Leflunomide to Prevent Cytomegalovirus Reactivation in Stem Cell Transplant Patients

Summary

Patients undergoing half-matched hematopoietic stem cell transplantation (HSCT) are at high risk of viral reactivation after bone marrow transplantation (BMT). The purpose of this study is to evaluate whether leflunomide can prevent cytomegalovirus (CMV) reactivation in these patients and to assess its safety. The main questions it aims to answer are - 1. Does leflunomide prevent cytomegalovirus (CMV) related organ damage? 2. Does leflunomide prevent a rise in cytomegalovirus (CMV) copy number to more than 2000 copies/ml? 3. Does leflunomide prevent the need to start pre-emptive therapy for cytomegalovirus (CMV)? 4. Is it safe to use in bone marrow transplant ( BMT) patients? 5. Does leflunomide prevent other viral reactivations - like Adeno virus and BK virus? 6. Does leflunomide affect the risk of acute graft-versus-host disease ( acute GVHD) after bone marrow transplant (BMT)? What medicine will the patients receive? Patients in study shall receive loading dose of Tab. Leflunomide 100 mg daily for 3 days followed by 20 mg daily orally. Leflunomide will be given till day +180 post transplant or till patient is on immunosuppressant medicines.

Timeline

Start

2024-10-18

Primary completion

2029-04

Completion

2029-04

Publications

• Results PREVYMIS™ (letermovir) Whitehouse Station, NJ: Merck & Co., Inc.; 2017
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• Results Fox R, Helfgott S (2021). Leflunomide. In St Clair EW (Ed.), UpToDate. https://www.uptodate.com/drug-interactions. Accessed June 01, 2023
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• Results US Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2017) Common Terminology Criteria for Adverse Events (CTCAE) Version Study protocol Version -1.1 dated 22/02/2024 17 of 16 5.0 2017. https://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 01 May 2020
• Results Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch HH, Cordonnier C, Ljungman P; Fourth European Conference on Infections in Leukemia. European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 (2011). Transpl Infect Dis. 2012 Dec;14(6):555-63. doi: 10.1111/tid.12022. Epub 2012 Nov 12.
• Results Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. 2010 Dec 16;116(25):5476-85. doi: 10.1182/blood-2010-04-259291. Epub 2010 Sep 13.
• Results Anderson EJ, Guzman-Cottrill JA, Kletzel M, Thormann K, Sullivan C, Zheng X, Katz BZ. High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy. Pediatr Transplant. 2008 Mar;12(2):219-27. doi: 10.1111/j.1399-3046.2007.00851.x.
• Results Jeffers-Francis LK, Burger-Calderon R, Webster-Cyriaque J. Effect of Leflunomide, Cidofovir and Ciprofloxacin on replication of BKPyV in a salivary gland in vitro culture system. Antiviral Res. 2015 Jun;118:46-55. doi: 10.1016/j.antiviral.2015.02.002. Epub 2015 Mar 16.
• Results Cesaro S, Dalianis T, Hanssen Rinaldo C, Koskenvuo M, Pegoraro A, Einsele H, Cordonnier C, Hirsch HH; ECIL-6 Group. ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother. 2018 Jan 1;73(1):12-21. doi: 10.1093/jac/dkx324.
• Results Bogdanovic G, Priftakis P, Giraud G, Kuzniar M, Ferraldeschi R, Kokhaei P, Mellstedt H, Remberger M, Ljungman P, Winiarski J, Dalianis T. Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation. J Clin Microbiol. 2004 Nov;42(11):5394-6. doi: 10.1128/JCM.42.11.5394-5396.2004.
• Results Erard V, Kim HW, Corey L, Limaye A, Huang ML, Myerson D, Davis C, Boeckh M. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood. 2005 Aug 1;106(3):1130-2. doi: 10.1182/blood-2004-12-4988. Epub 2005 Apr 21.
• Results Bernhoff E, Tylden GD, Kjerpeseth LJ, Gutteberg TJ, Hirsch HH, Rinaldo CH. Leflunomide inhibition of BK virus replication in renal tubular epithelial cells. J Virol. 2010 Feb;84(4):2150-6. doi: 10.1128/JVI.01737-09. Epub 2009 Dec 2.
• Results Nesselhauf N, Strutt J, Bastani B. Evaluation of leflunomide for the treatment of BK viremia and biopsy proven BK nephropathy; a single center experience. J Nephropathol. 2016 Jan;5(1):34-7. doi: 10.15171/jnp.2016.06. Epub 2015 Dec 23.
• Results Chacko B, John GT. Leflunomide for cytomegalovirus: bench to bedside. Transpl Infect Dis. 2012 Apr;14(2):111-20. doi: 10.1111/j.1399-3062.2011.00682.x. Epub 2011 Oct 9.
• Results Andrassy J, Illner WD, Rentsch M, Jaeger G, Jauch KW, Fischereder M. Leflunomide: a treatment option for ganciclovir-resistant cytomegalovirus infection after renal transplantation. NDT Plus. 2009 Apr;2(2):149-51. doi: 10.1093/ndtplus/sfp004.
• Results Waldman WJ, Knight DA, Lurain NS, Miller DM, Sedmak DD, Williams JW, Chong AS. Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation. 1999 Sep 27;68(6):814-25. doi: 10.1097/00007890-199909270-00014.
• Results Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.
• Results Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, Hubacek P, Navarro D, Cordonnier C, Ward KN; 2017 European Conference on Infections in Leukaemia group. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019 Aug;19(8):e260-e272. doi: 10.1016/S1473-3099(19)30107-0. Epub 2019 May 29.
• Results Einsele H, Ljungman P, Boeckh M. How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation. Blood. 2020 May 7;135(19):1619-1629. doi: 10.1182/blood.2019000956.
• Results Uppuluri R, Subburaj D, Jayaraman D, Swaminathan VV, Mullanfiroze K, Vaidhyanathan L, Raj R. Cytomegalovirus reactivation posthematopoietic stem cell transplantation (HSCT) and type of graft: A step toward rationalizing CMV testing and positively impacting the economics of HSCT in developing countries. Pediatr Blood Cancer. 2017 Nov;64(11). doi: 10.1002/pbc.26639. Epub 2017 May 22.
• Results Kothari A, Ramachandran VG, Gupta P, Singh B, Talwar V. Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India. J Health Popul Nutr. 2002 Dec;20(4):348-51.
• Results Gokarn A, Toshniwal A, Pathak A, Arora S, Bonda A, Punatar S, Nayak L, Dwivedi P, Bhat V, Biswas S, Kelkar R, Kannan S, Khattry N. Use of Leflunomide for Treatment of Cytomegalovirus Infection in Recipients of Allogeneic Stem Cell Transplant. Biol Blood Marrow Transplant. 2019 Sep;25(9):1832-1836. doi: 10.1016/j.bbmt.2019.04.028. Epub 2019 May 2.
• Results Zaia JA. Cytomegalovirus infection. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR, eds. Thomas' Hematopoietic Cell Transplantation. West Sussex, UK: Wiley-Blackwell; 2016:1069-1079.
• Results Hammerstrom AE, Lombardi LR, Pingali SR, Rondon G, Chen J, Milton DR, Chemaly RF, Champlin RE, Gulbis A, Ciurea SO. Prevention of Cytomegalovirus Reactivation in Haploidentical Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018 Feb;24(2):353-358. doi: 10.1016/j.bbmt.2017.09.018. Epub 2017 Oct 3.
• Results Steering Committee Of The Blood And Marrow Transplant Clinical Trials Network. The Blood and Marrow Transplant Clinical Trials Network: An Effective Infrastructure for Addressing Important Issues in Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016 Oct;22(10):1747-1757. doi: 10.1016/j.bbmt.2016.07.003. Epub 2016 Jul 11.
• Results Jakharia N, Howard D, Riedel DJ. CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies. Curr Treat Options Infect Dis. 2021;13(3):123-140. doi: 10.1007/s40506-021-00253-w. Epub 2021 Jul 21.
• Results Ljungman P. Viral Infections in Hematopoietic Stem Cell Transplant Recipients. Allogeneic Stem Cell Transplantation. 2009;505-532. Published 2009 Nov 27. doi:10.1007/978-1-59745- 478-0_29
• Results Duver F, Weissbrich B, Eyrich M, Wolfl M, Schlegel PG, Wiegering V. Viral reactivations following hematopoietic stem cell transplantation in pediatric patients - A single center 11-year analysis. PLoS One. 2020 Feb 4;15(2):e0228451. doi: 10.1371/journal.pone.0228451. eCollection 2020.

Drugs

Indications