Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Novel targets in the treatment of chronic graft-versus-host disease

Leukemia volume 31, pages 543–554 (2017)Cite this article

Subjects

Abstract

Despite advances that have improved survival after allogeneic hematopoietic stem cell transplantation (HCT), chronic graft-versus-host disease (GVHD) remains a leading cause of late morbidity and mortality after transplant. Current treatment options show limited efficacy in steroid-refractory disease, and there exists a paucity of robust data to guide management decisions. Lack of United States Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved agents in GVHD underscore the importance of developing novel therapies. Better understanding of the biology of chronic GVHD has provided novel targets for treatment, and structured guidelines in diagnosis and in clinical trial design have provided a common language and pathways for research in this area. These, combined with the surge of drug development in Oncology and Immunology, are factors that have contributed to the accelerating field of drug development and clinical research in chronic GVHD. In these exciting times, it is possible to foresee long awaited advances in the treatment of this devastating complication of HCT. This review will summarize the ongoing clinical development for novel therapies in chronic GVHD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Baird K, Pavletic SZ . Chronic graft versus host disease. Curr Opin Hematol 2006; 13: 426–435.

    PubMed  Google Scholar 

  2. Lee SJ, Vogelsang G, Flowers ME . Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003; 9: 215–233.

    CAS  PubMed  Google Scholar 

  3. Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2015; 21: 266–274.

    PubMed  Google Scholar 

  4. Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 2011; 29: 2230–2239.

    PubMed  PubMed Central  Google Scholar 

  5. Martin PJ, Counts GW Jr., Appelbaum FR, Lee SJ, Sanders JE, Deeg HJ et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol 2010; 28: 1011–1016.

    PubMed  PubMed Central  Google Scholar 

  6. Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood 2011; 117: 4651–4657.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Socie G, Ritz J . Current issues in chronic graft-versus-host disease. Blood 2014; 124: 374–384.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Blazar BR, Murphy WJ, Abedi M . Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 2012; 12: 443–458.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sarantopoulos S, Blazar BR, Cutler C, Ritz J . B cells in chronic graft-versus-host disease. Biol Blood Marrow Transplant 2015; 21: 16–23.

    CAS  PubMed  Google Scholar 

  10. Jin H, Ni X, Deng R, Song Q, Young J, Cassady K et al. Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice. Blood 2016; 127: 2249–2260.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood 2016; 128: 130–137.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365: 2055–2066.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Martin PJ, Inamoto Y, Carpenter PA, Lee SJ, Flowers ME . Treatment of chronic graft-versus-host disease: Past, present and future. Korean J Hematol 2011; 46: 153–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M et al. Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2011; 17: 1–17.

    PubMed  Google Scholar 

  15. Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 2004; 104: 3501–3506.

    CAS  PubMed  Google Scholar 

  16. Chu YW, Gress RE . Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant 2008; 14: 365–378.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Zeiser R, Blazar BR . Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 2016; 127: 3117–3126.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood 2011; 118: 4242–4249.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Baird K, Steinberg SM, Grkovic L, Pulanic D, Cowen EW, Mitchell SA et al. National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis. Biol Blood Marrow Transplant 2013; 19: 632–639.

    PubMed  PubMed Central  Google Scholar 

  20. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. the 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant 2015; 21: 389–401, e1.

    PubMed  Google Scholar 

  21. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. the 2014 response criteria working group report. Biol Blood Marrow Transplant 2015; 21: 984–999.

    PubMed  PubMed Central  Google Scholar 

  22. Martin PJ, Lee SJ, Przepiorka D, Horowitz MM, Koreth J, Vogelsang GB et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. the 2014 clinical trial design working group report. Biol Blood Marrow Transplant 2015; 21: 1343–1359.

    PubMed  PubMed Central  Google Scholar 

  23. Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 2016; 127: 2144–2154.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tawara I, Koyama M, Liu C, Toubai T, Thomas D, Evers R et al. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res 2011; 17: 77–88.

    CAS  PubMed  Google Scholar 

  25. Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont MC, Ranchin B et al. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol 2009; 10: 778–785.

    CAS  PubMed  Google Scholar 

  26. Zerr P, Distler A, Palumbo-Zerr K, Tomcik M, Vollath S, Dees C et al. Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease. Am J Pathol 2012; 181: 1672–1680.

    CAS  PubMed  Google Scholar 

  27. Sanchez-Ortega I, Parody R, Servitje O, Muniesa C, Arnan M, Patino B et al. Imatinib and dasatinib as salvage therapy for sclerotic chronic graft-vs-host disease. Croatian Med J 2016; 57: 247–254.

    Google Scholar 

  28. Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 2010; 45: 1732–1740.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gao L, Zhang Y, Hu B, Liu J, Kong P, Lou S et al. Phase II multicenter, randomized, double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation. J Clin Oncol 2016; 34: 2843–2850.

    CAS  PubMed  Google Scholar 

  30. Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood 2016; 127: 1044–1051.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest 2015; 125: 2677–2689.

    PubMed  PubMed Central  Google Scholar 

  32. Kanakry CG, Fuchs EJ, Luznik L . Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol 2016; 13: 10–24.

    CAS  PubMed  Google Scholar 

  33. Chaudhry MS, Velardi E, Dudakov JA, van den Brink MR . Thymus: the next (re)generation. Immunol Rev 2016; 271: 56–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ghoreschi K, Laurence A, O'Shea JJ . Janus kinases in immune cell signaling. Immunol Rev 2009; 228: 273–287.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. O'Shea JJ, Holland SM, Staudt LM . JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013; 368: 161–170.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Choi J, Ziga ED, Ritchey J, Collins L, Prior JL, Cooper ML et al. IFNgammaR signaling mediates alloreactive T-cell trafficking and GVHD. Blood 2012; 120: 4093–4103.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hakim FT, Memon S, Jin P, Imanguli MM, Wang H, Rehman N et al. Upregulation of IFN-inducible and damage-response pathways in chronic graft-versus-host disease. J Immunol 2016; 197: 3490–3503.

    CAS  PubMed  Google Scholar 

  39. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013; 122: 1192–1202.

    CAS  PubMed  Google Scholar 

  40. Choi J, Cooper ML, Alahmari B, Ritchey J, Collins L, Holt M et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PloS One 2014; 9: e109799.

    PubMed  PubMed Central  Google Scholar 

  41. Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123: 3832–3842.

    CAS  PubMed  Google Scholar 

  42. Carniti C, Gimondi S, Vendramin A, Recordati C, Confalonieri D, Bermema A et al. Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects. Clin Cancer Res 2015; 21: 3740–3749.

    CAS  PubMed  Google Scholar 

  43. Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015; 29: 2062–2068.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Khoury HJ, Kota V, Arellano M, Bauer SL, Jillela AP, Langston A et al. Ruxolitinib as sparing agent for steroid-dependent chronic graft-versus-host disease. Blood 2015; 126: abstract 1938.

  45. Sun K, Welniak LA, Panoskaltsis-Mortari A, O'Shaughnessy MJ, Liu H, Barao I et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA 2004; 101: 8120–8125.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Blanco B, Perez-Simon JA, Sanchez-Abarca LI, Carvajal-Vergara X, Mateos J, Vidriales B et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood 2006; 107: 3575–3583.

    CAS  PubMed  Google Scholar 

  47. Kim JS, Lee JI, Shin JY, Kim SY, Shin JS, Lim JH et al. Bortezomib can suppress activation of rapamycin-resistant memory T cells without affecting regulatory T-cell viability in non-human primates. Transplantation 2009; 88: 1349–1359.

    CAS  PubMed  Google Scholar 

  48. Pai CC, Chen M, Mirsoian A, Grossenbacher SK, Tellez J, Ames E et al. Treatment of chronic graft-versus-host disease with bortezomib. Blood 2014; 124: 1677–1688.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Herrera AF, Kim HT, Bindra B, Jones KT, Alyea EP 3rd, Armand P et al. A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20: 1737–1743.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Koreth J, Kim HT, Lange PB, Bindra B, Reynolds CG, Chammas MJ et al. A bortezomib-based regimen offers promising survival and graft-versus-host disease prophylaxis in myeloablative HLA-mismatched and unrelated donor transplantation: a phase II trial. Biol Blood Marrow Transplant 2015; 21: 1907–1913.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Koreth J, Stevenson KE, Kim HT, McDonough SM, Bindra B, Armand P et al. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol 2012; 30: 3202–3208.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015; 372: 142–152.

    PubMed  Google Scholar 

  53. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016; 374: 1621–1634.

    CAS  PubMed  Google Scholar 

  54. Chi H . Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol Sci 2011; 32: 16–24.

    CAS  PubMed  Google Scholar 

  55. Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM . FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 2000; 164: 5761–5770.

    CAS  PubMed  Google Scholar 

  56. Kim YM, Sachs T, Asavaroengchai W, Bronson R, Sykes M . Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. The J Clin Invest 2003; 111: 659–669.

    CAS  PubMed  Google Scholar 

  57. Huu DL, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, Takehara K et al. FTY720 ameliorates murine sclerodermatous chronic graft-versus-host disease by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into skin. Arthritis Rheum 2013; 65: 1624–1635.

    CAS  PubMed  Google Scholar 

  58. Taylor PA, Ehrhardt MJ, Lees CJ, Tolar J, Weigel BJ, Panoskaltsis-Mortari A et al. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD). Blood 2007; 110: 3480–3488.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. D'Ambrosio D, Freedman MS, Prinz J . Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis 2016; 7: 18–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu G, Yang K, Burns S, Shrestha S, Chi H . The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol 2010; 11: 1047–1056.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Olsson T, Boster A, Fernandez O, Freedman MS, Pozzilli C, Bach D et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry 2014; 85: 1198–1208.

    PubMed  Google Scholar 

  62. Blazar BR, Taylor PA, Linsley PS, Vallera DA . In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood 1994; 83: 3815–3825.

    CAS  PubMed  Google Scholar 

  63. Via CS, Rus V, Nguyen P, Linsley P, Gause WC . Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD. J Immunol 1996; 157: 4258–4267.

    CAS  PubMed  Google Scholar 

  64. Guinan EC, Boussiotis VA, Neuberg D, Brennan LL, Hirano N, Nadler LM et al. Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med 1999; 340: 1704–1714.

    CAS  PubMed  Google Scholar 

  65. Koura DT, Horan JT, Langston AA, Qayed M, Mehta A, Khoury HJ et al. In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant 2013; 19: 1638–1649.

    CAS  PubMed  Google Scholar 

  66. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS . The role of B cells in the pathogenesis of graft-versus-host disease. Blood 2009; 114: 4919–4927.

    PubMed  Google Scholar 

  67. Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA et al. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood 2012; 119: 1570–1580.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 2005; 105: 2973–2978.

    CAS  PubMed  Google Scholar 

  69. Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res 2007; 13: 6107–6114.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 2009; 113: 3865–3874.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Allen JL, Tata PV, Fore MS, Wooten J, Rudra S, Deal AM et al. Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood 2014; 123: 2108–2115.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Flynn R, Allen JL, Luznik L, MacDonald KP, Paz K, Alexander KA et al. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease. Blood 2015; 125: 4085–4094.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sarantopoulos S, Ritz J . Aberrant B-cell homeostasis in chronic GVHD. Blood 2015; 125: 1703–1707.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kharfan-Dabaja MA, Cutler CS . Rituximab for prevention and treatment of graft-versus-host disease. Int J Hematol 2011; 93: 578–585.

    CAS  PubMed  Google Scholar 

  75. Arai S, Pidala J, Pusic I, Chai X, Jaglowski S, Khera N et al. A randomized phase II crossover study of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell transplantation. Clin Cancer Res 2016; 22: 319–327.

    CAS  PubMed  Google Scholar 

  76. Sahaf B, Yang Y, Arai S, Herzenberg LA, Herzenberg LA, Miklos DB . H-Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease. Proc Natl Acad Sci USA 2013; 110: 3005–3010.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Cutler C, Kim HT, Bindra B, Sarantopoulos S, Ho VT, Chen YB et al. Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood 2013; 122: 1510–1517.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Arai S, Sahaf B, Narasimhan B, Chen GL, Jones CD, Lowsky R et al. Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 2012; 119: 6145–6154.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Pidala J, Kim J, Betts BC, Alsina M, Ayala E, Fernandez HF et al. Ofatumumab in combination with glucocorticoids for primary therapy of chronic graft-versus-host disease: phase I trial results. Biol Blood Marrow Transplant 2015; 21: 1074–1082.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 2014; 124: 4867–4876.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Schutt SD, Fu J, Nguyen H, Bastian D, Heinrichs J, Wu Y et al. Inhibition of BTK and ITK with ibrutinib is effective in the prevention of chronic graft-versus-host disease in mice. PloS One 2015; 10: e0137641.

    PubMed  PubMed Central  Google Scholar 

  82. Miklos DB, Arora M, Cutler CS, Nakamura R, Juretic M, Li Y et al. A multicenter open-label phase 1b/2 study of ibrutinib in steroid dependent or refractory chronic graft versus host disease. J Clin Oncol 2015; 33 (suppl): 7024 (abstract 7024).

    Google Scholar 

  83. Miklos D, Cutler C, Arora M, Walker E, Jagasia M, Nakamura R et al. Multicenter open-label phase 1b/2 study of ibrutinib in steroid-depenedent/refractory chronic graft versus host disease. Bone Marrow Transplant 2016; 51: S176 (abstract P124).

    Google Scholar 

  84. Le Huu D, Kimura H, Date M, Hamaguchi Y, Hasegawa M, Hau KT et al. Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease. J Dermatol Sci 2014; 74: 214–221.

    CAS  PubMed  Google Scholar 

  85. Chien JW, Duncan S, Williams KM, Pavletic SZ . Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16 (1 Suppl): S106–S114.

    PubMed  Google Scholar 

  86. DiGiovine B, Lynch JP 3rd, Martinez FJ, Flint A, Whyte RI, Iannettoni MD et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol 1996; 157: 4194–4202.

    CAS  PubMed  Google Scholar 

  87. Henke JA, Golden JA, Yelin EH, Keith FA, Blanc PD . Persistent increases of BAL neutrophils as a predictor of mortality following lung transplant. Chest 1999; 115: 403–409.

    CAS  PubMed  Google Scholar 

  88. Hirsch J, Elssner A, Mazur G, Maier KL, Bittmann I, Behr J et al. Bronchiolitis obliterans syndrome after (heart-)lung transplantation. impaired antiprotease defense and increased oxidant activity. Am J Respiratory Crit Care Med 1999; 160 (5 Pt 1): 1640–1646.

    CAS  Google Scholar 

  89. Kennedy VE, Todd JL, Palmer SM . Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome. Am J Transplant 2013; 13: 552–561.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Stevens T, Ekholm K, Granse M, Lindahl M, Kozma V, Jungar C et al. AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase. J Pharmacol Exp Ther 2011; 339: 313–320.

    CAS  PubMed  Google Scholar 

  91. Elborn JS, Perrett J, Forsman-Semb K, Marks-Konczalik J, Gunawardena K, Entwistle N . Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis. Eur Respir J 2012; 40: 969–976.

    CAS  PubMed  Google Scholar 

  92. Kuna P, Jenkins M, O'Brien CD, Fahy WA . AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD. Respir Med 2012; 106: 531–539.

    PubMed  Google Scholar 

  93. Stockley R, De Soyza A, Gunawardena K, Perrett J, Forsman-Semb K, Entwistle N et al. Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis. Respir Med 2013; 107: 524–533.

    PubMed  Google Scholar 

  94. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH Jr, Scott MP . Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 1997; 276: 817–821.

    CAS  PubMed  Google Scholar 

  95. Horn A, Kireva T, Palumbo-Zerr K, Dees C, Tomcik M, Cordazzo C et al. Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann Rheum Dis 2012; 71: 785–789.

    CAS  PubMed  Google Scholar 

  96. Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE et al. Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood 2012; 120: 2909–2917.

    CAS  PubMed  Google Scholar 

  97. Chao NJ, Parker PM, Niland JC, Wong RM, Dagis A, Long GD et al. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease. Biol Blood Marrow Transplant 1996; 2: 86–92.

    CAS  PubMed  Google Scholar 

  98. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood 2000; 96: 3995–3996.

    CAS  PubMed  Google Scholar 

  99. Fink EC, Ebert BL . The novel mechanism of lenalidomide activity. Blood 2015; 126: 2366–2369.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 2007; 8: 958–966.

    PubMed  Google Scholar 

  101. Paczesny S, Hakim FT, Pidala J, Cooke KR, Lathrop J, Griffith LM et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. the 2014 biomarker working group report. Biol Blood Marrow Transplant 2015; 21: 780–792.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health’s (NIH) National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program. The opinions expressed here are those of the authors and do not represent the official position of the NIH, NCI or the United States Government.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute and UPMC Cancer Centers, Pittsburgh, PA, USA

    A Im

  2. Experimental Transplantation and Immunology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA

    A Im, F T Hakim & S Z Pavletic

Authors
  1. A Im
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F T Hakim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Z Pavletic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Z Pavletic.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Im, A., Hakim, F. & Pavletic, S. Novel targets in the treatment of chronic graft-versus-host disease. Leukemia 31, 543–554 (2017). https://doi.org/10.1038/leu.2016.367

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.367

This article is cited by

Search

Advanced search

Quick links