Chronic ocular graft-versus-host disease after allogeneic haematopoietic stem cell transplantation in Denmark – factors associated with risks and rates in adults according to conditioning regimen

Abstract

We investigated risks and hazard rates of developing chronic ocular graft-versus-host disease (oGVHD) in a large nationwide, single centre study by using the criteria proposed by “The International Chronic oGVHD Consensus Group”. This retrospective study included 1407 consecutive adults who underwent allogeneic haematopoietic stem cell transplantation (HSCT). Patients were examined by an ophthalmologist according to the hospital’s guidelines: baseline examination before HSCT, annually up to 5 years after HSCT. The 186 (13%) had dry eye disease before HSCT. The 5-year cumulative incidence of oGVHD was 18% (95% CI: 15–21) after myeloablative (MA) and 35% (95% CI: 30–39) after non-myeloablative conditioning (NMA). Factors associated with the rate of oGVHD were assessed separately according to conditioning regimen by using multiple Cox regression analyses. Factors that increased the rate in the MA group: Malignant disease, Schirmer’s test≤10 mm/5 min before transplantation, use of female donor, matched unrelated donor, peripheral blood as stem cell source, and grade III-IV acute GVHD. Factors that increased the rate in the NMA group: Schirmer’s test≤10 mm/5 min before transplantation and higher recipient age. We recommend a baseline ophthalmological examination before HSCT since many of the patients have signs of dry eyes before transplantation which increased the risk and rate of developing oGVHD.

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Fig. 1: The cumulative incidence curves of ocular cGVHD after HSCT according to conditioning.
Fig. 2: Myeloablative conditioning: cumulative incidence curves of ocular cGVHD according to the five risk factors.
Fig. 3: Non-myeloablative conditioning: cumulative incidence curves of ocular cGVHD according to “Family relation” and “Schirmer’s test before HSCT”.
Fig. 4: Non-myeloablative conditioning: the 5-year cumulative incidence of assumed oGVHD is higher in the group with “DEWS score 1” before transplantation (43%) than the 5-year cumulative incidence of oGVHD in the group with no DED before transplantation (35%) (p = 0.0428).

References

  1. 1.

    Anderson NG, Regillo C. Ocular manifestations of graft versus host disease. Curr Opin Ophthalmol. 2004;15:503–7.

    Article  Google Scholar 

  2. 2.

    Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15:1628–33.

    Article  Google Scholar 

  3. 3.

    Kim SK. Update on ocular graft versus host disease. Curr Opin Ophthalmol. 2006;17:344–8.

    Article  Google Scholar 

  4. 4.

    Dietrich-Ntoukas T, Cursiefen C, Westekemper H, Eberwein P, Reinhard T, Bertz H, et al. Diagnosis and treatment of ocular chronic graft-versus-host disease: report from the German-Austrian-Swiss Consensus Conference on Clinical Practice in chronic GVHD. Cornea. 2012;31:299–310.

    Article  Google Scholar 

  5. 5.

    Riemens A, te Boome L, Imhof S, Kuball J, Rothova A. Current insights into ocular graft-versus-host disease. Curr Opin Ophthalmol. 2010;21:485–94.

    Article  Google Scholar 

  6. 6.

    Ogawa Y, Kim SK, Dana R, Clayton J, Jain S, Rosenblatt MI, et al. International chronic ocular graft-vs-host-disease (GVHD) Consensus Group: proposed diagnostic criteria for chronic GVHD (Part I). Sci Rep. 2013;3:3419.

    Article  Google Scholar 

  7. 7.

    Rapoport Y, Freeman T, Koyama T, Engelhardt BG, Jagasia M, Savani BN, et al. Validation of international chronic ocular graft-versus-host disease (GVHD) group diagnostic criteria as a chronic ocular GVHD-specific metric. Cornea. 2017;36:258–63.

    Article  Google Scholar 

  8. 8.

    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 Transpl. 2015;21:389–401. e1.

    Article  Google Scholar 

  9. 9.

    Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf. 2017;15:539–74.

    Article  Google Scholar 

  10. 10.

    DEWS. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye workshop (2007). Ocul Surf. 2007;5:75–92.

    Article  Google Scholar 

  11. 11.

    Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Arch Ophthalmol. 2000;118:615–21.

    CAS  Article  Google Scholar 

  12. 12.

    Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, et al. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975;292:895–902.

    CAS  Article  Google Scholar 

  13. 13.

    Aalen OO, Johansen S. An empirical transition matrix for non-homogeneous markov chains based on censored observations. Scand J Stat. 1978;5:141–50.

    Google Scholar 

  14. 14.

    Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  15. 15.

    Bartlett JW, Seaman SR, White IR, Carpenter JR. Multiple imputation of covariates by fully conditional specification: Accommodating the substantive model. Stat Methods Med Res. 2015;24:462–87.

    Article  Google Scholar 

  16. 16.

    Shikari H, Antin JH, Dana R. Ocular graft-versus-host disease: a review. Surv Ophthalmol 2013;58:233–51.

    Article  Google Scholar 

  17. 17.

    Na KS, Yoo YS, Mok JW, Lee JW, Joo CK. Incidence and risk factors for ocular GVHD after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transpl. 2015;50:1459–64.

    CAS  Article  Google Scholar 

  18. 18.

    Jacobs R, Tran U, Chen H, Kassim A, Engelhardt BG, Greer JP, et al. Prevalence and risk factors associated with development of ocular GVHD defined by NIH consensus criteria. Bone Marrow Transpl. 2012;47:1470–3.

    CAS  Article  Google Scholar 

  19. 19.

    Westeneng AC, Hettinga Y, Lokhorst H, Verdonck L, van Dorp S, Rothova A. Ocular graft-versus-host disease after allogeneic stem cell transplantation. Cornea. 2010;29:758–63.

    Article  Google Scholar 

  20. 20.

    Tabbara KF, Al-Ghamdi A, Al-Mohareb F, Ayas M, Chaudhri N, Al-Sharif F, et al. Ocular findings after allogeneic hematopoietic stem cell transplantation. Ophthalmology. 2009;116:1624–9.

    Article  Google Scholar 

  21. 21.

    Wang JC, Teichman JC, Mustafa M, OʼDonnell H, Broady R, Yeung SN. Risk factors for the development of ocular graft-versus-host disease (GVHD) dry eye syndrome in patients with chronic GVHD. Br J Ophthalmol. 2015;99:1514–8.

  22. 22.

    Schmid KE, Kornek GV, Scheithauer W, Binder S. Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol. 2006;51:19–40.

    Article  Google Scholar 

  23. 23.

    Mohty M, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood. 2002;100:3128–34.

    CAS  Article  Google Scholar 

  24. 24.

    Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol. 2001;19:3685–91.

    CAS  Article  Google Scholar 

  25. 25.

    Uchino M, Ogawa Y, Uchino Y, Mori T, Okamoto S, Tsubota K. Comparison of stem cell sources in the severity of dry eye after allogeneic haematopoietic stem cell transplantation. Br J Ophthalmol. 2012;96:34–7.

    Article  Google Scholar 

  26. 26.

    Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487–96.

    CAS  Article  Google Scholar 

  27. 27.

    Lee SJ, Logan B, Westervelt P, Cutler C, Woolfrey A, Khan SP, et al. Comparison of patient-reported outcomes in 5-year survivors who received bone marrow vs peripheral blood unrelated donor transplantation: long-term follow-up of a randomized clinical trial. JAMA Oncol. 2016;2:1583–9.

    Article  Google Scholar 

  28. 28.

    Linhares YP, Pavletic S, Gale RP. Chronic GVHD: where are we? Where do we want to be? Will immunomodulatory drugs help? Bone Marrow Transpl. 2013;48:203–9.

    CAS  Article  Google Scholar 

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Acknowledgements

We would like to thank the following foundation for financial support to this study: The Danish Cancer Society (grant R108-A7021-14-S31), Fight for Sight Denmark, Synoptik-Fonden, Novo Nordic Foundation (grant NNF15OC0014158) and Dansk Kræftforskningsfond.

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Correspondence to Helene Jeppesen.

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Jeppesen, H., Sengeløv, H., Eriksson, F. et al. Chronic ocular graft-versus-host disease after allogeneic haematopoietic stem cell transplantation in Denmark – factors associated with risks and rates in adults according to conditioning regimen. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-0993-3

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