- Email: [email protected]
Conversion to Sirolimus in Posttransplant Renal Neoplasms
Conversion to Sirolimus in Posttransplant Renal Neoplasms V. Lopez, C. Gutierrez, M. Cabello, D. Burgos, E. Sola, and M. Gonzalez-Molina ABSTRACT Background. Calcineurin inhibitors (CNIs) have been associated with the development of posttransplant malignancies, especially lymphoma and solid organ tumors. Sirolimus (SRL) has been shown to inhibit the growth of tumor cell lines in vitro and in vivo and has proven effective in clinical practice for the treatment of Kaposi’s sarcoma. Organ transplant patients treated with CNIs who develop a tumor may thus benefit from conversion to SRL. Patients and methods. From December 2001 to May 2006, 25 patients who developed a tumor were converted from a CNI-based immunosuppressive regimen to SRL. We analyzed the evolution of the tumor, renal function, and the adverse effects resulting from the change of immunosuppression. Results. The mean follow-up was 19 months. Creatinine clearance (Cockcroft-Gault) increased from 59.5 ⫾ 21.7 to 66.0 ⫾ 24.2 mL/min at 12 months (P ⫽ .4) and serum cholesterol from 176.7 ⫾ 46.8 to 216.4 ⫾ 40.3 mg/dL (P ⫽ .01). Proteinuria rose from 0.3 ⫾ 0.1 to 1.3 ⫾ 0.9 g/24 hours (P ⫽ .004). Adverse events included anemia, thrombocytopenia, and oral ulcers in 20% of cases, cutaneous eruption and gastrointestinal alterations in 12%, and edema in 24%. Four (16%) patients had improved blood pressure readings. Six (24%) patients died and one experienced an acute rejection episode after conversion to SRL. Nineteen (76%) patients displayed a favorable evolution with no evidence of tumor progression. Conclusions. Conversion to SRL stabilized tumor progression in 76% of long-term renal transplant patients who developed a neoplasm over a mean follow-up of 19 months. Moreover, renal function improved. The most important adverse effects were increased cholesterol and proteinuria.
T
HE INCIDENCE OF NEOPLASMS among organ transplant recipients is greater than among the general population. It is related to the type and intensity of the immunosuppressive regimen. Once the presence of a neoplasm is diagnosed, the usual practice is to reduce the
Table 1. Immunosuppressive Therapy Before Conversion CsA ⫹ Aza ⫹ S CsA ⫹ MMF ⫹ S CsA ⫹ S FK ⫹ Aza ⫹ S FK ⫹ MMF ⫹ S FK ⫹ MMF Induction with anti-IL-2R
16% (n ⫽ 4) 20% (n ⫽ 5) 16% (n ⫽ 4) 4% (n ⫽ 1) 40% (n ⫽ 10) 4% (n ⫽ 1) 20% (n ⫽ 5)
Abbreviations: CsA, cyclosporine; FK, tacrolimus; S, steroids; Aza, azathioprine; MMF, mycophenolate mofetil; IL, interleukin.
immunosuppression. This strategy includes suspension or minimization of calcineurin inhibitors (CNIs),1 which leads to an increased risk of acute rejection. Sirolimus (SRL), an mTOR inhibitor, appears to have an antineoplastic effect independent of its immunosuppressive properties. SRL inhibits the in vitro proliferation of transformed lymphoid, central nervous system, hepatic, melanocytic, osteoblastic, myogenic, renal, and connective tissue cell lines.2– 4 In vivo, activity has been shown against melanoma, colon cancer, renal adenocarcinoma, ependymoblastoma, and breast canFrom the Nephrology Department, Carlos Haya Hospital, Malaga, Spain. Address reprint requests to V. Lopez, Servicio de Nefrologia, Hospital Carlos Haya, Av Carlos Haya, 29010 Malaga, Spain. E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.055
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2264
Transplantation Proceedings, 39, 2264 –2266 (2007)
CONVERSION TO SIROLIMUS
2265
Table 2. Immunosuppressive Therapy After Conversion SRL ⫹ MMF ⫹ S SRL ⫹ S SRL ⫹ MMF
72% (n ⫽ 18) 24% (n ⫽ 6) 4% (n ⫽ 1)
Abbreviations: SRL, sirolimus; MMF, mycophenolate moffetil; S, steroids.
cer in murine models2,5 and in humans against Kaposi’s sarcoma.6 – 8 These data suggested that SRL may be a therapeutic option for organ transplant patients who develop neoplasms. PATIENTS AND METHODS From December 2001 to May 2006, 25 patients (6 women, 19 men) were converted from a CNI-based immunosuppressive regimen to SRL following detection of a tumor: 11 lymphomas, 10 skin cancers (basal cell or squamous cell), 1 thyroid, 1 lung, 1 native kidney, and 1 laryngeal carcinoma. We analyzed the safety of conversion the evolution of the neoplasm, the renal function, and the appearance of adverse events.
RESULTS
The mean time from transplant to the development of a tumor was 74 months (range ⫽ 5 to 192 months). All patients were being treated with CNIs; 13 with cyclosporine and 12 with tacrolimus (Table 1). Conversion to SRL was rapid in seven patients; in the others, SRL was introduced with progressive reduction of the CNI until its suspension when the SRL levels were above 6 ng/mL. The dose of SRL was adjusted weekly to maintain levels between 6 and 8 ng/mL. The median time during which the CNI and SRL overlapped was 7 days (range ⫽ 4 to 35 days). Five patients were receiving azathioprine, which was replaced by mycophenolate mofetil. Corticosteroid therapy was continued with no change (Table 2). Table 3 shows the evolution of renal function, proteinuria, and lipid profile at 3, 6, and 12 months after conversion. Improvement was detected in renal function. There was a significant increase in proteinuria and serum cholesterol. The proportion of patients requiring lipid-lowering agents before versus after conversion increased from 45% to 68%. Adverse effects included anemia, thrombocytopenia, and oral ulcers (20%), cutaneous eruptions and gastrointestinal complications (12%), and edema (24%). Four patients showed improved blood pressure readings.
The evolution of patients after a mean follow-up of 16 months was: five died due to tumor evolution (three lymphomas, one lung cancer, and one squamous cell carcinoma) and one died due to pulmonary tuberculosis (laryngeal carcinoma). The remaining patients evolved favorably with no evidence of tumor extension. One patient had an episode of Banff grade IA acute rejection at 8 months after conversion with a good response to steroid therapy. SRL was suspended in two patients; one after 2 months due to an episode of interstitial pneumonitis that was initially interpreted as related to the drug but later confirmed to be caused by cytomegalovirus and the other after 11 months due to severe limb edema resistant to diuretics treatment. No patient lost the graft.
DISCUSSION
The incidence of neoplasms in organ transplant patients has increased over recent years. In some countries it now surpasses infections as the cause of death in this population. Several factors have contributed to this situation, notably the use of certain immunosuppressive regimens with polyclonal antibody induction and the increasing age of the recipients, enhancing the likelihood of developing a tumor.9,10 This complication undermines patient and graft survival, due to the process itself and the changes in immunosuppressive therapy. Graft survival during the first year posttransplantation has increased significantly, whereas long-term results have hardly changed. The reasons for this include the use of immunosuppressive drugs with nephrotoxic effects, the increase in infections resulting in graft loss among a high percentage of cases, for example, BK polyomavirus nephropathy, and the increase in neoplasms following the use of drugs with a greater immunosuppressive potential. SRL has powerful antiproliferative antineoplastic effects both in vitro and in vivo. This action appears to be mediated by several mechanisms, including direct inhibition of cancer cell replication, apoptosis induction, inhibition of interleukin-10 production, and inhibition of tumor angiogenesis through down-regulation of vascular endothelial growth factor.11,12 Conversion to SRL in patients who develop a tumor may, theoretically, be effective as a therapeutic measure in these cases.
Table 3. Analytical Data Before Conversion and 3, 6, and 12 Months After Conversion
Ccr* (mL/min) Cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Proteinuria (g/24 h)
Baseline
3 mon
6 mon
1y
59.5 ⫾ 21.7 176.7 ⫾ 46.8 102.4 ⫾ 28.8 42.8 ⫾ 19.6 147 ⫾ 107.4 0.3 ⫾ 0.1
62.9 ⫾ 21.0 231.2 ⫾ 75.9† 135.4 ⫾ 57.8† 50.1 ⫾ 19.3 181.3 ⫾ 80.2 0.9 ⫾ 0.8†
64.1 ⫾ 21.5 227.7 ⫾ 55.8† 132.5 ⫾ 36.5† 50.5 ⫾ 18.3 162.6 ⫾ 96.6 1.3 ⫾ 1.2†
66.0 ⫾ 24.2 216.4 ⫾ 40.3† 127.6 ⫾ 38.8† 52.7 ⫾ 20.3 142.0 ⫾ 63.9 1.3 ⫾ 0.9†
Data are presented as mean values ⫾ SEM. Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein. *Ccr: creatinine clearance measured with the Cockcroft-Gault equation. † P ⬍ .05 compared to baseline values.
2266
The present study examined the results of conversion to SRL among 25 patients who had developed a tumor after renal transplantation under CNI treatment. The most notable finding was the favorable evolution of a high percentage of the patients over a mean follow-up of 19 months. Moreover, the patients displayed improved renal function. The most important adverse events were a significant increase in proteinuria and changes in the lipid profile. The other side effects were generally well tolerated and reversible, except for one case of edema resistant to diuretic treatment. We plan to observe these patients for the longer-term results.
REFERENCES 1. Sanchez-Fructuoso A, Conesa J, Perez Flores I: Conversion to sirolimus in renal transplant patients with tumors. Transplant Proc 38:2451, 2006 2. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35:7S, 2003 3. Lee V, Chapman J: Sirolimus: its role in nephrology. Nephrology 10:606, 2005
LOPEZ, GUTIERREZ, CABELLO ET AL 4. Kochl GE, Andrassy J, Guba M, et al: Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 77:1319, 2004 5. Luan FL, Hojo M, Maluccio M, et al: Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 73:1565, 2002 6. Zmonarski SC, Boratynska M, Rabzynski J: Regression of Kaposi’s sarcoma in renal graft recipients after conversion to sirolimus treatment. Transplant Proc 37:964, 2005 7. Stallone G, Shena A, Infante B, et al: Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352:1317, 2005 8. Gutierrez-Dalmau A, Sanchez-Fructuoso A, Sanz-Guajardo A, et al: Efficacy of conversion to sirolimus in post-transplantation Kaposi’s sarcoma. Transplant Proc 37:3836, 2005 9. Penn I: Post-transplant malignancy: the role of immunosuppression. Drug Saf 23:101, 2000 10. Buell JF, Gross TG, Woodle ES: Malignancy after transplantation. Transplantation 15:S254, 2005 11. Luan FL, Ding R, Sharma VK, et al: Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 63:917, 2003 12. Nepomuceno RR, Balatoni CE, Natkunam Y, et al: Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 63:4472, 2003
T
HE INCIDENCE OF NEOPLASMS among organ transplant recipients is greater than among the general population. It is related to the type and intensity of the immunosuppressive regimen. Once the presence of a neoplasm is diagnosed, the usual practice is to reduce the
Table 1. Immunosuppressive Therapy Before Conversion CsA ⫹ Aza ⫹ S CsA ⫹ MMF ⫹ S CsA ⫹ S FK ⫹ Aza ⫹ S FK ⫹ MMF ⫹ S FK ⫹ MMF Induction with anti-IL-2R
16% (n ⫽ 4) 20% (n ⫽ 5) 16% (n ⫽ 4) 4% (n ⫽ 1) 40% (n ⫽ 10) 4% (n ⫽ 1) 20% (n ⫽ 5)
Abbreviations: CsA, cyclosporine; FK, tacrolimus; S, steroids; Aza, azathioprine; MMF, mycophenolate mofetil; IL, interleukin.
immunosuppression. This strategy includes suspension or minimization of calcineurin inhibitors (CNIs),1 which leads to an increased risk of acute rejection. Sirolimus (SRL), an mTOR inhibitor, appears to have an antineoplastic effect independent of its immunosuppressive properties. SRL inhibits the in vitro proliferation of transformed lymphoid, central nervous system, hepatic, melanocytic, osteoblastic, myogenic, renal, and connective tissue cell lines.2– 4 In vivo, activity has been shown against melanoma, colon cancer, renal adenocarcinoma, ependymoblastoma, and breast canFrom the Nephrology Department, Carlos Haya Hospital, Malaga, Spain. Address reprint requests to V. Lopez, Servicio de Nefrologia, Hospital Carlos Haya, Av Carlos Haya, 29010 Malaga, Spain. E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.055
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2264
Transplantation Proceedings, 39, 2264 –2266 (2007)
CONVERSION TO SIROLIMUS
2265
Table 2. Immunosuppressive Therapy After Conversion SRL ⫹ MMF ⫹ S SRL ⫹ S SRL ⫹ MMF
72% (n ⫽ 18) 24% (n ⫽ 6) 4% (n ⫽ 1)
Abbreviations: SRL, sirolimus; MMF, mycophenolate moffetil; S, steroids.
cer in murine models2,5 and in humans against Kaposi’s sarcoma.6 – 8 These data suggested that SRL may be a therapeutic option for organ transplant patients who develop neoplasms. PATIENTS AND METHODS From December 2001 to May 2006, 25 patients (6 women, 19 men) were converted from a CNI-based immunosuppressive regimen to SRL following detection of a tumor: 11 lymphomas, 10 skin cancers (basal cell or squamous cell), 1 thyroid, 1 lung, 1 native kidney, and 1 laryngeal carcinoma. We analyzed the safety of conversion the evolution of the neoplasm, the renal function, and the appearance of adverse events.
RESULTS
The mean time from transplant to the development of a tumor was 74 months (range ⫽ 5 to 192 months). All patients were being treated with CNIs; 13 with cyclosporine and 12 with tacrolimus (Table 1). Conversion to SRL was rapid in seven patients; in the others, SRL was introduced with progressive reduction of the CNI until its suspension when the SRL levels were above 6 ng/mL. The dose of SRL was adjusted weekly to maintain levels between 6 and 8 ng/mL. The median time during which the CNI and SRL overlapped was 7 days (range ⫽ 4 to 35 days). Five patients were receiving azathioprine, which was replaced by mycophenolate mofetil. Corticosteroid therapy was continued with no change (Table 2). Table 3 shows the evolution of renal function, proteinuria, and lipid profile at 3, 6, and 12 months after conversion. Improvement was detected in renal function. There was a significant increase in proteinuria and serum cholesterol. The proportion of patients requiring lipid-lowering agents before versus after conversion increased from 45% to 68%. Adverse effects included anemia, thrombocytopenia, and oral ulcers (20%), cutaneous eruptions and gastrointestinal complications (12%), and edema (24%). Four patients showed improved blood pressure readings.
The evolution of patients after a mean follow-up of 16 months was: five died due to tumor evolution (three lymphomas, one lung cancer, and one squamous cell carcinoma) and one died due to pulmonary tuberculosis (laryngeal carcinoma). The remaining patients evolved favorably with no evidence of tumor extension. One patient had an episode of Banff grade IA acute rejection at 8 months after conversion with a good response to steroid therapy. SRL was suspended in two patients; one after 2 months due to an episode of interstitial pneumonitis that was initially interpreted as related to the drug but later confirmed to be caused by cytomegalovirus and the other after 11 months due to severe limb edema resistant to diuretics treatment. No patient lost the graft.
DISCUSSION
The incidence of neoplasms in organ transplant patients has increased over recent years. In some countries it now surpasses infections as the cause of death in this population. Several factors have contributed to this situation, notably the use of certain immunosuppressive regimens with polyclonal antibody induction and the increasing age of the recipients, enhancing the likelihood of developing a tumor.9,10 This complication undermines patient and graft survival, due to the process itself and the changes in immunosuppressive therapy. Graft survival during the first year posttransplantation has increased significantly, whereas long-term results have hardly changed. The reasons for this include the use of immunosuppressive drugs with nephrotoxic effects, the increase in infections resulting in graft loss among a high percentage of cases, for example, BK polyomavirus nephropathy, and the increase in neoplasms following the use of drugs with a greater immunosuppressive potential. SRL has powerful antiproliferative antineoplastic effects both in vitro and in vivo. This action appears to be mediated by several mechanisms, including direct inhibition of cancer cell replication, apoptosis induction, inhibition of interleukin-10 production, and inhibition of tumor angiogenesis through down-regulation of vascular endothelial growth factor.11,12 Conversion to SRL in patients who develop a tumor may, theoretically, be effective as a therapeutic measure in these cases.
Table 3. Analytical Data Before Conversion and 3, 6, and 12 Months After Conversion
Ccr* (mL/min) Cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Proteinuria (g/24 h)
Baseline
3 mon
6 mon
1y
59.5 ⫾ 21.7 176.7 ⫾ 46.8 102.4 ⫾ 28.8 42.8 ⫾ 19.6 147 ⫾ 107.4 0.3 ⫾ 0.1
62.9 ⫾ 21.0 231.2 ⫾ 75.9† 135.4 ⫾ 57.8† 50.1 ⫾ 19.3 181.3 ⫾ 80.2 0.9 ⫾ 0.8†
64.1 ⫾ 21.5 227.7 ⫾ 55.8† 132.5 ⫾ 36.5† 50.5 ⫾ 18.3 162.6 ⫾ 96.6 1.3 ⫾ 1.2†
66.0 ⫾ 24.2 216.4 ⫾ 40.3† 127.6 ⫾ 38.8† 52.7 ⫾ 20.3 142.0 ⫾ 63.9 1.3 ⫾ 0.9†
Data are presented as mean values ⫾ SEM. Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein. *Ccr: creatinine clearance measured with the Cockcroft-Gault equation. † P ⬍ .05 compared to baseline values.
2266
The present study examined the results of conversion to SRL among 25 patients who had developed a tumor after renal transplantation under CNI treatment. The most notable finding was the favorable evolution of a high percentage of the patients over a mean follow-up of 19 months. Moreover, the patients displayed improved renal function. The most important adverse events were a significant increase in proteinuria and changes in the lipid profile. The other side effects were generally well tolerated and reversible, except for one case of edema resistant to diuretic treatment. We plan to observe these patients for the longer-term results.
REFERENCES 1. Sanchez-Fructuoso A, Conesa J, Perez Flores I: Conversion to sirolimus in renal transplant patients with tumors. Transplant Proc 38:2451, 2006 2. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35:7S, 2003 3. Lee V, Chapman J: Sirolimus: its role in nephrology. Nephrology 10:606, 2005
LOPEZ, GUTIERREZ, CABELLO ET AL 4. Kochl GE, Andrassy J, Guba M, et al: Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 77:1319, 2004 5. Luan FL, Hojo M, Maluccio M, et al: Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 73:1565, 2002 6. Zmonarski SC, Boratynska M, Rabzynski J: Regression of Kaposi’s sarcoma in renal graft recipients after conversion to sirolimus treatment. Transplant Proc 37:964, 2005 7. Stallone G, Shena A, Infante B, et al: Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352:1317, 2005 8. Gutierrez-Dalmau A, Sanchez-Fructuoso A, Sanz-Guajardo A, et al: Efficacy of conversion to sirolimus in post-transplantation Kaposi’s sarcoma. Transplant Proc 37:3836, 2005 9. Penn I: Post-transplant malignancy: the role of immunosuppression. Drug Saf 23:101, 2000 10. Buell JF, Gross TG, Woodle ES: Malignancy after transplantation. Transplantation 15:S254, 2005 11. Luan FL, Ding R, Sharma VK, et al: Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 63:917, 2003 12. Nepomuceno RR, Balatoni CE, Natkunam Y, et al: Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 63:4472, 2003