Top

Published in:

Open Access 01-12-2016 | Case report

Ruxolitinib in steroid refractory graft-vs.-host disease: a case report

Authors: Enrico Maffini, Luisa Giaccone, Moreno Festuccia, Lucia Brunello, Ilaria Buondonno, Dario Ferrero, Mario Boccadoro, Chiara Dellacasa, Alessandro Busca, Domenico Novero, Benedetto Bruno

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

Background

Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited.

Case presentation

A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34⁺ cells/kg infused were 8.69 × 10⁶ kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54.

Conclusions

At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.

Deeg J. How I, treat refractory acute GVHD. Blood. 2007;109(10):4119–26.CrossRefPubMedPubMedCentral

Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, Litzow MR, Nieto Y, Savani BN, Schriber JR, Shaughnessy PJ, Wall DA, Carpenter PA. 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(8):1150–63.CrossRefPubMedPubMedCentral

Xhaard A, Rocha V, Bueno B, et al. Steroid refractory acute GVHD: lack of long-term improved survival using new generation anti cytokine treatment. Biol Blood Marrow Transplant. 2012;18(3):406–13.CrossRefPubMed

Robin M, Porcher R, de Castro R, et al. Initial liver involvement in acute GVHD is predictive for non relapse mortality. Transplantation. 2009;88:1131–6.CrossRefPubMed

Inagaki J, Kodama Y, Fukano R, Noguchi M, Okamura J. Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2015;19(6):652–8.CrossRefPubMed

Nadeau M, Perreault S, Seropian S, Foss F, Isufi I, Cooper DL. The use of basiliximab-infliximab combination for the treatment of severe gastrointestinal acute GvHD. Bone Marrow Transplant. 2016;51(2):273–6.CrossRefPubMed

Van Groningen LF, Liefferink AM, de Haan AF, Schaap NP, Donnelly JP, Blijlevens NM, van der Velden WJ. Combination therapy with inolimomab and etanercept for severe steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22(1):179–82.CrossRefPubMed

Park JH, Lee HJ, Kim SR, Song GW, Lee SK, Park SY, Kim KC, Hwang SH, Park JS. Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation. Korean J Intern Med. 2014;29(5):630–6.CrossRefPubMedPubMedCentral

Meunier M, Bulabois CE, Thiebaut-Bertrand A, Itzykson R, Carre M, Carras S, Garban F, Cahn JY. Alemtuzumab for severe steroid-refractory gastrointestinal acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(9):1451–4.CrossRefPubMed

10.

Abu-Dalle I, Reljic T, Nishihori T, Antar A, Bazarbachi A, Djulbegovic B, Kumar A, Kharfan-Dabaja MA. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies. Biol Blood Marrow Transplant. 2014;20(11):1677–86.CrossRefPubMed

11.

Alam N, Atenafu EG, Tse G, Viswabandya A, Gupta V, Kim D, Lipton JH, Messner HA, Kuruvilla J. Limited benefit of pentostatin salvage therapy for steroid-refractory grade III-IV acute graft-versus host disease. Clin Transplant. 2013;27(6):930–7.CrossRefPubMed

12.

Hoda D, Pidala J, Salgado-Vila N, Kim J, Perkins J, Bookout R, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2010;45:1347–51.CrossRefPubMed

13.

Ghez D, Rubio MT, Maillard N, Suarez F, Chandesris MO, Delarue R, et al. Rapamycin for refractory acute graft-versus-host disease. Transplantation. 2009;88:1081–7.CrossRefPubMed

14.

Brattsand R, Linden M. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther. 1996;10(2):81–90.PubMed

15.

Baer PC, Wegner B, Geiger H. Effects of mycophenolic acid on IL-6 expression of human renal proximal and distal tubular cells in vitro. Nephro Dyal Transpl. 2004;19:47–52.CrossRef

16.

Teshima T, Reddy P, Zeiser R. Acute graft-versus-host disease. Biol Blood Marrow Transpl. 2016;22:11–6.CrossRef

17.

Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:779–87.CrossRef

18.

Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, Di Persio JF, Catalano J, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey Jr JH, Arasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Vitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.CrossRefPubMedPubMedCentral

19.

Hasselbach C. Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res. 2013;2:214–20.CrossRef

20.

Teshima T. JAK inhibitors: a home run for GVHD patients? Blood. 2014;123(24):3691–3.CrossRefPubMed

21.

Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle. 2008;7(4):458–62.CrossRefPubMed

22.

Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea 3rd EP, Armand P, Cutler C, Ho VT, Treister NS, Bienfang DC, Prasad S, Tzachanis D, Joyce RM, Avigan DE, Antin JH, Ritz J, Soiffer RJ. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–66.CrossRefPubMedPubMedCentral

23.

Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J, Hou JZ, Negrin RS. Differential impact of mammalian target of rapamycin inhibition on CD4 + CD25 + FoxP3+ regulatory T cells compared with conventional CD4+ T cells. Blood. 2008;111(1):453–62.CrossRefPubMedPubMedCentral

24.

Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, Verbeek M, Fischer J, Otten V, Schmickl M, Maas-Bauer K, Finke J, Peschel C, Duyster J, Poeck H, Zeiser R, von Bubnoff N. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123(24):3832–42.CrossRefPubMed

25.

Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, Ajib S, de Fontbrune FS, Na IK, Penter L, Holtick U, Wolf D, Schuler E, Meyer E, Apostolova P, Bertz H, Marks R, Lübbert M, Wäsch R, Scheid C, Stölzel F, Ordemann R, Bug G, Kobbe G, Negrin R, Brune M, Spyridonidis A, Schmitt-Gräff A, van der Velden W, Huls G, Mielke S, Grigoleit GU, Kuball J, Flynn R, Ihorst G, Du J, Blazar BR, Arnold R, Kröger N, Passweg J, Halter J, Socié G, Beelen D, Peschel C, Neubauer A, Finke J, Duyster J, von Bubnoff N. Ruxolitinib in corticosteroidrefractory graft-versus-host disease after allogeneic stem cell transplantation: a multi-center survey. Leukemia. 2015;29(10):2062–8.PubMed

26.

Khoury HJ, Kota V, Arellano M et al. Ruxolitinib as sparing agent for steroid-dependent chronic graft-versus-host disease (cGVHD). Presented at: 2016 ASH Annual Meeting; December 5–8, 2015. Orlando, Florida; Abstract 1938.

27.

Vertovsek S, Gotlib J, Gupta V, Atallah E, Mascarehas J, Quintas-Cardama A, Sun W, Sarlis NJ, Sandor V, Levy RS, Kantarjian HM, Mesa RA. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13–21.CrossRef

28.

Bruno B, Gooley T, Sullivan KM, Davis C, Bensinger WI, Storb R, Nash RA. Secondary failure of platelet recovery after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001;7(3):154–62.CrossRefPubMed

Title: Ruxolitinib in steroid refractory graft-vs.-host disease: a case report
Authors: Enrico Maffini
Luisa Giaccone
Moreno Festuccia
Lucia Brunello
Ilaria Buondonno
Dario Ferrero
Mario Boccadoro
Chiara Dellacasa
Alessandro Busca
Domenico Novero
Benedetto Bruno
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0298-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma

Aberrant splicing and drug resistance in AML

Short telomere length and its correlation with gene mutations in myelodysplastic syndrome

Synergistic effect of oridonin and a PI3K/mTOR inhibitor on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma

Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy

Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms

Keynote webinar | Spotlight on antibody–drug conjugates in cancer