Public Statement: Medical Policy Statement: Medical Policy Title: Transplant, Allogeneic, Islet Cell or Pancreas for Diabetes Mellitus

Transcription

1 ARBenefits Approval: 02/08/2012 Effective Date: 01/01/2013 Revision Date: 01/15/2014 Medical Policy Title: Transplant, Allogeneic, Islet Cell or Pancreas for Diabetes Mellitus Document: ARB0387:02 Administered by: Public Statement: The object of pancreas transplantation is to improve the life of the patient by making them insulin-independent, thus reducing the risks of complications from diabetes mellitus. Pancreas transplant may be done simultaneously with kidney transplant for those patients who also are uremic, may be done after a period of time following a kidney transplant, or may be done unrelated to a kidney transplant. The transplanted pancreatic tissue may come from a cadaver or a living donor. Pancreas transplantation is considered to be an effective therapy for diabetes mellitus, and the potential complications from the surgery and risks of immunosuppression therapy are felt to be outweighed by the benefit of the transplant, although it is unknown if the mortality rate following transplantation is less than that inherent in a population of patients with 20 or more years of chronic diabetes who have extreme swings in glycemia, overt diabetic complications, and poor quality of life. This procedure requires authorization through case management by American Health Holding at (option 2). Medical Policy Statement: Pancreas transplantation is considered medically necessary and is covered in insulin dependent diabetic patients with imminent or established end-stage renal disease who have had or plan to have a kidney transplant, because the successful addition of a pancreas does not jeopardize patient survival, may improve kidney survival, and will restore normal glycemia. Such patients also must meet the medical indications and criteria for kidney transplantation and not have excessive surgical risk for the dual transplant procedure. The pancreas transplant may be done simultaneous with, or subsequent to, a kidney transplant. In the absence of indications for kidney transplantation, pancreas transplantation is only covered for patients who meet the following three criteria: Page 1 of 11

2 o o o A history of frequent, acute, and severe metabolic complications (hypoglycemia, hyperglycemia, ketoacidosis) requiring medical attention and documented in medical records; Clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; and Consistent failure of insulin-based management to prevent acute complications. Limits: Pancreas retransplant following a failed primary transplant is covered one time only, as there is no information available that more than one transplant attempt following the primary transplant is successful. Pancreatic islet cell transplants are considered investigational when done as an allogeneic transplant for a patient with diabetes mellitus. Background: Pancreas After Kidney (PAK) Transplant Based on current pancreas transplant registry data, at nearly 3 years, 64% of transplant recipients have a functioning pancreas compared to 77% among recipients of simultaneous pancreas and kidney transplants. PAK transplantation allows the uremic patient the benefits of a living-related kidney graft, if available, and the benefits of a subsequent pancreas transplant that is likely to result in improved quality of life compared to a kidney transplant alone. Uremic patients for whom a cadaveric kidney graft is available but a pancreas graft is not simultaneously available benefit similarly from a later pancreas transplant. Pancreas Transplant Alone (PTA) PTA graft survival has improved in recent years; available data suggest that 60% of grafts are functioning at 2 years, with potential insulin independence. In carefully selected IDDM patients with severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and labile diabetes that persists despite optimal medical management, the benefits of PTA were judged to outweigh the risk of performing pancreas transplantation with subsequent immunosuppression. The majority of patients undergoing PTA are those with either hypoglycemic unawareness or labile diabetes. However, other exceptional circumstances may exist where nonuremic IDDM patients have significant morbidity risks due to secondary complications of diabetes (i.e., peripheral neuropathy) that exceed those of the transplant surgery and subsequent chronic immunosuppression. Because there is virtually no published evidence regarding outcomes of medical management in this very small group of exceptional diabetic patients, it is not possible to generalize about which circumstances represent appropriate indications for pancreas transplantation alone. Case-by-case Page 2 of 11

3 consideration of each patient s clinical situation may be the best option for determining the balance of risks and benefits. Pancreas Retransplantation For all three types of pancreas transplant (i.e., pancreas transplant alone, simultaneous pancreas kidney transplant, and pancreas after kidney transplant), the survival of a second pancreas transplant was lower than for the primary transplant of the same type. However, patients receiving second pancreas transplants have a good chance of remaining insulin-independent for 3 years or more. There are inadequate data to permit scientific conclusion regarding the health outcomes associated with third or subsequent pancreas transplants. Islet Cell Transplantation Allogeneic islet cell transplantation to treat type 1 diabetes has been investigated for over 20 years. Allograft survival had been universally poor until A.M.J. Shapiro at the University of Alberta in Edmonton, Canada, developed what is now called the Edmonton Protocol. An international multi-center trial using that protocol in 36 patients (out of 2000 screened for eligibility) reported that 1) 44% of patients attained the stringent primary end point of insulin independence (defined as a glycated hemoglobin value of less than 6.5%, a glucose level after an overnight fast not exceeding 140 mg/dl more than 3 times per week, and a 2-hour postprandial glucose level not exceeding 180 mg/dl more than 4 times a week); 2) 28% of patients had partial graft function; 3) and 28% had complete graft loss. Unfortunately, 76% became insulin dependent again by 2 years after transplantation. Only 10% of another 65 patients transplanted by the Edmonton group with the same protocol have maintained insulin independence after 5 years. The American Diabetes Association has provided the following recommendation regarding islet cell transplants: "Pancreatic islet transplants hold significant potential advantages over whole-gland transplants. Recent strides have been made in improving the success rates of this procedure. However, at this time, islet transplantation is a rapidly evolving technology that also requires systemic immunosuppression and should be performed only within the setting of controlled research studies." Clinical trials on the effectiveness of allogeneic islet cell transplants are ongoing. Changes to the pancreas and kidney allocation system in 2010 may positively affect the availability of both organs for simultaneous kidney/pancreas transplant and therefore reduce the need for pancreas after kidney transplant considerations in diabetic uremic patients. The inferior graft survival rate in PAK, however, may be improved with current immunosuppressive regimens. In 2009, Fridell and colleagues reported a retrospective review (n=203) of a single center s experience with PAK and SPK since 2003, when current induction/tacrolimus immunosuppressive strategies became standard (Fridell, 2009). Of the cases studied, 61 (30%) were PAK and 142 (70%) were SPK. One-year patient survival rates were 98% and 95% (PAK and SPK, respectively; p=0.44). Pancreas graft survival rates at one year were observed to be 95% and 90%, Page 3 of 11

4 respectively (p=0.28). The authors conclude that in the modern immunosuppressive era, PAK should be considered as an acceptable alternative to SPK in candidates with an available living kidney donor. Data that suggest that SPK transplants have a higher overall graft survival rate than PAK, including kidney graft survival, has led to the question of whether kidney transplant alone (KTA) is superior to PAK. In 2009, Kleinclauss and colleagues retrospectively examined data from diabetic kidney transplant recipients (n=307) from a single center and compared renal graft survival rates in those who subsequently received a pancreatic transplant to those who did not (Kleinclauss, 2009). The comparative group was analyzed separately depending on whether they were medically eligible (KTA-E) for pancreas transplant, but chose not to proceed for financial or personal reasons, or were ineligible (KTA-I) for medical reasons. The KTA-I (n=57) group differed significantly at baseline from both the PAK group (n=175) and the KTA-E group (n=75) with respect to age, type of diabetes and dialysis experience; kidney graft survival rates were lower than either of the other groups, with one, five and 10-years rates of 75%, 54% and 22%, respectively (p<0.0001). The PAK and KTA-E groups were similar in age, race, type of diabetes, and dialysis experience. The authors compared one-, five- and ten-year kidney graft survival rates in PAK patients with those in the KTA-E group: 98%, 82% and 67% versus 100%, 84% and 62%, respectively, and concluded that the subsequent transplant of a pancreas after a living donor kidney transplant does not adversely affect patient or kidney graft survival rates. The Pancreas Allotransplantation for Diabetic Nephropathy and Mild Chronic REnal failure Stage (PANCREAS) Study (NCT ) is currently recruiting participants at Nantes University in France. The stated objective of the study is to assess the superiority of isolated pancreas transplant to intensive insulin therapy in Type 1 diabetes patients with overt proteinuric nephropathy and mildly reduced renal function. This is to be an open-label, randomized trial. The primary combined endpoint is to be patient mortality and renal function impairment at five years. Secondary endpoints measuring safety and extrarenal diabetic complications are planned. If completed, this would represent the first RCT comparing pancreas transplant to insulin therapy. In 2010, Mora and colleagues described the long-term outcome of 12 patients 15 years following simultaneous pancreas/kidney transplant (Mora, 2010). Metabolic measures of glucose control were measured at one, five, ten and 15 years following the procedure. Of this subset of patients, six (50%) had non-diabetic glucose challenge tests. Basal serum insulin levels declined over this period as well, from 24 mu/l to 16 mu/l at one and 15 years, respectively. The authors conclude that in a select group of patients whose pancreatic graft continued to function after 15 years, some glycemic control continued, albeit in a diminished fashion. It should be noted that this represents a small fraction of the 367 patients receiving the simultaneous pancreas/kidney transplant at this single center (12 of 367 SPK; 3.3%). The number of allograft survivals at five or more, and 10 or more years in this study was 43 (11.7%) and 28 (7.6%), respectively. Page 4 of 11

5 In 2009, Isla Pera and colleagues described the results of an observational quality of life (QoL) study in Spanish patients following SPK transplant (Isla Pera, 2009). Data on quality of life is particularly important in this patient population, due to the fact that alternatives to transplant exist, and quality of life post-transplant must be balanced by the harms introduced by lifelong immunosuppressive therapy. The Short Form health Survey 36-Item (SF-36) was administered to 69 SPK transplant recipients and 34 patients with Type 1 diabetes on hemodialysis. They also compared the transplant QoL results to a reference Spanish population. The authors attempted to control for group differences with multivariate analysis on variables of age, sex, and years duration of diabetes diagnosis. While SPK patients had lower QoL compared to the reference population across all eight domains of physical and mental well-being, they had a statistically significant higher score across these same domains in comparison to diabetic patients on dialysis. No aggregate measures were reported. Findings in a healthcare system outside the United States may not apply to U.S. populations. Codes Used in This Policy: Pancreatectomy, total or subtotal, with autologous transplantation of pancreas or pancreatic islet cells G0341 Percutaneous islet cell transplant, includes portal vein catheterization and infusion G0342 Laparoscopy for islet cell transplant, includes portal vein catheterization and infusion G0343 Laparotomy for islet cell transplant, includes portal vein catheterization and infusion References: Adang EM, Engel GL, van Hooff JP, et al.(1996) Comparison before and after transplantation of pancreas kidney and pancreas-kidney with loss of pancreas a prospective controlled quality of life study. Transplantation 1996; 62: Allen RD, Al-Harbi IS, Morris JG, et al.(1997) Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation 1997; 63: Andersson DKG, et al.(1993) Implications of the Diabetes Control and Complications. Trial American Diabetes Association. Diabetes Care 1993; 16: Bartlett ST, Schweitzer EJ, Johnson LB, et al.(1996) Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. Ann Surg 1996; 224: Page 5 of 11

6 Basadonna GP, Arrazola L, Matas AJ, et al.(1993) Morbidity, mortality, and long-term allograft function in kidney transplantation alone and simultaneous pancreas kidney in diabetic patients. Trans Proc 1993; 25: Benedetti E, Gruessner AC, Troppmann C, et al.(1996) Intra-abdominal fungal infections after pancreatic transplantation: Incidence, treatment, and outcome. J Am Col Surg 1996; 183: Bromberg JS, LeRoth D.(2006) Diabetes cure - Is the glass half full? New Engl J Med, 2006; 355: Caldara R, Bandello F, Vigano C, et al.(1994) Influence of successful pancreaticorenal transplantation on diabetic retinopathy. Trans Proc 1994; 26:490. Cheung AHS, Matas AJ, Gruessner RG, et al.(1993) Should uremic diabetic patients who want a pancreas transplant receive a simultaneous cadaver kidney-pancreas transplant or a pancreas transplant? Trans Proc 1993; 25: Cheung AHS, Sutherland DER, Dunn DL, et al.(1992) Morbidity following simultaneous pancreas-kidney transplants vs kidney transplants alone in diabetic patients. Trans Proc 1992; 24: Clinical Trial Registry of the U. S. National Institutes of Health. Pancreas Allotransplantation for Diabetic Nephropathy and Mild Chronic REnal failure Stage (PANCREAS) trial. Available online at: Last accessed January 26, Cranston I, Lomas J, Maran A, et al.(1994) Restoration of hypoglycemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 1994; 344: Dagogo-Jack S, Rattarasarn C, Cryer PE.(1994) Reversal of hypoglycemia unawareness, but not defective glucose counter regulation, in IDDM. Diabetes 1994; 43: Eisenbarth GS, Stegall M.(1996) Islet and pancreatic transplantation autoimmunity and alloimmunity. NEJM 1996; 335: [Editorial]. Ericzon BG, Groth CG, Bismuth A, et al.(1994) Glucose metabolism in liver transplant recipients treated with FK 506 or cyclosporin in the European multicenter study. Trans Int 1994; 7(sup 1): Fioretto P, Mauer SM, Bilous RW, et al.(1993) Effects of pancreas transplantation on glomerular structure in insulin dependent diabetic patients with their own kidneys. Lancet 1993; 342: Page 6 of 11

7 Fioretto P, Steffes MW, Mihatsch MJ, et al.(1995) Cyclosporine associated lesions in native kidneys of diabetic pancreas transplant recipients. Kidney Int 1995; 48: Foger B, Konigsrainer A, Palos G, et al.(1994) Effect of pancreas transplantation on lipoprotein lipase, postprandial lipemia, and HDL cholesterol. Transplantation 1994; 58: Fridell JA, Mangus RS, Hollinger EF et al.(2009) The case for pancreas after kidney transplantation. Clin Transplant 2009; 23(4): Gaber AO, El-Gebely S, Sugathan P, et al.(1995) Changes in cardiac function of Type I diabetics following pancreas-kidney and kidney-alone transplantation. Trans Proc 1995; 27: Gaber AO, Hathaway DK, Abell T, et al.(1994) Improved autonomic and gastric function in pancreas kidney vs kidney-alone transplantation contributes to quality of life. Trans Proc 1994; 26: Gross CR, Zehrer CL.(1993) Impact of the addition of a pancreas to quality of life in uremic diabetic recipients of kidney transplants. Trans Proc 1993; 25: Gruessner A, Gruessner R, Moudry-Munns K, et al.(1993) Influence of multiple factors (age, transplant number, recipient category, donor source) on outcome of pancreas transplantation at one institution. Trans Proc 1993; 25: Gruessner RW, Sutherland DE, Gruessner RW.(1997) Solitary pancreas transplants: improving results and factors that influence outcome. Trans Proc 1997; 29: Gruessner RW, Sutherland DE, Troppmann C, et al.(1997) The surgical risk of pancreas transplantation in the cyclosporine era: An overview. J Am Col Surg 1997; 185: Gruessner RW.(1997) Tacrolimus in pancreas transplantation: a multicenter analysis. Clin Trans 1997; 11: Hariharan S, Peddi VR, Munda R, et al.(1997) Long term renal and pancreas function with tacrolimus rescue therapy following kidney/pancreas transplantation. Trans Proc 1997; 29: Hathaway D, Abell T, Cardoso S, et al.(1993) Improvement in autonomic function following pancreas-kidney versus kidney-alone transplantation. Trans Proc 1993; 25: Hathaway DK, Hartwig MS, Milstead J, et al.(1994) Improvement in quality of life reported by diabetic recipients of kidney-only and pancreas-kidney allografts. Trans Proc 1994; 26: Page 7 of 11

8 Henley SE, Larsen JL, Mack-Shipman L, et al.(1995) Lipids following pancreas transplantation in recipients receiving FK 506. Trans Proc 1995; 27:2997. Hickey DP, Bakthavatsalam R, Bannon CA, et al.(1997) Urological complications of pancreatic transplantation. J Urol 1997; 157: Hricik DE, Phinney MS, Weigel KA, et al.(1997) Long term renal function in Type I diabetics after kidney or kidney-pancreas transplantation. Transplantation 1997; 64: Hughes TA, Gaber O, Amiri HS, et al.(1994) Lipoprotein composition in insulindependent diabetes mellitus with chronic renal failure: Effect of kidney and pancreas transplantation. Metabolism 1994; 43: Isla Pera P, Moncho Vasallo J, Torras Rabasa A et al.(2009) Quality of life in simultaneous pancreas-kidney transplant recipients. Clin Transplant 2009; 23(5): Katz HH, Nguyen TT, Velosa JA, et al.(1994) Effects of systemic delivery of insulin on plasma lipids and lipoprotein concentrations in pancreas transplant recipients. Mayo Clin Proc 1994; 29: Kendall DM, Rooney DP, Smets YFC, et al.(1997) Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 1997; 46: Ketel BL, Turton-Weeks S, Reed K, et al.(1996) Tacrolimus-based vs cyclosporinebased immunotherapy in combined kidney-pancreas transplantation. Trans Proc 1996; 28:899. Kiebert GM, van Oosterhout EC, van Bronswijk H, et al.(1994) Quality of life after combined kidney-pancreas or kidney transplantation in diabetic patients with end-stage renal disease. Clin Trans 1994; 8: Kleinclauss F, Fauda M, Sutherland DE et al.(2009) Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transplant 2009; 23(4): Laftavi MR, Chapuis F, Vial C, et al.(1995) Diabetic polyneuropathy outcome after successful pancreas transplantation: 1 to 9 year follow up. Trans Proc 1995; 27: Landgraf R.(1996) Impact of pancreas transplantation on diabetic secondary complications and quality of life. Diabetologia 1996; 39: Larsen JL, Stratta RJ.(1996) Pancreas transplantation: A treatment option for insulindependent diabetes mellitus. Diabetes Metab 1996; 22: Page 8 of 11

9 Lenisa L, Castoldi R, Socci C, et al.(1995) Cost-effective treatment for diabetic endstage renal disease: Dialysis, kidney, or kidney-pancreas transplantation. Trans Proc 1995; 27: Milde FK, Hart LK, Zehr PS.(1992) Quality of life of pancreatic transplant recipients. Diabetes Care 1992; 15: Mora M, Ricart MJ, Casamitjana R et al.(2010) Pancreas and kidney transplantation: long-term endocrine function. Clin Transplant 2010; 24(6):E Morrissey PE, Shaffer D, Madras PN, et al.(1997) Progression of peripheral vascular disease after combined kidney-pancreas transplantation in diabetic patients with endstage renal failure. Trans Proc 1997; 29: Moudry-Munns KC, Gruessner A, Sutherland DER.(1993) Analysis of United States Pancreas Transplant Registry data. Clin Trans Nakache R, Tyden G, Groth CG.(1994) Long-term quality of life in diabetic patients after combined pancreas- kidney transplantation or kidney transplantation. Trans Proc 1994; 26: Nankivell BJ, Chapman JR, Bovington KJ, et al.(1996) Clinical determinants of glucose homeostasis after pancreas transplantation. Transplantation 1996; 61: Navarro X, Sutherland DE, Kennedy WR.(1997) Long term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 1997; 42: Pancreas Retransplantation Blue Cross Blue Shield Association Technology Evaluation Center Assessment. Pancreas Transplantation Blue Cross Blue Shield Association Technology Evaluation Center Assessment. Papalois BE, Troppmann C, Gruessner AC, et al.(1996) Long-term peritoneal dialysis before transplantation and intra-abdominal infection after simultaneous pancreas kidney transplantations. Arch Surg 1996; 131: Pelletier RP, Elkhammas EA, Henry ML, et al.(1996) Update on the status of pancreaskidney transplantation. Curr Opin Nephrol Hypertens 1996; 5: Piehlmeier W, Bullinger M, Kirchberger I, et al.(1994) Prospective study of the quality of life in Type I diabetic patients before and after organ transplantation. Trans Proc 1994; 26: Pirsch JD, Andrews C, Hricik DE, et al.(1996) Pancreas transplantation for diabetes mellitus. Am J Kidney Dis 1996; 27: Page 9 of 11

10 Roberson RP, Latsen J, Davis C, et al.(2001) Pancreas transplantation for patients with type 1 diabetes. American Diabetes Association: Clinical Practice Recommendations. Diabetes Care 2001; 24 (sup 1). Robertson RP, Davis C, Larsen J, et al.(2000) Pancreas and islet transplantation for patients with diabetes mellitus. Diabetes Care 2000; 23: Robertson RP, Sutherland DE, Kendall DM, et al.(1996) Metabolic characterization of long-term successful pancreas transplants in Type I diabetes. J Invest Med 1996; 44: Ryan EA, Paty BW, Senior PA, et al.(2005) Five year follow-up after clinical islet transplantation. Diabetes, 2005; 54: Schulack JA, Mayes JT, Hricik DE.(1992) Kidney transplantation in diabetic patients undergoing combined kidney-pancreas or kidney-only transplantation. Transplantation 1992; 53: Shapiro AJM, Ricordi C, Hering BJ, et al.(2006) International trial of the Edmonton protocol for islet transplantation. New Engl J Med, 2006;355: Solders G, Tyden G, Persson A, et al.(1992) Improvement of nerve conduction in diabetic neuropathy: a follow-up study 4 yr after combined pancreatic and renal transplantation. Diabetes 1992; 41: Stegall MD, Ploeg RJ, Pirsch JD, et al.(1993) Living related kidney transplant or simultaneous pancreas-kidney for diabetic renal failure. Trans Proc 1993; 25: Stratta RJ, Lowell JA, Sudan D, et al.(1997) Retransplantation in the diabetic patient with a pancreas allograft. Am J Surg 1997; 174: Stratta RJ, Taylor RJ, Bynon JS, et al.(1994) Surgical treatment of diabetes mellitus with pancreas transplantation. Ann Surg 1994; 220: Stratta RJ, Taylor RJ, Ozaki CF, et al.(1993) Combined pancreas-kidney transplantation versus kidney transplantation alone: analysis of benefit and risk. Trans Proc 1993; 25: Stratta RJ, Taylor RJ, Sindhi R, et al.(1996) Analysis of early readmissions after combined pancreas kidney transplantation. Am J Kidney Dis 1996; 28: Stratta RJ, Weide LG, Sindhi R, et al.(1997) Solitary pancreas transplantation: Experience with 62 consecutive cases. Diabetes Care 1997;20: Sutherland DE, Gruessner AC, Moudry-Munns KC, et al.(1993) Tabulation of cases from the International Pancreas Transplant Registry and analysis of United Network for Page 10 of 11

11 Organ Sharing United States Pancreas Transplant Registry data according to multiple variables. Trans Proc 1993; 25:1707. Sutherland DE.(1994) Present status of pancreas transplantation alone in nonuremic diabetic patients. Trans Proc 1994; 26: Sutherland DER, Goren PF, Farney AC, et al.(1993) Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota. Am J Surg 1993; 166: Sutherland DER, Rainer WG, Dunn DL, et al.(2001) Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001; 233: Tibell A, Solders G, Larsson M, et al.(1997) Superior survival after simultaneous pancreas and kidney transplantation compared with transplantation of a kidney alone in diabetic recipients followed for 8 years. Trans Proc 1997; 29:668. Troppmann C, Gruessner AC, Benedetti E, et al.(1996) Vascular graft thrombosis after pancreatic transplantation: Univariate and multivariate operative and nonoperative risk factor analysis. J Am Col Surg 1996; 182: Tyden G, Reinholt FP, Sundkvist G, et al.(1996) Recurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts. NEJM 1996; 335: Zehrer CL, Gross CR.(1994) Patient perceptions of benefits and concerns following pancreas transplantation. Diabetes Educ 1994; 20: Application to Products This policy applies to ARBenefits. Consult ARBenefits Summary Plan Description (SPD) for additional information. Last modified by: SCS Date: 01/06/2014 Page 11 of 11