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Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib

Bone Marrow Transplantation volume 53, pages 1255–1262 (2018)Cite this article

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Abstract

Sclerotic chronic graft vs. host disease (cGVHD) still has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed the first prospective study to test whether sequential therapy of the anti-CD20 antibody rituximab followed by 6 months treatment with tyrosine kinase inhibitor nilotinib is a favorable treatment strategy for patients with sclerotic cGVHD. Twenty-nine patients were included, 24 were available for analysis. We observed objective responses in 71% of patients (two patients CR, 15 patients PR). Moreover, two out of five patients suffering from severe ulcerations showed complete resolution of ulcers. Observed responses lasted until the end of study follow-up. The majority of responding patients could reduce daily corticosteroid dose with more than 50%. Furthermore, CD5+ B-cells are significantly lower (p = 0.007) in responding patients at baseline, proposing a new biomarker predictive for response. In conclusion, sequential treatment of rituximab followed by nilotinib associates with a very high response rate in this difficult to treat patient population. CD5+ B-cells could assist in guiding treatment choices and might be a first step toward more personalized cGVHD treatment. This trial was registered at the Dutch clinical trial registry as NTR1222.

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References

  1. Mielcarek M, Furlong T, O’Donnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502–8.

    Article  CAS  Google Scholar 

  2. Pasquini MC, Devine S, Mendizabal A, Baden LR, Wingard JR, Lazarus HM, et al. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. J Clin Oncol. 2012;30:3194–201.

    Article  CAS  Google Scholar 

  3. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17:164–73.

    Article  CAS  Google Scholar 

  4. Kroger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374:43–53.

    Article  Google Scholar 

  5. Finke J, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, et al. Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial. Biol Blood Marrow Transplant. 2012;18:1716–26.

    Article  Google Scholar 

  6. Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke GJ, Verrest L, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4:e183–e91.

    Article  Google Scholar 

  7. Tsirigotis P, Byrne M, Schmid C, Baron F, Ciceri F, Esteve J, et al. Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant. 2016;51:1431–8.

    Article  CAS  Google Scholar 

  8. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–62.

    Article  CAS  Google Scholar 

  9. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009;15:1005–13.

    Article  CAS  Google Scholar 

  10. van Dorp S, Resemann H, te Boome L, Pietersma F, van Baarle D, Gmelig-Meyling F, et al. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study. Haematologica. 2011;96:1380–4.

    Article  Google Scholar 

  11. Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, Sanders CJ, van den Tweel JG, Verdonck LF. Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood. 2004;104:2603–6.

    Article  CAS  Google Scholar 

  12. Mohty M, Marchetti N, El-Cheikh J, Faucher C, Furst S, Blaise D. Rituximab as salvage therapy for refractory chronic GVHD. Bone Marrow Transplant. 2008;41:909–11.

    Article  CAS  Google Scholar 

  13. Magro L, Mohty M, Catteau B, Coiteux V, Chevallier P, Terriou L, et al. Imatinib mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease. Blood. 2009;114:719–22.

    Article  CAS  Google Scholar 

  14. Magro L, Catteau B, Coiteux V, Bruno B, Jouet JP, Yakoub-Agha I. Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD. Bone Marrow Transplant. 2008;42:757–60.

    Article  CAS  Google Scholar 

  15. Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood. 2009;114:709–18.

    Article  CAS  Google Scholar 

  16. de Masson A, Bouaziz JD, Peffault de Latour R, Wittnebel S, Ribaud P, Rubio MT, et al. Limited efficacy and tolerance of imatinib mesylate in steroid-refractory sclerodermatous chronic GVHD. Blood. 2012;120:5089–90.

    Article  Google Scholar 

  17. 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. 2015;22:319–27.

    Article  Google Scholar 

  18. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–41.

    Article  CAS  Google Scholar 

  19. Blay JY, von Mehren M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin Oncol. 2011;38(Suppl 1):S3–9.

    Article  CAS  Google Scholar 

  20. Beyer C, Distler JH, Distler O. Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases? Swiss Med Wkly. 2010;140:w13050.

    PubMed  Google Scholar 

  21. Kariminia A, Holtan SG, Ivison S, Rozmus J, Hebert MJ, Martin PJ, et al. Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells. Blood. 2016;127:3082–91.

    Article  CAS  Google Scholar 

  22. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56.

    Article  Google Scholar 

  23. 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;21:389–401e1.

    Article  Google Scholar 

  24. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, 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. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12:252–66.

    Article  Google Scholar 

  25. Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, et al. Rituximab-based first line treatment for chronic GVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017;130:2186–95.

    Article  CAS  Google Scholar 

  26. Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243–50.

    Article  CAS  Google Scholar 

  27. Lydyard PM, Lamour A, MacKenzie LE, Jamin C, Mageed RA, Youinou P. CD5+ B cells and the immune system. Immunol Lett. 1993;38:159–66.

    Article  CAS  Google Scholar 

  28. Bunch DO, McGregor JG, Khandoobhai NB, Aybar LT, Burkart ME, Hu Y, et al. Decreased CD5(+) B cells in active ANCA vasculitis and relapse after rituximab. Clin J Am Soc Nephrol. 2013;8:382–91.

    Article  Google Scholar 

  29. 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;29:2062–8.

    Article  CAS  Google Scholar 

  30. 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;123:3832–42.

    Article  CAS  Google Scholar 

  31. 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;124:4867–76.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Multiplex Core Facility UMC, Utrecht, for performing multiplex immunoassays; the Flow Cytometry Core Facility UMC, Utrecht, for support in performing FACS assays; Novartis and Roche for kindly providing study medication. This work was further supported in part by grants from the Dutch Cancer Society to LvdW: KWF-UU 2011-5250 and to JK KWF-UU 2010-4669, 2013-6426, 2014-6790, and 2015-7601.

Author contributions

LtB, EM, SvD, and JK designed the study. LvdW and MS performed the experiments. LvdW analyzed and interpreted the data. LvdW and JK wrote the manuscript. LtB, IN, SvD, MvD, and EM interpreted the data. LtB, IN, MS, RR, EP, MdW, NdJ, MB, BB, and EM provided the clinical data and commented on the manuscript. JK supervised the study.

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Author notes

  1. Liane te Boome

    Present address: Internal Medicine Department, MC Haaglanden Hospital, The Hague, The Netherlands

Authors and Affiliations

  1. Hematology Department, University Medical Center Utrecht, Utrecht, The Netherlands

    Lotte van der Wagen, Liane te Boome, Inger Nijhof, Reinier Raymakers, Eefke Petersen, Moniek de Witte & Jürgen Kuball

  2. Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    Lotte van der Wagen, Marleen Schiffler & Jürgen Kuball

  3. Hematology Department, VU Medical Center, Amsterdam, The Netherlands

    Marieke Schoordijk & Ellen Meijer

  4. Hematology Department, University Medical Center Radboud, Nijmegen, The Netherlands

    Suzanne van Dorp & Brigitte Bär

  5. Pathology Department, University Medical Center Utrecht, Utrecht, The Netherlands

    Marijke van Dijk

  6. Hematology Department, Erasmus Medical Center, Rotterdam, The Netherlands

    Niels de Jong

  7. Hematology Department, University Medical Center Groningen, Groningen, The Netherlands

    Mar Bellido

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  1. Lotte van der Wagen
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Correspondence to Jürgen Kuball.

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Conflict of interest

JK is cofounder and chief scientific officer of GADETA. His work is partly supported by a grant from Novartis; however, Novartis had no part in the design, analysis, or interpretation of the data or the writing of the manuscript.

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van der Wagen, L., te Boome, L., Schiffler, M. et al. Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib. Bone Marrow Transplant 53, 1255–1262 (2018). https://doi.org/10.1038/s41409-018-0158-9

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