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Sirolimus in pediatric transplant recipients
Sirolimus in Pediatric Transplant Recipients R. Sindhi ABSTRACT The side effects of calcineurin inhibitors (CI) have a unique spectrum in pediatric recipients of organ transplants. These include a lifelong risk of mortality due to sepsis, a nearly 5% risk of renal failure from protracted exposure to CI, and a significantly higher risk of posttransplant lymphoproliferative disorder (PTLD) when compared with adults (10% versus 2%).1– 4 This led us to explore the use of the new antiproliferative immunosuppressant sirolimus (SRL) for rescue and primary immunosuppression in recipients of pediatric abdominal and thoracic organs at the Children’s Hospital of Pittsburgh.5,6 Following initial success with SRL in 50 such children, we also explored its use for the elimination of tacrolimus (TAC) in patients experiencing toxicity and for maintenance immunosuppression in steroid-sparing regimens in liver transplantation.7 These early results suggest that sirolimus may hold promise as a primary immunosuppressive agent under defined protocol conditions. The salient features of our experience with SRL in over 85 children are summarized here. SUMMARY OF CLINICAL EXPERIENCE IN CHILDREN Initial Experience in 50 Children
Sirolimus was first evaluated as a rescue agent (n ⫽ 42) and as a component of primary immunosuppression (n ⫽ 8) in a mixed population of 50 transplanted children receiving TAC (liver-26, heart-5, intestinal-5, liver/intestine-9, lung-1, bone marrow-1, liver/kidney-1, multivisceral-1) at our center. As a rescue agent, it lowered TAC requirements by 50% and resulted in significant improvements in measured serum creatinine and in calculated creatinine clearance. Among children with Epstein Barr Virus-PTLD who rejected after withdrawal of immunosuppression, SRL alone or with low-dose TAC resulted in resolution of rejection and continued resolution of EBV viremia. SRL also appeared highly successful when used as a primary immunosuppressive agent in liver and intestinal transplantation. Experience in Pediatric Liver Transplantation
This success led us to evaluate SRL as a substitute for TAC in children experiencing side effects of TAC and as component of steroid-free primary immunosuppressive regimen in pediatric liver recipients. Overall, 11 of 15 eligible children (73%) are steroid free, and four who experienced mild acute rejection resolved with steroids. Mean TAC and SRL C0 in this group are 8 ⫾ 1.7 and 5 ⫾ 2.8 ng/mL, respectively. Of 15 eligible children, TAC has been discontinued in 12 of 15 children. Two children experienced acute rejection on © 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35 (Suppl 3A), 113S–114S (2003)
SRL with steroids and required TAC, while the third experienced severed neutropenia requiring discontinuation of SRL. At a mean follow-up of 14 ⫾ 11 months, mean SRL C0 is 5.1 ng/mL (range 3.4 to 11). Current status
SRL has been administered to over 85 pediatric allograft recipients at our center. It was discontinued for serious adverse events (SAE) in 10 (12%). Ten children experienced acute rejection (12%). Excluding those children with acute rejection or SAE (n ⫽ 18), overall success remains acceptable (67 of 85, 78%). Mean age of this group is 10.9 years (0.05 to 21); time to rescue after transplantation is 48 months (2 days to 180 months); and post-SRL follow-up exceeds 330 days (range 18 to 1080). DISCUSSION
These preliminary results suggest that in our series of selected patients, SRL-based regimens provide effective rejection prophylaxis without the risks of hypertension, From the University of Pittsburgh, Department of Pediatric Transplantation, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to Rakesh Sindhi, MD, Assistant Professor of Surgery, University of Pittsburgh, Pediatric Transplantation, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00223-9 113S
114S
interdose decline in renal function, and neurotoxicity associated with CI agents such as TAC. In three of our patients who received a steroid-free regimen, pretransplant malignancy confined to the liver provides an additional rationale to use SRL for its antiproliferative effect. Further, the addition of SRL to CI may not add significantly to the risk of PTLD. We have not been able to attribute hepatic artery thrombosis to SRL in 18 consecutive liver transplant recipients who were to receive sirolimus by intent immediately after liver transplantation. The only patient who experienced this complication in this series had received a combined liver and kidney transplant and developed thrombosis of both grafts before SRL could be introduced into his regimen. Sirolimus was never given, and the patient was subsequently found to have lupus anticoagulant. He has since been retransplanted, receives TAC for maintenance immunosuppression and lovenox for anticoagulation, and has normal liver and kidney allograft function. These findings were communicated to the US Food and Drug Administration and in subsequent patients, SRL has been introduced in the fourth week after liver transplantation in children (IND 64555) uneventfully. Pharmacodynamic evaluation in our population has suggested that in the presence of stable concentrations of SRL, mild dose-limiting toxicity has occurred at mean TAC whole blood concentrations ⬎10 ng/mL, while serious adverse events that required change in maintenance immunosuppression occurred at mean TAC whole blood concentrations ⱖ13 ng/mL of sirolimus.5,6 Because SRL whole blood concentrations were not different between these groups of patients experiencing serious and mild adverse events, these observations have suggested to us that in addition to lowering therapeutic concentration thresholds, the synergy between SRL and TAC may also lower toxicity thresholds for each agent. This was also apparent in pivotal phase III trials in which the addition of SRL to full-dose cyclosporine (CsA) resulted in greater nephrotoxicity than if CsA was used without SRL.8,9 This is somewhat contrary to the notion that combination therapy using two agents with nonoverlapping toxicity profiles may allow lower and therefore nontoxic amounts of each agent to be used together. At the very least, these experiences argue for drastically lower amounts of CsA and TAC in the presence of SRL, a fact that was confirmed by pharmacodynamic analysis of combination therapy effects in mitogen-stimulated response of human lymphocytes in our laboratory.10,11 Implications for the design and conduct of future evaluations are the use of longitudinal crossover designs in which CI can be eliminated altogether12 or a direct parallel group comparison in which SRL can truly be evaluated for efficacy relative to the standard of care. These two strategies of administration have relevance for the breadth of indications
SINDHI
for which SRL has and is likely to find utility in clinical transplantation. They may also help us realize the significantly greater safety margin of SRL that is hinted at in our clinical studies with this agent but which cannot be fully realized in evaluation strategies in which SRL, like its antiproliferative predecessors mycophenolate mofetil and azathioprine, receives adjunctive status to the best-known therapy—the calcineurin inhibitors. For these reasons, we believe that to relegate promising non-CI drugs such as SRL to secondary status on the basis of flawed conventional clinical trial designs is to deny the transplant recipient population of a much needed alternative with the greatest potential safety margin of any agent to date. DISCLOSURE
Rakesh Sindhi is Principal Investigator of four investigatorinitated protocols from which these data have been collected. These protocols, all of which have been approved by the Human Rights Committee of the Children’s Hospital, are: 1. 99-088-Research Advisory Committee, Children’s Hospital of Pittsburgh 2. RO1AI49156-02-National Institutes of Health, National Institute of Allergy and Infectious Diseases. 3. 0468-100295-partially supported by Institutional NIH award # MO1 RR00084 to the Children’s Hospital of Pittsburgh, and Wyeth-Ayerst Pharmaceuticals, St. David, PA. 5. IND 64555-supported by Institutional NIH award # MO1 RR00084 to the Children’s Hospital of Pittsburgh. REFERENCES 1. Sudan DL, Shaw BW Jr, Langnas AN: Ann Surg 227:289, 1998 2. Fridell JA, Jain A, Reyes J, et al: Transplantation 74:1721, 2002 3. Jain A, Reyes J, Kashyap R, et al: Transplant Proc 30:1403, 1998 4. Reyes J, Jain A, Mazariegos G, et al: Transplantation 69:2573, 2000 5. Sindhi R, Webber S, Venkataramanan R, et al: Transplantation 72:851, 2001 6. Sindhi R, Webber S, Goyal R, et al: Transplant Proc 34:1960, 2002 7. Sindhi R, Ganjoo J, McGhee W, et al: Transplant Proc 34:1972, 2002 8. MacDonald A: Transplantation 71:271, 2001 9. Kahan BD: Lancet 356:194, 2000 10. Sindhi R, LaVia MF, Paulling E, et al: Transplantation 69:432, 2000 11. Sindhi R, Allaert J, Gladding D, et al: J Immunol Meth 272:257, 2003 12. Johnson RW, Kreis H, Oberbauer R, et al: Transplantation 72:777, 2001
Sirolimus was first evaluated as a rescue agent (n ⫽ 42) and as a component of primary immunosuppression (n ⫽ 8) in a mixed population of 50 transplanted children receiving TAC (liver-26, heart-5, intestinal-5, liver/intestine-9, lung-1, bone marrow-1, liver/kidney-1, multivisceral-1) at our center. As a rescue agent, it lowered TAC requirements by 50% and resulted in significant improvements in measured serum creatinine and in calculated creatinine clearance. Among children with Epstein Barr Virus-PTLD who rejected after withdrawal of immunosuppression, SRL alone or with low-dose TAC resulted in resolution of rejection and continued resolution of EBV viremia. SRL also appeared highly successful when used as a primary immunosuppressive agent in liver and intestinal transplantation. Experience in Pediatric Liver Transplantation
This success led us to evaluate SRL as a substitute for TAC in children experiencing side effects of TAC and as component of steroid-free primary immunosuppressive regimen in pediatric liver recipients. Overall, 11 of 15 eligible children (73%) are steroid free, and four who experienced mild acute rejection resolved with steroids. Mean TAC and SRL C0 in this group are 8 ⫾ 1.7 and 5 ⫾ 2.8 ng/mL, respectively. Of 15 eligible children, TAC has been discontinued in 12 of 15 children. Two children experienced acute rejection on © 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35 (Suppl 3A), 113S–114S (2003)
SRL with steroids and required TAC, while the third experienced severed neutropenia requiring discontinuation of SRL. At a mean follow-up of 14 ⫾ 11 months, mean SRL C0 is 5.1 ng/mL (range 3.4 to 11). Current status
SRL has been administered to over 85 pediatric allograft recipients at our center. It was discontinued for serious adverse events (SAE) in 10 (12%). Ten children experienced acute rejection (12%). Excluding those children with acute rejection or SAE (n ⫽ 18), overall success remains acceptable (67 of 85, 78%). Mean age of this group is 10.9 years (0.05 to 21); time to rescue after transplantation is 48 months (2 days to 180 months); and post-SRL follow-up exceeds 330 days (range 18 to 1080). DISCUSSION
These preliminary results suggest that in our series of selected patients, SRL-based regimens provide effective rejection prophylaxis without the risks of hypertension, From the University of Pittsburgh, Department of Pediatric Transplantation, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to Rakesh Sindhi, MD, Assistant Professor of Surgery, University of Pittsburgh, Pediatric Transplantation, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00223-9 113S
114S
interdose decline in renal function, and neurotoxicity associated with CI agents such as TAC. In three of our patients who received a steroid-free regimen, pretransplant malignancy confined to the liver provides an additional rationale to use SRL for its antiproliferative effect. Further, the addition of SRL to CI may not add significantly to the risk of PTLD. We have not been able to attribute hepatic artery thrombosis to SRL in 18 consecutive liver transplant recipients who were to receive sirolimus by intent immediately after liver transplantation. The only patient who experienced this complication in this series had received a combined liver and kidney transplant and developed thrombosis of both grafts before SRL could be introduced into his regimen. Sirolimus was never given, and the patient was subsequently found to have lupus anticoagulant. He has since been retransplanted, receives TAC for maintenance immunosuppression and lovenox for anticoagulation, and has normal liver and kidney allograft function. These findings were communicated to the US Food and Drug Administration and in subsequent patients, SRL has been introduced in the fourth week after liver transplantation in children (IND 64555) uneventfully. Pharmacodynamic evaluation in our population has suggested that in the presence of stable concentrations of SRL, mild dose-limiting toxicity has occurred at mean TAC whole blood concentrations ⬎10 ng/mL, while serious adverse events that required change in maintenance immunosuppression occurred at mean TAC whole blood concentrations ⱖ13 ng/mL of sirolimus.5,6 Because SRL whole blood concentrations were not different between these groups of patients experiencing serious and mild adverse events, these observations have suggested to us that in addition to lowering therapeutic concentration thresholds, the synergy between SRL and TAC may also lower toxicity thresholds for each agent. This was also apparent in pivotal phase III trials in which the addition of SRL to full-dose cyclosporine (CsA) resulted in greater nephrotoxicity than if CsA was used without SRL.8,9 This is somewhat contrary to the notion that combination therapy using two agents with nonoverlapping toxicity profiles may allow lower and therefore nontoxic amounts of each agent to be used together. At the very least, these experiences argue for drastically lower amounts of CsA and TAC in the presence of SRL, a fact that was confirmed by pharmacodynamic analysis of combination therapy effects in mitogen-stimulated response of human lymphocytes in our laboratory.10,11 Implications for the design and conduct of future evaluations are the use of longitudinal crossover designs in which CI can be eliminated altogether12 or a direct parallel group comparison in which SRL can truly be evaluated for efficacy relative to the standard of care. These two strategies of administration have relevance for the breadth of indications
SINDHI
for which SRL has and is likely to find utility in clinical transplantation. They may also help us realize the significantly greater safety margin of SRL that is hinted at in our clinical studies with this agent but which cannot be fully realized in evaluation strategies in which SRL, like its antiproliferative predecessors mycophenolate mofetil and azathioprine, receives adjunctive status to the best-known therapy—the calcineurin inhibitors. For these reasons, we believe that to relegate promising non-CI drugs such as SRL to secondary status on the basis of flawed conventional clinical trial designs is to deny the transplant recipient population of a much needed alternative with the greatest potential safety margin of any agent to date. DISCLOSURE
Rakesh Sindhi is Principal Investigator of four investigatorinitated protocols from which these data have been collected. These protocols, all of which have been approved by the Human Rights Committee of the Children’s Hospital, are: 1. 99-088-Research Advisory Committee, Children’s Hospital of Pittsburgh 2. RO1AI49156-02-National Institutes of Health, National Institute of Allergy and Infectious Diseases. 3. 0468-100295-partially supported by Institutional NIH award # MO1 RR00084 to the Children’s Hospital of Pittsburgh, and Wyeth-Ayerst Pharmaceuticals, St. David, PA. 5. IND 64555-supported by Institutional NIH award # MO1 RR00084 to the Children’s Hospital of Pittsburgh. REFERENCES 1. Sudan DL, Shaw BW Jr, Langnas AN: Ann Surg 227:289, 1998 2. Fridell JA, Jain A, Reyes J, et al: Transplantation 74:1721, 2002 3. Jain A, Reyes J, Kashyap R, et al: Transplant Proc 30:1403, 1998 4. Reyes J, Jain A, Mazariegos G, et al: Transplantation 69:2573, 2000 5. Sindhi R, Webber S, Venkataramanan R, et al: Transplantation 72:851, 2001 6. Sindhi R, Webber S, Goyal R, et al: Transplant Proc 34:1960, 2002 7. Sindhi R, Ganjoo J, McGhee W, et al: Transplant Proc 34:1972, 2002 8. MacDonald A: Transplantation 71:271, 2001 9. Kahan BD: Lancet 356:194, 2000 10. Sindhi R, LaVia MF, Paulling E, et al: Transplantation 69:432, 2000 11. Sindhi R, Allaert J, Gladding D, et al: J Immunol Meth 272:257, 2003 12. Johnson RW, Kreis H, Oberbauer R, et al: Transplantation 72:777, 2001