Anti-CD25 Antibody (Daclizumab) Maintenance Therapy in Pancreas Transplantation

Anti-CD25 Antibody (Daclizumab) Maintenance Therapy in Pancreas Transplantation V.A. Kirchner, T.M. Suszynski, D.M. Radosevich, A. Humar, T.B. Dunn, M.J. Hill, E.B. Finger, D.E.R. Sutherland, and R. Kandaswamy ABSTRACT Background. Calcineurin inhibitors (CNI) are the basis of contemporary immunosuppression in clinical pancreas transplantation (PT). Nevertheless, CNI toxicities, especially nephrotoxicity, have stimulated the search for CNI-sparing protocols. We performed a retrospective analysis of 25 PT patients with progressive CNI toxicities that were switched to a daclizumab (DAC)– based maintenance regimen. Methods. From 2003 to 2007, 25 PT patients with progressive CNI toxicity (predominantly nephrotoxicity) were identified and switched from CNI to monthly DAC maintenance therapy. The DAC group was compared with matched control subjects (1:1) by transplant type and number, age, year of transplant, and duct management. Results and conclusions. Results showed improved graft survival rates and decreased immunologic loss rates at 1, 3, and 5 years in the DAC group compared with the control group. There was no difference in patient survival rate between the 2 groups. Analysis demonstrates that DAC maintenance therapy is safe and effective for PT patients experiencing CNI toxicities. A randomized trial to compare DAC- and CNI-based regimens is needed in CNI-intolerant patients, with particular attention to the impact on renal function and patient morbidity (eg, infection rates). alcineurin inhibitors (CNIs) have been the mainstay immunosuppression (IS) therapy in solid organ transplantation throughout the past 20 years.1,2 Their use has decreased the risk of acute rejection and improved shortterm transplant outcomes.2,3 Nevertheless, CNIs are associated with nephrotoxicity, hypertension, neurotoxicity, and glucose intolerance.2– 4 Because chronic renal failure is accompanied by significant morbidity and mortality in transplant patients,3,5 the primary effort is directed toward CNI-sparing strategies to prevent progressive nephrotoxicity. Alternative regimens use mycophenolate mofetil (MMF) or sirolimus (SIR) to limit the dose of CNIs. Unfortunately, the persistent exposure to even low-dose CNIs contributes to cumulative renal damage and subsequent dysfunction in some patients. The combination of MMF and SIR to avoid de novo CNI exposure showed improved renal function in several renal transplantation studies.3 Nevertheless, SIRassociated delayed graft function, impaired wound healing, and other related complications have made these regimens less attractive.3 Additionally, the CNI-free maintenance therapy in combination with rapid steroid withdrawal has

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been associated with higher incidence of acute rejection in pancreas transplant (PT) patients.6 In the past decade, a humanized monoclonal anti– interleukin-2 receptor antibody, daclizumab (DAC), has been used with considerable success for induction IS in solid organ transplantation.7,8 In fact, compared with placebo, DAC induction therapy does not appear to result in additional posttransplantation complications and is not associated with adverse reactions.9,10 Recently, DAC-based maintenance therapy with minimization or avoidance of CNIs was reported after liver,11 kidney,12,13 and pancreatic islet14 transplantation. However, to our knowledge, no

From the Schulze Diabetes Institute (V.A.K., T.M.S., D.E.R.S., R.K.), Department of Surgery (V.A.K., T.M.S., D.M.R., A.H., T.B.D., M.J.H., E.B.F., D.E.R.S., R.K.), University of Minnesota, Minneapolis, Minnesota. Address reprint requests to Dr. R. Kandaswamy, MD, Department of Surgery, 420 Delaware St SE, MMC 195 (8195), University of Minnesota, Minneapolis, MN 55455. E-mail: kanda003@ umn.edu

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0041-1345/–see front matter doi:10.1016/j.transproceed.2010.05.083

Transplantation Proceedings, 42, 2003–2005 (2010)

2003

2004

KIRCHNER, SUSZYNSKI, RADOSEVICH ET AL

reports have been published regarding DAC maintenance IS in PT patients. Our group performed a retrospective analysis of 25 PT patients with progressive CNI-related nephrotoxicity, neurotoxicity, glucose intolerance, or a combination of these. These patients were switched to a DAC-based maintenance regimen. The safety and efficacy of this therapy was compared, in paired fashion, with a CNI-based maintenance IS that was administered in control subjects. MATERIALS AND METHODS Between 2003 and 2007, 25 PT patients with progressive CNI toxicity, predominantly nephrotoxicity of the native or transplanted kidneys (as manifested by a rise in creatinine and biopsy negative for rejection with CNI lesions), were identified. This cohort was started on monthly intravenous DAC maintenance therapy (ie, first dose of 2 mg/kg, followed by 1 mg/kg) in combination with MMF (at 2 g/d) or SIR (with trough blood levels of 6 – 8 ng/mL) as the sole oral agent. All patients were kept on corticosteroid-free IS. Patients receiving DAC maintenance were compared with an equal number of control subjects (n ⫽ 25), matched 1:1 by transplant type (ie, PT alone [PTA], pancreas after kidney [PAK], or simultaneous pancreas-kidney [SPK]) and number, age (within 5 y), year of transplant, and type of duct management (ie, bladder-drained, enterically drained, or other). SPK recipients were enterically drained and PTA recipients were bladder-drained, in accordance with our transplant center protocol. The patients were not matched for renal function, number of previous rejection episodes, or their sole oral immunosuppressant (whether MMF or SIR). Each group had 11 patients with first PT, 11 with second PT, and 3 with third PT. Ten patients were PTA, 13 were PAK, and 2 were SPK recipients. Mean age was 42 ⫾ 10 and 42 ⫾ 8 years in the DAC and control groups, respectively, with 13 women and 12 men in each group. Patient survival rate (PSR), graft survival rate (GSR), and immunologic loss rate (ILR) were calculated by the Kaplan-Meier method. Death with a functioning graft (DWFG) was counted as a graft failure. For the ILR, DWFG was censored. Table 1 summarizes matched characteristics in the 2 patient cohorts, except for the year of transplant and type of drainage.

RESULTS

The GSR at 1, 3, and 5 years, respectively, was 88%, 79%, and 60% in the DAC group and 67%, 44%, and 44% in the control group (P values .06, .01, and .05, respectively). The ILR at 1, 3, and 5 years, respectively, was 8%, 17%, and Table 1. Transplant Recipient Demographics Matched Characteristic

Mean age (y) Transplant No. 1st 2nd 3rd Transplant type PTA PAK SPK

42 ⫾ 10 (DAC), 42 ⫾ 8 (Control) 11 11 3 10 13 2

Abbreviations: DAC, daclizumab; PTA, pancreas transplant alone; PAK, pancreas after kidney; SPK, simultaneous pancreas-kidney.

Table 2. GSR, ILR, and PSR Results at 1, 3, and 5 Years

GSR (%) DAC Control ILR (%) DAC Control PSR (%) DAC Control

1y

3y

5y

88 67

79 44

60 44

8 28

17 53

22 53

96 92

96 86

80 74

Abbreviations: GSR, graft survival rate; ILR, immunologic loss rate; PSR, patient survival rate; DAC, daclizumab.

22% in the DAC group and 28%, 53%, and 53% in the control group (P values .05, .01, and .02 respectively). The PSR at 1, 3, and 5 years, respectively, was 96%, 96%, and 80% in the DAC group and 92%, 86%, and 74% in the control group (P values .5, .2, and .3, respectively). Results are summarized in Table 2. DISCUSSION

Maintenance therapy with humanized monoclonal anti– interleukin-2 receptor antibodies appears to be safe, effective, and well tolerated by PT patients. Retrospective chart review revealed similar PSRs between DAC and control patients at 1, 3, and 5 years after transplantation. However, the DAC cohort had significantly higher GSR and lower ILR compared with the control group. Experiences with longer-term or bridge DAC therapy in liver,11 kidney,12,13 and pancreatic islet14 transplantation have been described. Extended DAC induction has also been used safely in the pediatric population, albeit in the presence of tacrolimus (TAC).15 Post et al11 recently reported that a low-dose DAC regimen after liver transplantation improved creatinine levels and clearance in patients experiencing pretransplant renal dysfunction (eg, due to hepatorenal syndrome). Chaudhuri et al12 described 2 cases in which monthly DAC administration was successfully used as a monotherapy for extended periods of time (ie, up to 1 y) and prevented acute rejection in renal allograft recipients. Other sources have reported that DAC therapy has been shown to reduce the frequency of acute renal allograft rejection,9,16 which may decrease the risk of chronic graft failure.17,18 Furthermore, in the past year, Kaplan et al14 presented an interesting case report describing an adjustment of maintenance IS from the Edmonton Protocol to low-dose tacrolimus, MMF, and monthly injections of DAC in an islet transplant recipient suffering from numerous complications, including renal dysfunction. The renal function and the overall complication profile of the patient had improved without any measurable effect on islet graft function. Further studies are needed for evaluation of DAC as a maintenance therapy in PT, because it appears to be safe and shows promise in preventing acute rejection episodes in solid organ recipients.7,11–13 Extended DAC administration may benefit transplant patients with certain drug intoler-

DACLIZUMAB AFTER PANCREAS TRANSPLANTATION

ances, because DAC does not appear to contribute appreciably to the development of adverse clinical events and is not associated with significant toxicity.10 Additionally, longterm DAC administration may decrease acute graft rejection rates over conventional IS. With PT, in particular, reducing or eliminating CNIs from the immunosuppressive regimen may actually improve the endocrine function of the graft. Several studies provide evidence that CNIs impair insulin transcription and secretion by pancreatic ␤ cells.19 –23 Interestingly, corticosteroid-free IS has been established in an attempt to prevent posttransplantation hyperglycemia, yet there is evidence that the 2 mainstay replacements, TAC and SIR, may induce insulin resistance.24 Very little is known about the long-term risks of DAC therapy regarding bacterial, viral, and fungal infections or lymphoproliferative or otherwise neoplastic disorders. CNIs have been shown to promote cancer progression by a transforming growth factor ␤–mediated signaling mechanism and to enhance tumor growth in immunodeficient mice.25 In the present study, none of the patients developed posttransplantation lymphoproliferative disorder. It is important to note that cytomegalovirus, Epstein-Barr virus, and BK virus antibody titers were not studied during this retrospective analysis. A prospective, randomized, controlled study needs to be performed to elucidate the safety and efficacy of DAC maintenance within the context of PT. The obvious weaknesses of this study include the small number of subjects, the matched control subjects being only 1:1 (eg, 1:2 or 1:3 may provide a better method of control), and the lack of a method to accurately quantify the degree of CNI toxicity (eg, elevated creatinine values over baseline) as an additional and important point of comparison. This study did not allow us to monitor changes in the CNI toxicity profile in PT recipients after a switch to DAC maintenance. In conclusion, DAC maintenance IS therapy appears to be safe, well tolerated, and effective in preventing acute pancreatic graft rejection among selected patients in the face of steroid avoidance. Despite these results, many issues still need to be addressed, starting with timing of CNI withdrawal, impact of DAC on renal function, and the potential need of additional induction therapies. REFERENCES 1. Singh R, Stratta R: Advances in immunosuppression for pancreas transplantation. Curr Opin Organ Transplant 13:79, 2008 2. Baczkowska T, Durlik M: Calcineurin inhibitor sparing immunosuppressive regimens in kidney allograft recipients. Pol Arch Med Wewn 119:318, 2009 3. Flechner S, Kobashigawa J, Klintmalm G: Calcineurin inhibitor–sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant 22: 1–15, 2008 4. Kaczmarek I, Schmauss D, Sodian R, et al: Late-onset tacrolimus-associated cerebellar atrophy in a heart transplant recipient. J Heart Lung Transplant 26:89, 2007 5. Ojo, A, Held P, Port F, et al: Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 349:931, 2003

2005 6. Ekberg H, Tedesco-Silva H, Demirbas A, et al: SYMPHONY: comparing standard immunosuppression to low-dose cyclosporine, tacrolimus, or sirolimus in combination with MMF, daclizumab and corticosteroids in renal transplantation. Am J Transplant 6(suppl 2):83, 2006 7. Sageshima J, Ciancio G, Chen L, et al: Anti–interleukin-2 receptor antibodies— basiliximab and daclizumab—for the prevention of acute rejection in renal transplantation. Biologics 3:319, 2009 8. Bruce D, Sollinger H, Humar A, et al: Multicenter survey of daclizumab induction in simultaneous kidney-pancreas transplant recipients. Transplantation 72:1637, 2001 9. Vincenti F, Kirkman R, Light S, et al: Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 338:161, 1998 10. Webster A, Playford E, Higgins G, et al: Interleukin-2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation 77:166, 2004 11. Post M, Raszeja-Wyszomirska J, Jarosz K, et al: Immunosuppression with low-dose daclizumab in liver transplant recipients with impaired kidney function: a single-center experience. Transplant Proc 41, pp. 3107, 2009 12. Chaudhuri A, Salvatierra O, Sarwal M, et al: Extended daclizumab monotherapy for rejection-free survival in non-adherent adolescent recipients of renal allograft. Pediatr Transplant 13:927, 2009 13. Sundberg A, Rohr M, Hartmann E, et al: Conversion to sirolimus-based maintenance immunosuppression using daclizumab bridge therapy in renal transplant recipients. Clin Transplant 18(suppl 12):61, 2004 14. Kaplan B, West P, Neeley H, et al: Case report: use of low dose tacrolimus, mycophenolate mofetil and maintenance IL-2 receptor blockade in an islet transplant recipient. Clin Transplant 22:250, 2008 15. Sarwal M, Vidhun J, Alexander S, et al: Continued superior outcomes with modification and lengthened follow-up of a steroidavoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation 76:1331, 2003 16. Nashan B, Light S, Hardie I, et al: Reduction of acute renal allograft rejection by daclizumab. Transplantation 67:110, 1999 17. Tesi R, Henry M, Elkammas E, et al: Predictors of long-term primary cadaveric renal transplant survival. Clin Transplant 7:345, 1993 18. Matas A, “Chronic rejection in renal transplant recipients: risk factors and correlates. Clin Transplant 8:332, 1994 19. Filler G, Neuschulz I, Vollmer I, et al: Tacrolimus reversibly reduces insulin secretion in paediatric renal transplant recipients. Nephrol Dial Transplant 15:867, 2000 20. Tamura K, Fujimura T, Tsutsumi T, et al: Transcriptional inhibition of insulin by FK506 and possible involvement of FK506 binding protein-12 in pancreatic beta-cell. Transplantation 59:1606, 1995 21. Hirano Y, Fujihura S, Ohara K, et al: Mechanism of FK506-induced glucose intolerance in rats. J Toxicol Sci 19:61, 1994 22. Neto A, Haapalainen E, Ferreira R, et al: Metabolic and ultrastructural effects of cyclosporin A on pancreatic islets. Transplant Int 12:208, 1999 23. Uchizono Y, Iwase M, Nakamura U, et al: Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling. Endocrinology 145:2264, 2004 24. Larsen J, Bennett R, Burkman T, et al: Tacrolimus and sirolimus cause insulin resistance in normal Sprague Dawley rats. Transplantation 82:466, 2006 25. Hojo M, Morimoto T, Maluccio M, et al: Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397:530, 1999