- Email: [email protected]
Preliminary Experience With Conversion From Calcineurin Inhibitors to Everolimus in Cardiac Transplantation Maintenance Therapy
COMPLICATIONS Nephrotoxic
Preliminary Experience With Conversion From Calcineurin Inhibitors to Everolimus in Cardiac Transplantation Maintenance Therapy J.A. Sánchez-Brotons, J.M. Sobrino-Márquez, E. Lage-Gallé, N. Romero-Rodriguez, A. Guisado, J. Jiménez-Dı´az, J. Benezet-Mazuecos, J.M. Arizón-Muñoz, M.V. Mogollón, and A. Martı´nez ABSTRACT Introduction. Everolimus has been prescribed both for initial and maintenance therapy after cardiac transplantation. Herein, we present our initial experience with everolimus as maintenance therapy after cardiac transplantation. Methods. We retrospectively included all of our patients in whom therapy was changed from calcineurin inhibitors to everolimus between September 2006 and October 2007. We analyzed their baseline clinical characteristics, indications for conversion to everolimus therapy, and beneficial vs adverse effects of the maneuver. Results. In 16 heart transplant recipients, therapy was changed to everolimus because of allograft vasculopathy (n ⫽ 8), renal failure (n ⫽ 4), or sirolimus toxicity (n ⫽ 4). Treatment with everolimus was initiated at a mean (SD) of 79.8 (52.7) months (range, 10 –163 mo) after transplantation. The initial dose was 1.4 (0.2) mg (range, 1.0 –1.5 mg), and the maintenance dose was 1 (0.31) mg (range, 0.5–1.5 mg). Follow-up was 7.28 (3.22) months (range, 0.5–13 mo). Observed side effects included hypertriglyceridemia, hypertension, and edema. Only 1 of 4 patients included because of sirolimus intolerance did not tolerate everolimus; renal dysfunction did not worsen in any of these 4 patients. No allograft vasculopathy was observed. Conclusions. Renal function seem to stabilize after conversion to everolimus therapy in patients with previous progressive dysfunction. The safety profile was proved in all patients, although conclusions cannot be established about the evolution of allograft vasculopathy.
S
IROLIMUS AND EVEROLIMUS are immunosuppressive drugs that belong to the group of proliferation signal inhibitors. Everolimus has been used in heart transplant recipients both as initial and maintenance therapy. There are three primary indications: renal failure, allograft vasculopathy, and neoplastic disease. Herein, we present our initial experience with everolimus as maintenance therapy after heart transplantation.
From the Cardiology Department, Virgen del Rocio University Hospital, Seville, Spain. Address reprint requests to Dr Juan Antonio Sánchez Brotons, C/Estrasburgo 4, Escalera Sur, 3°A, 41012 Seville, Spain. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.111
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3046
Transplantation Proceedings, 40, 3046 –3048 (2008)
EVEROLIMUS THERAPY AFTER CARDIAC TRANSPLANTATION
3047
METHODS
DISCUSSION
We retrospectively included all patients in whom therapy was changed from calcineurin inhibitors to everolimus between September 2006 and October 2007. We analyzed their baseline clinical characteristics, indications for change in therapy, time since heart transplantation, and beneficial vs adverse effects, considering all causes for conversion. At the start of treatment with everolimus, we paid special attention to the indication and the concomitant immunosuppressive treatment.
Everolimus, like sirolimus, is included in the group of inhibition of mammalian target of rampamycin. Everolimus inhibits T-cell proliferation signals mediated by interleukin-2 and interleukin-15,1 with a consequent interruption in the initial portion of the G1 phase of the cell cycle, blocking clonal proliferation of lymphocytes due to inhibition of the activation cascade after interleukin-2 reception.2 Everolimus is responsible for certain indirect effects; it blocks CD4 and CD8 lymphocytes and monocytes, and B-lymphocyte proliferation and differentiation without affecting T-cell apoptosis mechanisms. Moreover, it also blocks both hematopoietic and nonhematopoietic families. In animal models, everolimus blocks bronchial and vascular3 smooth muscle proliferation, protecting against the development of allograft vasculopathy as validated at intravascular ultrasonography two years after cardiac transplantation.4 Moreover, everolimus has been considered to be more effective than azathioprine in reducing the incidence and severity of allograft vasculopathy.5 Less information is available about the effect of this group of drugs on established vasculopathy. Another indication for everolimus is renal failure, both as a substitute or in association with low dosages of calcineurin inhibitors, with greater benefit in early stages. Other indications for its use include sirolimus toxicity or concomitant oncologic disease; experimental studies have demonstrated an antitumor effect.6 Maximal blood concentrations of everolimus are detected 3 hours after its administration, with a half-life of 24 hours. Recommended doses are 0.75–1.5 mg every 12 hours, with recommended levels between 3 and 8 ng/mL7 and optimum levels between 6 and 8 ng/mL.8 Levels lower than 3 ng/mL are significantly associated with acute rejection episodes.9 The most frequent adverse events related to everolimus therapy include cutaneous disorders (fundamentally, acne, which usually appears at the start of treatment and spontaneously improves shortly thereafter), hypertriglyceridemia, hematologic disorders (anemia, leukopenia, and especially thrombocytopenia), bacterial infections, impaired wound healing (everolimus is not recommended during the week after any surgery), diarrhea, edema, interstitial pneumonia, and neurologic disorders.5 In conclusion, renal function seems to stabilize after conversion to everolimus therapy in patients with previous progressive dysfunction. The safety profile was acceptable in all patients, although conclusions cannot be established about the evolution of allograft vasculopathy because longer follow-up and periodic angiographic controls are needed.
RESULTS
Sixteen heart transplant recipients (14 men) were included in the study. Their mean (SD) age was 58.9 (8.9) years (age range, 34 –71 y, Table 1). Reasons for conversion to everolimus therapy were allograft vasculopathy in eight patients, renal failure in four, and sirolimus toxicity in four. The previous immunosuppressive treatment was cyclosporine in seven patients, tacrolimus in five, sirolimus in three, and sirolimus plus cyclosporine in one. All patients were receiving mycophenolate mofetil, five (31.25%) were receiving steroids, and 15 (93.75%) were receiving statins. Treatment with everolimus was initiated at a mean (SD) of 79.8 (52.7) months after transplantation (range, 10 –163 mo). Initial doses were 1.4 (0.2) mg/d (range, 1.0 –1.5 mg/d), and the maintenance dose was 1 (0.31) mg/d (range, 0.5–1.5 mg/d). Follow-up was 7.28 (3.22) months (range, 0.5–13 mo). Adverse effects included worsening hypertriglyceridemia in one patient, uncontrolled hypertension in two, and edema in four, with the need to discontinue the treatment in one because of the severity of the reaction. Only one of the four patients with sirolimus intolerance failed to tolerate everolimus, because of severe edema in the other three patients continued with the treatment, with disappearance of the edema that motivated the conversion in two of them. Nevertheless, one of them exhibited toxic levels of sirolimus even after the doses were diminished to 1 mg/d. The third patient with intolerance had sirolimusinduced pneumonia. Renal dysfunction did not worsen in any of the four patients who received everolimus for that reason. In addition, we did not observe progressive allograft vasculopathy. Table 1. Baseline Characteristics of 16 Study Patients Characteristic
Age at transplantation, mean (SD), y Sex, no. (%) Men Women Cardiovascular risk factors, no. (%) Hypertension Diabetes mellitus Hypercholesterolemia Transplant indication, no. (%) Dilated cardiomyopathy Ischemic coronary disease Time since transplantation, mean (SD) mo
Value
58.9 (8.9) 14 (87.5) 2 (12.5) 9 (56.2) 4 (25) 6 (37.5)
REFERENCES 9 (56.2) 7 (43.8) 79.8 (52.7)
1. Schuler W, Sedrani R, Cottens S, et al: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 64:36, 1997
3048 2. Tereda N, Lucas JJ, Szepesi A, et al: Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle. J Cell Physiol 154:7, 1993 3. Augustine JJ, Hricik DE: Experience with everolimus. Transplant Proc 36(2 suppl):500S, 2004 4. Tuzcu E, Kobashigawa J, Eisen H, et al: Favourable effect of everolimus on cardiac allograft vasculopathy is maintained through 24 months. J Heart Lung Transplant 23(suppl):S51, 2004 5. Eisen H, Tuzcu E, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 349:847, 2003 6. Majewski M, Korecka M, Joergensen J, et al: Inmunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of
SÁNCHEZ-BROTONS, SOBRINO-MÁRQUEZ, LAGE-GALLÉ ET AL cells derived from postransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 75:1710, 2003 7. Starling RC, Hareb JM, Hauptmann P, et al: Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure effect modelling. Am J Transplant 4:2126, 2004 8. Hummel M: Recommendations for use of Certican (everolimus) after heart transplantation: results from a German and Austrian Consensus Conference. J Heart Lung Transpl 24(4 suppl):196, 2005 9. Kovarik JM, Eisen H, Dorent R, et al: Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure. J Heart Lung Transpl 22:1117, 2003
Preliminary Experience With Conversion From Calcineurin Inhibitors to Everolimus in Cardiac Transplantation Maintenance Therapy J.A. Sánchez-Brotons, J.M. Sobrino-Márquez, E. Lage-Gallé, N. Romero-Rodriguez, A. Guisado, J. Jiménez-Dı´az, J. Benezet-Mazuecos, J.M. Arizón-Muñoz, M.V. Mogollón, and A. Martı´nez ABSTRACT Introduction. Everolimus has been prescribed both for initial and maintenance therapy after cardiac transplantation. Herein, we present our initial experience with everolimus as maintenance therapy after cardiac transplantation. Methods. We retrospectively included all of our patients in whom therapy was changed from calcineurin inhibitors to everolimus between September 2006 and October 2007. We analyzed their baseline clinical characteristics, indications for conversion to everolimus therapy, and beneficial vs adverse effects of the maneuver. Results. In 16 heart transplant recipients, therapy was changed to everolimus because of allograft vasculopathy (n ⫽ 8), renal failure (n ⫽ 4), or sirolimus toxicity (n ⫽ 4). Treatment with everolimus was initiated at a mean (SD) of 79.8 (52.7) months (range, 10 –163 mo) after transplantation. The initial dose was 1.4 (0.2) mg (range, 1.0 –1.5 mg), and the maintenance dose was 1 (0.31) mg (range, 0.5–1.5 mg). Follow-up was 7.28 (3.22) months (range, 0.5–13 mo). Observed side effects included hypertriglyceridemia, hypertension, and edema. Only 1 of 4 patients included because of sirolimus intolerance did not tolerate everolimus; renal dysfunction did not worsen in any of these 4 patients. No allograft vasculopathy was observed. Conclusions. Renal function seem to stabilize after conversion to everolimus therapy in patients with previous progressive dysfunction. The safety profile was proved in all patients, although conclusions cannot be established about the evolution of allograft vasculopathy.
S
IROLIMUS AND EVEROLIMUS are immunosuppressive drugs that belong to the group of proliferation signal inhibitors. Everolimus has been used in heart transplant recipients both as initial and maintenance therapy. There are three primary indications: renal failure, allograft vasculopathy, and neoplastic disease. Herein, we present our initial experience with everolimus as maintenance therapy after heart transplantation.
From the Cardiology Department, Virgen del Rocio University Hospital, Seville, Spain. Address reprint requests to Dr Juan Antonio Sánchez Brotons, C/Estrasburgo 4, Escalera Sur, 3°A, 41012 Seville, Spain. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.111
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3046
Transplantation Proceedings, 40, 3046 –3048 (2008)
EVEROLIMUS THERAPY AFTER CARDIAC TRANSPLANTATION
3047
METHODS
DISCUSSION
We retrospectively included all patients in whom therapy was changed from calcineurin inhibitors to everolimus between September 2006 and October 2007. We analyzed their baseline clinical characteristics, indications for change in therapy, time since heart transplantation, and beneficial vs adverse effects, considering all causes for conversion. At the start of treatment with everolimus, we paid special attention to the indication and the concomitant immunosuppressive treatment.
Everolimus, like sirolimus, is included in the group of inhibition of mammalian target of rampamycin. Everolimus inhibits T-cell proliferation signals mediated by interleukin-2 and interleukin-15,1 with a consequent interruption in the initial portion of the G1 phase of the cell cycle, blocking clonal proliferation of lymphocytes due to inhibition of the activation cascade after interleukin-2 reception.2 Everolimus is responsible for certain indirect effects; it blocks CD4 and CD8 lymphocytes and monocytes, and B-lymphocyte proliferation and differentiation without affecting T-cell apoptosis mechanisms. Moreover, it also blocks both hematopoietic and nonhematopoietic families. In animal models, everolimus blocks bronchial and vascular3 smooth muscle proliferation, protecting against the development of allograft vasculopathy as validated at intravascular ultrasonography two years after cardiac transplantation.4 Moreover, everolimus has been considered to be more effective than azathioprine in reducing the incidence and severity of allograft vasculopathy.5 Less information is available about the effect of this group of drugs on established vasculopathy. Another indication for everolimus is renal failure, both as a substitute or in association with low dosages of calcineurin inhibitors, with greater benefit in early stages. Other indications for its use include sirolimus toxicity or concomitant oncologic disease; experimental studies have demonstrated an antitumor effect.6 Maximal blood concentrations of everolimus are detected 3 hours after its administration, with a half-life of 24 hours. Recommended doses are 0.75–1.5 mg every 12 hours, with recommended levels between 3 and 8 ng/mL7 and optimum levels between 6 and 8 ng/mL.8 Levels lower than 3 ng/mL are significantly associated with acute rejection episodes.9 The most frequent adverse events related to everolimus therapy include cutaneous disorders (fundamentally, acne, which usually appears at the start of treatment and spontaneously improves shortly thereafter), hypertriglyceridemia, hematologic disorders (anemia, leukopenia, and especially thrombocytopenia), bacterial infections, impaired wound healing (everolimus is not recommended during the week after any surgery), diarrhea, edema, interstitial pneumonia, and neurologic disorders.5 In conclusion, renal function seems to stabilize after conversion to everolimus therapy in patients with previous progressive dysfunction. The safety profile was acceptable in all patients, although conclusions cannot be established about the evolution of allograft vasculopathy because longer follow-up and periodic angiographic controls are needed.
RESULTS
Sixteen heart transplant recipients (14 men) were included in the study. Their mean (SD) age was 58.9 (8.9) years (age range, 34 –71 y, Table 1). Reasons for conversion to everolimus therapy were allograft vasculopathy in eight patients, renal failure in four, and sirolimus toxicity in four. The previous immunosuppressive treatment was cyclosporine in seven patients, tacrolimus in five, sirolimus in three, and sirolimus plus cyclosporine in one. All patients were receiving mycophenolate mofetil, five (31.25%) were receiving steroids, and 15 (93.75%) were receiving statins. Treatment with everolimus was initiated at a mean (SD) of 79.8 (52.7) months after transplantation (range, 10 –163 mo). Initial doses were 1.4 (0.2) mg/d (range, 1.0 –1.5 mg/d), and the maintenance dose was 1 (0.31) mg/d (range, 0.5–1.5 mg/d). Follow-up was 7.28 (3.22) months (range, 0.5–13 mo). Adverse effects included worsening hypertriglyceridemia in one patient, uncontrolled hypertension in two, and edema in four, with the need to discontinue the treatment in one because of the severity of the reaction. Only one of the four patients with sirolimus intolerance failed to tolerate everolimus, because of severe edema in the other three patients continued with the treatment, with disappearance of the edema that motivated the conversion in two of them. Nevertheless, one of them exhibited toxic levels of sirolimus even after the doses were diminished to 1 mg/d. The third patient with intolerance had sirolimusinduced pneumonia. Renal dysfunction did not worsen in any of the four patients who received everolimus for that reason. In addition, we did not observe progressive allograft vasculopathy. Table 1. Baseline Characteristics of 16 Study Patients Characteristic
Age at transplantation, mean (SD), y Sex, no. (%) Men Women Cardiovascular risk factors, no. (%) Hypertension Diabetes mellitus Hypercholesterolemia Transplant indication, no. (%) Dilated cardiomyopathy Ischemic coronary disease Time since transplantation, mean (SD) mo
Value
58.9 (8.9) 14 (87.5) 2 (12.5) 9 (56.2) 4 (25) 6 (37.5)
REFERENCES 9 (56.2) 7 (43.8) 79.8 (52.7)
1. Schuler W, Sedrani R, Cottens S, et al: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 64:36, 1997
3048 2. Tereda N, Lucas JJ, Szepesi A, et al: Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle. J Cell Physiol 154:7, 1993 3. Augustine JJ, Hricik DE: Experience with everolimus. Transplant Proc 36(2 suppl):500S, 2004 4. Tuzcu E, Kobashigawa J, Eisen H, et al: Favourable effect of everolimus on cardiac allograft vasculopathy is maintained through 24 months. J Heart Lung Transplant 23(suppl):S51, 2004 5. Eisen H, Tuzcu E, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 349:847, 2003 6. Majewski M, Korecka M, Joergensen J, et al: Inmunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of
SÁNCHEZ-BROTONS, SOBRINO-MÁRQUEZ, LAGE-GALLÉ ET AL cells derived from postransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 75:1710, 2003 7. Starling RC, Hareb JM, Hauptmann P, et al: Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure effect modelling. Am J Transplant 4:2126, 2004 8. Hummel M: Recommendations for use of Certican (everolimus) after heart transplantation: results from a German and Austrian Consensus Conference. J Heart Lung Transpl 24(4 suppl):196, 2005 9. Kovarik JM, Eisen H, Dorent R, et al: Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure. J Heart Lung Transpl 22:1117, 2003