Scholar 

  37. Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, et al. Long-term follow-up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013;19:6030–8. https://doi.org/10.1158/1078-0432.CCR-12-3211

    Article  CAS  PubMed  Google Scholar 

  38. Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788–93. https://doi.org/10.1200/JCO.2008.18.8573

    Article  CAS  PubMed  Google Scholar 

  39. Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12:1195–203. https://doi.org/10.1016/S1470-2045(11)70243-1

    Article  PubMed  PubMed Central  Google Scholar 

  40. Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, et al. Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012;87:948–52. https://doi.org/10.1002/ajh.23274

    Article  CAS  PubMed  Google Scholar 

  41. Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, et al. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013;121:1517–23. https://doi.org/10.1182/blood-2012-09-451872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–81. https://doi.org/10.1056/NEJMoa1114083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Holstein SA, Owzar K, Richardson PG, Jiang C, Hofmeister CC, Hassoun H, et al. Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT)for multiple myeloma (MM). J Clin Oncol. 2015;33(suppl):abstr 8523.

    Article  Google Scholar 

  44. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–91. https://doi.org/10.1056/NEJMoa1114138

    Article  CAS  PubMed  Google Scholar 

  45. Attal M, Lauwers-Cances V, Marit G, Caillot D, Facon T, Hulin C, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma: follow-up analysis of the IFM 2005-02 trial. Blood. 2013;122:406.

    Google Scholar 

  46. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905. https://doi.org/10.1056/NEJMoa1402888

    Article  CAS  PubMed  Google Scholar 

  47. Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the phase III Myeloma XI study. Blood. 2016;128:1143.

    Google Scholar 

  48. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16:1617–29. https://doi.org/10.1016/S1470-2045(15)00389-7

    Article  CAS  PubMed  Google Scholar 

  49. McCarthy PL, Holstein SA, Petrucci MT, et a. Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol. 2017 Oct 10;35(29):3279–3289

    Article  CAS  Google Scholar 

  50. Laubach JP, Paba Prada CE, Richardson PG, Longo DL. Daratumumab, elotuzumab, and the development of therapeutic monoclonal antibodies in multiple myeloma. Clin Pharmacol Ther. 2017;101:81–8. https://doi.org/10.1002/cpt.550. e-pub ahead of print 2016/11/03

    Article  CAS  PubMed  Google Scholar 

  51. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005;11:5984–92. https://doi.org/10.1158/1078-0432.CCR-05-0577

    Article  CAS  PubMed  Google Scholar 

  52. Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest. 2008;118:2427–37. https://doi.org/10.1172/JCI35017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. 2015;126:779–89. https://doi.org/10.1182/blood-2015-02-628669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bjorklund CC,Kang J,Lu L,Amatangelo M,Chiu H,Gandhi AK, et al. CC-220 is a potent cereblon modulating agent that displays anti-proliferative, pro-apoptotic and immunomodulatory activity on sensitive and resistant multiple myeloma cell lines. Blood. 2016;128:1591.

    Google Scholar 

  55. Bjorklund CC, Kang J, Lu L, Amatangelo M, Chiu H, Hagner P, et al. CC-122 is a cereblon modulating agent that is active in lenalidomide-resistant and lenalidomide/dexamethasone-double-resistant multiple myeloma pre-clinical models. Blood. 2016;128:1592–1592.

    Google Scholar 

  56. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature. 2016;535:252–7. https://doi.org/10.1038/nature18611

    Article  CAS  PubMed  Google Scholar 

  57. Kneppers E, van der Holt B, Kersten MJ, Zweegman S, Meijer E, Huls G, et al. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. Blood. 2011;118:2413–9. https://doi.org/10.1182/blood-2011-04-348292

    Article  CAS  PubMed  Google Scholar 

  58. Alsina M, Becker PS, Zhong X, Adams A, Hari P, Rowley S, et al. Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20:1183–9. https://doi.org/10.1016/j.bbmt.2014.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wapenaar H, Dekker FJ. Histone acetyltransferases: challenges in targeting bi-substrate enzymes. Clin Epigenetics. 2016;8:59 https://doi.org/10.1186/s13148-016-0225-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Reddy P, Maeda Y, Hotary K, Liu C, Reznikov LL, Dinarello CA, et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl Acad Sci USA. 2004;101:3921–6. https://doi.org/10.1073/pnas.0400380101

    Article  CAS  PubMed  Google Scholar 

  61. Choi SW, Braun T, Chang L, Ferrara JL, Pawarode A, Magenau JM, et al. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014;15:87–95. https://doi.org/10.1016/S1470-2045(13)70512-6

    Article  CAS  PubMed  Google Scholar 

  62. Choi SW, Gatza E, Hou G, Sun Y, Whitfield J, Song Y, et al. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans. Blood. 2015;125:815–9. https://doi.org/10.1182/blood-2014-10-605238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bug G,Burchert A,Wagner EM,Kroger N,Berg T,Guller S, et al. Phase I/II study of the deacetylase inhibitor panobinostat after allogeneic stem cell transplantation in patients with high-risk MDS or AML (PANOBEST trial). Leukemia. 2017;31:2523–5.https://doi.org/10.1038/leu.2017.242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cornelissen JvNY, van Gelder M, Breems D, Maertens J, Jongen-Lavrencic M, Broers A, Zeerleder S, Noens L, Ossenkoppele G, Meijer E. Early post-transplant epigenetic therapy by panobinostat and decitabine followed by donor lymphocyte infusion (DLI): interim results of the HOVON-116 phase I/II feasibility study in poor-risk aml recipients of allogeneic stem cell transplantation (alloHSCT). Blood. 2016;128:832.

    Google Scholar 

  65. Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jager E, et al. The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res. 2010;34:899–905. https://doi.org/10.1016/j.leukres.2010.02.004

    Article  CAS  PubMed  Google Scholar 

  66. Pinto A, Attadia V, Fusco A, Ferrara F, Spada OA, Di Fiore PP. 5-Aza-2′-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood. 1984;64:922–9.

    CAS  PubMed  Google Scholar 

  67. Pinto A, Maio M, Attadia V, Zappacosta S, Cimino R. Modulation of HLA-DR antigens expression in human myeloid leukaemia cells by cytarabine and 5-aza-2’-deoxycytidine. Lancet. 1984;2:867–8.

    Article  CAS  Google Scholar 

  68. Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G, et al. Induction of a CD8 + T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116:1908–18. https://doi.org/10.1182/blood-2009-11-249474

    Article  CAS  PubMed  Google Scholar 

  69. Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, Caballero-Velazquez T, Blanco B, Herrero-Sanchez C, et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood. 2010;115:107–21. https://doi.org/10.1182/blood-2009-03-210393

    Article  CAS  PubMed  Google Scholar 

  70. Schroeder T, Frobel J, Cadeddu RP, Czibere A, Dienst A, Platzbecker U, et al. Salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse after allogeneic blood stem cell transplantation. Leukemia. 2013;27:1910–3. https://doi.org/10.1038/leu.2013.64

    Article  CAS  PubMed  Google Scholar 

  71. 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

    Article  CAS  PubMed  Google Scholar 

  72. Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015;21:653–60. https://doi.org/10.1016/j.bbmt.2014.12.016

    Article  CAS  PubMed  Google Scholar 

  73. Tessoulin B, Delaunay J, Chevallier P, Loirat M, Ayari S, Peterlin P, et al. Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49:567–71. https://doi.org/10.1038/bmt.2013.233

    Article  CAS  PubMed  Google Scholar 

  74. Steinmann J, Bertz H, Wasch R, Marks R, Zeiser R, Bogatyreva L, et al. 5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft. Bone Marrow Transplant. 2015;50:690–5. https://doi.org/10.1038/bmt.2015.10

    Article  CAS  PubMed  Google Scholar 

  75. Woo J,Deeg HJ,Storer B,Yeung C,Fang M,Mielcarek M, et al. Factors determining responses to azacitidine in patients with myelodysplastic syndromes and acute myeloid leukemia with early post-transplantation relapse: a prospective trial. Biol Blood Marrow Transplant. 2017;23:176–9.https://doi.org/10.1016/j.bbmt.2016.10.016.

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. de Lima M,Giralt S,Thall PF,de Padua Silva L,Jones RB,Komanduri K, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010;116:5420–31.https://doi.org/10.1002/cncr.25500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ueda M, Lazarus HM, Cooper B, Caimi PF, Creger R, Little A, et al. Low-dose azacitidine (AZA) for treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) relapse after allogeneic hematopoietic cell transplant (HCT). Biol Blood Marrow Transplant. 2016;22:S212–3.

    Article  Google Scholar 

  80. Jabbour E,Giralt S,Kantarjian H,Garcia-Manero G,Jagasia M,Kebriaei P, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115:1899–905.https://doi.org/10.1002/cncr.24198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Platzbecker U,Wermke M,Radke J,Oelschlaegel U,Seltmann F,Kiani A, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012;26:381–9.https://doi.org/10.1038/leu.2011.234.

    Article  CAS  PubMed  Google Scholar 

  82. Saunthararajah Y, Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes. Hematol Am Soc Hematol Educ Program. 2013;2013:511–21.https://doi.org/10.1182/asheducation-2013.1.511.

    Article  Google Scholar 

  83. de Lima M, Oran B, Papadopoulos EB, Scott BL, William BM, Giralt S, et al. CC-486 (Oral Azacitidine) maintenance therapy is well tolerated after allogeneic hematopoietic stem cell transplantation (AlloHSCT) in patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Biol Blood Marrow Transplant. 2016;22:S312–3.

    Article  Google Scholar 

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Author notes

  1. These authors contributed equally: Yi-Bin Chen, Philip L. McCarthy, Theresa Hahn, Sarah A. Holstein, Masumi Ueda, Nicolaus Kröger, Michael Bishop, Marcos de Lima

Authors and Affiliations

  1. Blood and Marrow Transplant Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Yi-Bin Chen

  2. Blood and Marrow Transplant Program, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    Philip L. McCarthy & Theresa Hahn

  3. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Sarah A. Holstein

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA

    Masumi Ueda

  5. Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Nicolaus Kröger

  6. Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    Michael Bishop

  7. Stem Cell Transplant Program, University Hospital Cleveland Medical Center, Case Western Reserve University, Cleveland, USA

    Marcos de Lima

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  1. Yi-Bin Chen
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Correspondence to Nicolaus Kröger.

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Y-BC has received consulting fees from Takeda, Incyte, Jazz, and Magenta. The other authors declare that they have no conflict of interest.

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Chen, YB., McCarthy, P.L., Hahn, T. et al. Methods to prevent and treat relapse after hematopoietic stem cell transplantation with tyrosine kinase inhibitors, immunomodulating drugs, deacetylase inhibitors, and hypomethylating agents. Bone Marrow Transplant 54, 497–507 (2019). https://doi.org/10.1038/s41409-018-0269-3

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