Skip to main content
SpringerLink
Log in

Effect of Rituximab on Pulmonary Function in Bronchiolitis Obliterans Syndrome due to Graft-Versus-Host-Disease

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Purpose

Rituximab is an anti-CD20 monoclonal antibody that is used to suppress B-cell function in graft-versus-host-disease (GVHD). We sought to determine the effects of rituximab treatment on lung function in those patients with bronchiolitis obliterans syndrome (BOS) as a manifestation of GVHD.

Methods

Thirteen patients were treated with rituximab with a diagnosis of BOS and a significant reduction in the forced expiratory volume in 1 s (FEV1) after hematopoietic stem cell transplantation (HSCT). The changes in their pulmonary function for 12 months following treatment with rituximab were followed, along with other intervention performed and daily average dosing of prednisone.

Results

Following rituximab administration, there was an improvement in the slope of decline in lung function from −5.12 ml/month prior to rituximab infusion to −0.31 ml/month after 3 months and to +2.27 ml/month 12 months later. Seven of the 13 patients had an increase in their FEV1 after treatment with rituximab. Additionally, the mean daily dose of prednisone decreased from 27 mg prior to rituximab treatment to 11 mg 12 months after treatment. Nine out of 13 patients survived 12 months after rituximab treatment. All of the patients with improvement in FEV1 following rituximab treatment were receiving concomitant extracorporeal photopheresis.

Conclusion

Rituximab is safe with the potential to stabilize or improve lung function in patients with BOS after HSCT and should be considered as a treatment option in those patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME (2015) 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 Transpl 21(3):389–401. doi:10.1016/j.bbmt.2014.12.001

    Article  Google Scholar 

  2. Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR, Urbano-Ispizua A, Cutler CS, Bacigalupo AA, Battiwalla M, Flowers ME, Juckett MB, Lee SJ, Loren AW, Klumpp TR, Prockup SE, Ringden OT, Savani BN, Socie G, Schultz KR, Spitzer T, Teshima T, Bredeson CN, Jacobsohn DA, Hayashi RJ, Drobyski WR, Frangoul HA, Akpek G, Ho VT, Lewis VA, Gale RP, Koreth J, Chao NJ, Aljurf MD, Cooper BW, Laughlin MJ, Hsu JW, Hematti P, Verdonck LF, Solh MM, Norkin M, Reddy V, Martino R, Gadalla S, Goldberg JD, McCarthy PL, Perez-Simon JA, Khera N, Lewis ID, Atsuta Y, Olsson RF, Saber W, Waller EK, Blaise D, Pidala JA, Martin PJ, Satwani P, Bornhauser M, Inamoto Y, Weisdorf DJ, Horowitz MM, Pavletic SZ, Graft-vs-Host Disease Working Committee of the C (2015) 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 Transpl 21(2):266–274. doi:10.1016/j.bbmt.2014.10.021

    Article  Google Scholar 

  3. Carlens S, Ringden O, Remberger M, Lonnqvist B, Hagglund H, Klaesson S, Mattsson J, Svahn BM, Winiarski J, Ljungman P, Aschan J (1998) Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis. Bone Marrow Transpl 22(8):755–761. doi:10.1038/sj.bmt.1701423

    Article  CAS  Google Scholar 

  4. Ochs LA, Miller WJ, Filipovich AH, Haake RJ, McGlave PB, Blazar BR, Ramsay NK, Kersey JH, Weisdorf DJ (1994) Predictive factors for chronic graft-versus-host disease after histocompatible sibling donor bone marrow transplantation. Bone Marrow Transpl 13(4):455–460

    CAS  Google Scholar 

  5. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME (2005) 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 Transpl 11(12):945–956. doi:10.1016/j.bbmt.2005.09.004

    Article  Google Scholar 

  6. Jacobsohn DA, Kurland BF, Pidala J, Inamoto Y, Chai X, Palmer JM, Arai S, Arora M, Jagasia M, Cutler C, Weisdorf D, Martin PJ, Pavletic SZ, Vogelsang G, Lee SJ, Flowers ME (2012) Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood 120(13):2545–2552. doi:10.1182/blood-2012-04-424135 quiz 2774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yanik G, Kitko C (2013) Management of noninfectious lung injury following hematopoietic cell transplantation. Curr Opin Oncol 25(2):187–194. doi:10.1097/CCO.0b013e32835dc8a5

    Article  CAS  PubMed  Google Scholar 

  8. Williams KM, Chien JW, Gladwin MT, Pavletic SZ (2009) Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA 302(3):306–314. doi:10.1001/jama.2009.1018

    Article  CAS  PubMed  Google Scholar 

  9. Chi AK, Soubani AO, White AC, Miller KB (2013) An update on pulmonary complications of hematopoietic stem cell transplantation. Chest 144(6):1913–1922. doi:10.1378/chest.12-1708

    Article  PubMed  Google Scholar 

  10. Bergeron A, Chevret S, Chagnon K, Godet C, Bergot E, Peffault de Latour R, Dominique S, de Revel T, Juvin K, Maillard N, Reman O, Contentin N, Robin M, Buzyn A, Socie G, Tazi A (2015) Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 191(11):1242–1249. doi:10.1164/rccm.201410-1818OC

    Article  CAS  PubMed  Google Scholar 

  11. Hildebrandt GC, Fazekas T, Lawitschka A, Bertz H, Greinix H, Halter J, Pavletic SZ, Holler E, Wolff D (2011) Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transpl 46(10):1283–1295. doi:10.1038/bmt.2011.35

    Article  CAS  Google Scholar 

  12. Norman BC, Jacobsohn DA, Williams KM, Au BK, Au MA, Lee SJ, Moravec CK, Chien JW (2011) Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transpl 46(10):1369–1373. doi:10.1038/bmt.2010.311

    Article  CAS  Google Scholar 

  13. Brownback KR, Simpson SQ, Pitts LR, Polineni D, McGuirk JP, Ganguly S, Aljitawi OS, Lin TL, Singh A, Abhyankar S (2015) Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation. J Clin Apheresis. doi:10.1002/jca.21404

    PubMed  Google Scholar 

  14. Del Fante C, Galasso T, Bernasconi P, Scudeller L, Ripamonti F, Perotti C, Meloni F (2016) Extracorporeal photopheresis as a new supportive therapy for bronchiolitis obliterans syndrome after allogeneic stem cell transplantation. Bone Marrow Transpl 51(5):728–731. doi:10.1038/bmt.2015.324

    Article  Google Scholar 

  15. Lucid CE, Savani BN, Engelhardt BG, Shah P, Clifton C, Greenhut SL, Vaughan LA, Kassim A, Schuening F, Jagasia M (2011) Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT. Bone Marrow Transpl 46(3):426–429. doi:10.1038/bmt.2010.152

    Article  CAS  Google Scholar 

  16. Alousi AM, Uberti J, Ratanatharathorn V (2010) The role of B cell depleting therapy in graft versus host disease after allogeneic hematopoietic cell transplant. Leuk Lymphoma 51(3):376–389. doi:10.3109/10428190903586318

    Article  PubMed  Google Scholar 

  17. Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, Hochberg EP, Wu CJ, Alyea EP, Cutler C, Ho V, Soiffer RJ, Antin JH, Ritz J (2005) Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 105(7):2973–2978. doi:10.1182/blood-2004-09-3660

    Article  CAS  PubMed  Google Scholar 

  18. Miklos DB, Kim HT, Zorn E, Hochberg EP, Guo L, Mattes-Ritz A, Viatte S, Soiffer RJ, Antin JH, Ritz J (2004) Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors. Blood 103(1):353–359. doi:10.1182/blood-2003-03-0984

    Article  CAS  PubMed  Google Scholar 

  19. Clavert A, Chevallier P, Guillaume T, Delaunay J, Le Gouill S, Mahe B, Dubruille V, Gastinne T, Blin N, Moreau P, Mohty M (2013) Safety and efficacy of rituximab in steroid-refractory chronic GVHD. Bone Marrow Transpl 48(5):734–736. doi:10.1038/bmt.2012.203

    Article  CAS  Google Scholar 

  20. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, Klickstein LB, Levin J, Miller K, Reynolds C, Macdonell R, Pasek M, Lee SJ, Ho V, Soiffer R, Antin JH, Ritz J, Alyea E (2006) Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108(2):756–762. doi:10.1182/blood-2006-01-0233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim SJ, Lee JW, Jung CW, Min CK, Cho B, Shin HJ, Chung JS, Kim H, Lee WS, Joo YD, Yang DH, Kook H, Kang HJ, Ahn HS, Yoon SS, Sohn SK, Min YH, Min WS, Park HS, Won JH (2010) Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica 95(11):1935–1942. doi:10.3324/haematol.2010.026104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Solomon SR, Sizemore CA, Ridgeway M, Zhang X, Smith J, Brown S, Holland HK, Morris LE, Bashey A (2015) Corticosteroid-free primary treatment of chronic extensive graft-versus-host disease incorporating rituximab. Biol Blood Marrow Transpl. doi:10.1016/j.bbmt.2015.04.023

    Google Scholar 

  23. Lorillon G, Robin M, Meignin V, Ribaud P, Lescoeur B, Gossot D, Socie G, Tazi A, Bergeron A (2011) Rituximab in bronchiolitis obliterans after haematopoietic stem cell transplantation. Eur Respir J 38(2):470–472. doi:10.1183/09031936.00003711

    Article  CAS  PubMed  Google Scholar 

  24. Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA, Ritz J, Antin JH, Murphy WJ, Luznik L, Shlomchik MJ, Panoskaltsis-Mortari A, Blazar BR (2012) Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood 119(6):1570–1580. doi:10.1182/blood-2011-07-364414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Allen JL, Fore MS, Wooten J, Roehrs PA, Bhuiya NS, Hoffert T, Sharf A, Deal AM, Armistead P, Coghill J, Gabriel DA, Irons R, Essenmacher A, Shea TC, Richards K, Cutler C, Ritz J, Serody J, Baldwin AS, Sarantopoulos S (2012) B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. Blood 120(12):2529–2536. doi:10.1182/blood-2012-06-438911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rafiq K, Bergtold A, Clynes R (2002) Immune complex-mediated antigen presentation induces tumor immunity. J Clin Investig 110(1):71–79. doi:10.1172/JCI15640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A (2009) Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transpl 15(9):1005–1013. doi:10.1016/j.bbmt.2009.04.003

    Article  CAS  Google Scholar 

  28. Arai S, Sahaf B, Narasimhan B, Chen GL, Jones CD, Lowsky R, Shizuru JA, Johnston LJ, Laport GG, Weng WK, Benjamin JE, Schaenman J, Brown J, Ramirez J, Zehnder JL, Negrin RS, Miklos DB (2012) Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 119(25):6145–6154. doi:10.1182/blood-2011-12-395970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cutler C, Kim HT, Bindra B, Sarantopoulos S, Ho VT, Chen YB, Rosenblatt J, McDonough S, Watanaboonyongcharoen P, Armand P, Koreth J, Glotzbecker B, Alyea E, Blazar BR, Soiffer RJ, Ritz J, Antin JH (2013) Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood 122(8):1510–1517. doi:10.1182/blood-2013-04-495895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Benden C, Speich R, Hofbauer GF, Irani S, Eich-Wanger C, Russi EW, Weder W, Boehler A (2008) Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation 86(11):1625–1627. doi:10.1097/TP.0b013e31818bc024

    Article  PubMed  Google Scholar 

  31. Biagi E, Di Biaso I, Leoni V, Gaipa G, Rossi V, Bugarin C, Renoldi G, Parma M, Balduzzi A, Perseghin P, Biondi A (2007) Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4 + CD25 + GITR + Foxp3 + CD62L + functional regulatory T-cells in patients with graft-versus-host disease. Transplantation 84(1):31–39. doi:10.1097/01.tp.0000267785.52567.9c

    Article  CAS  PubMed  Google Scholar 

  32. Axelrod L (1976) Glucocorticoid therapy. Medicine 55(1):39–65

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the physicians involved with the bone marrow transplant team at the University of Kansas Medical Center, including Dr. Anurag Singh, Dr. Tara Lin, Dr. Leyla Shune and Dr. Omar Aljitawi.

Funding

No funding was received in the production of this manuscript.

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, 3901 Rainbow BLVD, Mail Stop 3007, Kansas City, KS, USA

    Kyle R. Brownback & Laura A. Thomas

  2. Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, KS, USA

    Joseph P. McGuirk, Siddhartha Ganguly & Sunil Abhyankar

  3. Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    Christopher Streiler

Authors
  1. Kyle R. Brownback
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura A. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph P. McGuirk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siddhartha Ganguly
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher Streiler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sunil Abhyankar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyle R. Brownback.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to disclose.

Ethical Approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional review board of the University of Kansas Medical Center and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brownback, K.R., Thomas, L.A., McGuirk, J.P. et al. Effect of Rituximab on Pulmonary Function in Bronchiolitis Obliterans Syndrome due to Graft-Versus-Host-Disease. Lung 195, 781–788 (2017). https://doi.org/10.1007/s00408-017-0051-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-017-0051-0

Keywords

Search

Navigation