For prevention of GVHD, 12 mg of sirolimus is typically given at day -3 followed by 4 mg daily with a target trough level of 3 to 12 ng/mL. The patient continues to take sirolimus for approximately 6 to 9 months and then is slowly tapered off.5,6
Some clinical studies have used sirolimus at doses of 4 mg/m2 to 5 mg/m2 for 14 days for treatment of refractory acute GVHD.7 Treatment of chronic GVHD has been studied using 6 mg of sirolimus followed by 2 mg daily with a slightly higher trough of 7 ng/mL to 12 ng/mL for up to 9 months.8 As there is no FDA-indication for sirolimus in GVHD prophylaxis or treatment, the dosing may vary from study to study. Therefore this must be taken into account when considering such a medication.
When considering sirolimus in a GVHD patient, the potential adverse events must also be discussed. Many of the studies evaluating the adverse event profile of sirolimus have been in solid organ transplant recipients, therefore the reproducibility in GVHD patients may not exactly be the same. Sirolimus has been associated with side effects in most systems including the central nervous system, cardiovascular, dermatologic, gastrointestinal, endocrine, and renal.1
Sirolimus carries a black box warning for increased risk of infection and malignancy (as an immunosuppressant). The literature is relatively mixed with respect to its malignancy potential, as there is some evidence that sirolimus has antineoplastic properties.2 Several studies have shown an increased risk of overall mortality in kidney and kidney-pancreas transplant recipient patients receiving sirolimus which was mostly associated with its infectious- and cardiovascular-related complications.9
Sirolimus represents a potential option for prophylaxis and treatment of refractory GVHD. Many of the clinical studies evaluating these indications are small and have used varying dosing protocols and follow ups. It is vital to review both the efficacy and safety data prior to initiating sirolimus in patients with GVHD.
- Rapamune (sirolimus) [package insert]. Philadelphia, PA: Wyeth: 1999. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021110s058lbl.pdf. Accessed August 28. 2017.
- Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367(4):329-339. doi: 10.1056/NEJMoa1204166
- Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009; 373(9674):1550-1561. doi: 10.1016/S0140-6736(09)60237-3
- Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic GVHD: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-956.
- Armand P, Gannamaneni S, Kim HT, et al. Improved survival in lymphoma patients receiving sirolimus for GVHD prophylaxis after allogeneic HSCT with reduced intensity conditioning. J Clin Oncol. 2008;26(35):5767-5774. doi: 10.1200/JCO.2008.17.7279
- Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109(7): 3108-3114.
- Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation. 2001;72(12):1924-1929.
- Couriel DR, Saliba R, Escalón MP, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005;130(3):409-417.
- Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014;349:g6679. doi: 10.1136/bmj.g6679