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Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults

Bone Marrow Transplantation volume 55, pages 1379–1387 (2020)Cite this article

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Abstract

Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III–IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57–89%) in acute GVHD and 81% (95% CI 67–92%) in chronic. Overall survival was 59% (95% CI 49–74%) in acute group and 85% (95% CI 70–93%). The major risk factors for lower survival were grade III–IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III–IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.

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References

  1. Greinix HT, Eikema DJ, Koster L, Penack O, Yakoub-Agha I, Montoto S, et al. Incidence of acute graft-versus-host disease and survival after allogeneic hematopoietic cell transplantation over time: a study from the Transplant Complications and Chronic Malignancies Working Party of the EBMT. Blood. 2018;132(Suppl 1):2120. https://doi.org/10.1182/blood-2018-99-111764.

    Article  Google Scholar 

  2. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18:1150–63.

    Article  Google Scholar 

  3. Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133:1191–1200.

    Article  CAS  Google Scholar 

  4. 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 

  5. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10:391–402.

    Article  CAS  Google Scholar 

  6. Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, et al. COMFORT-I investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10:55.

    Article  Google Scholar 

  7. 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;122:1192–202.

    Article  CAS  Google Scholar 

  8. 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 

  9. Zeiser R, Burchert A, Lengerke C, 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 

  10. Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168–73.

    Article  CAS  Google Scholar 

  11. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  12. 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 

  13. Martin PJ, Bachier CR, Klingemann HG, McCarthy PL, Szabolcs P, Uberti JP, et al. Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant. 2009;15:777–84.

    Article  CAS  Google Scholar 

  14. 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;21:984–99.

    Article  Google Scholar 

  15. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.

    Article  CAS  Google Scholar 

  16. Veeraraghavan S, Thappali S, Viswanadha S, Chennupati S, Nalla S, Golla M, et al. Simultaneous quantification of ruxolitinib and nilotinib in rat plasma by LC-MS/MS: application to a pharmacokinetic study. J Pharm Biomed Anal. 2014;94:125–31.

    Article  CAS  Google Scholar 

  17. Escamilla Gómez V, García-Gutiérrez V, López Corral L, García Cadenas I, Pérez Martínez A, Márquez Malaver FJ, et al. Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study. Bone Marrow Transplant. 2019. https://doi.org/10.1038/s41409-019-0731-x.

  18. Steinbach G, Hockenbery DM, Huls G, Furlong T, Myerson D, Loeb KR, et al. Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. PLoS ONE. 2017;12:e0183284.

    Article  Google Scholar 

  19. Sadowska-Klasa A, Piekarska A, Prejzner W, Sadowska-Klasa A, Piekarska A, Prejzner W, et al. Colonization with multidrug-resistant bacteria increases the risk of complications and a fatal outcome after allogeneic hematopoietic cell transplantation. Ann Hematol. 2018;97:509–17.

    Article  CAS  Google Scholar 

  20. Goloshchapov OV, Kucher MA, Moiseev IS, Afanasyev BV. Fecal microbiota transplantation in patients after allogeneichematopoietic stem cell transplantation. Cell Ther Transplant. 2017;6:20–29.

    Article  Google Scholar 

  21. Ferrara JLM, Chaudhry MS. GVHD: biology matters. Blood Adv. 2018;2:3411–7.

    Article  CAS  Google Scholar 

  22. Markey KA, MacDonald KP, Hill GR. The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood. 2014;124:354–62.

    Article  CAS  Google Scholar 

  23. Leveque-El Mouttie L, Koyama M, Le Texier L, Markey KA, Cheong M, Kuns RD, et al. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD. Blood. 2016;128:794–804.

    Article  CAS  Google Scholar 

  24. Dertschnig S, Hauri-Hohl MM, Vollmer M, Holländer GA, Krenger W. Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD. Blood. 2015;125:2720–3.

    Article  CAS  Google Scholar 

  25. Allen JL, Fore MS, Wooten J, Roehrs PA, Bhuiya NS, Hoffert T, et al. B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. Blood. 2012;120:2529–36.

    Article  CAS  Google Scholar 

  26. MacMillan ML, Robin M, Harris AC, DeFor TE, Martin PJ, Alousi A, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21:761–7.

    Article  Google Scholar 

  27. Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest. 2013;143:1478–9.

    Article  Google Scholar 

  28. Afram G, Watz E, Remberger M, Nygell UA, Sundin M, Hägglund H, et al. Higher response rates in patients with severe chronic skin graft-versus-host disease treated with extracorporeal photopheresis. Cent Eur J Immunol. 2019;44:84–91.

    Article  CAS  Google Scholar 

  29. Greinix HT, van Besien K, Elmaagacli AH, Hillen U, Grigg A, Knobler R, et al. UVADEX Chronic GVHD Study Group. Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week course of extracorporeal photopheresis-results of a crossover randomized study. Biol Blood Marrow Transplant. 2011;17:1775–82.

    Article  Google Scholar 

  30. Hamilton BK, Storer BE, Wood WA, Pidala JA, Cutler CS, Martin PJ, et al. Disability related to chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2019. pii: S1083-8791(19)30676-7. https://doi.org/10.1016/j.bbmt.2019.10.019.

  31. Khoury HJ, Langston AA, Kota VK, Wilkinson JA, Pusic I, Jillella A, et al. Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant. 2018;53:826–31.

    Article  CAS  Google Scholar 

  32. Holland HK, Wingard JR, Beschorner WE, Saral R, Santos GW. Bronchiolitis obliterans in bone marrow transplantation and its relationship to chronic graft-v-host disease and low serum IgG. Blood. 1988;72:621–7.

    Article  CAS  Google Scholar 

  33. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood. 2002;100:48–51.

    Article  CAS  Google Scholar 

  34. Ayuk F, Veit R, Zabelina T, Bussmann L, Christopeit M, Alchalby H. Prognostic factors for survival of patients with newly diagnosed chronic GVHD according to NIH criteria. Ann Hematol. 2015;94:1727–32.

    Article  Google Scholar 

  35. González Vicent M, Molina B, González de Pablo J, González de Pablo J, Castillo A, Díaz MÁ. Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease in children: Clinical and immunological results. Am J Hematol. 2019;94:319–26.

    PubMed  Google Scholar 

  36. Khandelwal P, Teusink-Cross A, Davies SM, Nelson AS, Dandoy CE, El-Bietar J, et al. Ruxolitinib as salvage therapy in steroid-refractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients. Biol Blood Marrow Transplant. 2017;23:1122–7.

    Article  CAS  Google Scholar 

  37. Dominietto A, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, Berisso G, et al. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol. 2001;112:219–27.

    Article  CAS  Google Scholar 

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Acknowledgements

The study was supported clinical approbation program No.2016–29–1 by the Ministry of Health of Russian Federation. The laboratory assays were performed with the support of Russian Science Fund, grant No 17–75–20145. We thank Valerii Beklenischev for managing the frozen samples.

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Authors and Affiliations

  1. R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov University, Saint-Petersburg, Russian Federation

    I. S. Moiseev, E. V. Morozova, T. A. Bykova, O. V. Paina, A. G. Smirnova, A. A. Dotsenko, E. S. Borzenkova, A. N. Galimov, Ya. V. Gudognikova, K. A. Ekushov, P. V. Kozhokar, A. A. Osipova, O. V. Pirogova, T. A. Rudakova, O. U. Klimova, N. Yu Tcvetkov, E. A. Kulagin, Yu. A. Serov, L. S. Zubarovskaya & B. V. Afanasyev

  2. Laboratory of Autoimmune Diagnostics, Pavlov University, Saint-Petersburg, Russian Federation

    E. A. Surkova & S. V. Lapin

  3. Nikiforov’s All-Russian Center for Emergency and Radiation Medicine, Saint-Petersburg, Russian Federation

    G. G. Rodionov & S. I. Moiseev

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Correspondence to I. S. Moiseev.

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ISM received consultancy and lecturer honoraria from Novartis. EVM received lecturer honoraria from Novartis. The other authors have no conflicts of interest.

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Moiseev, I.S., Morozova, E.V., Bykova, T.A. et al. Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults. Bone Marrow Transplant 55, 1379–1387 (2020). https://doi.org/10.1038/s41409-020-0834-4

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