Transplant Section - Islet Transplantation

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

Chronic Pancreatitis

Patients with chronic pancreatitis may experience intractable pain that can only be relieved with a total or near total pancreatectomy. However, the pain relief must be balanced against the certainty that the patient will be rendered an insulin-dependent diabetic. Autologous islet cell transplantation has been investigated as a technique to prevent this serious morbidity. Specifically, during the pancreatectomy procedure a suspension of isolated islet cells is created from the resected pancreas specimen and then injected into the portal vein of the liver, where the cells function as a free graft.

Type I Diabetes

Allogeneic islet cell transplantation has been used to treat type 1 diabetes to restore normoglycemia and ultimately, to reduce or eliminate the long-term complications of diabetes, such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Islet cell transplantation potentially offers an alternative to whole-organ pancreas transplantation. However, a limitation of islet cell transplantation is that two or more donor organs are usually required for successful transplantation. A pancreas that is rejected for whole-organ transplant is typically used for islet transplantation. Therefore, islet cell transplantation is recommended only for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin-based management.

Islet cells are subject to regulation by the U.S. Food and Drug Administration (FDA), which classifies allogeneic islet cell transplantation as somatic cell therapy, requiring premarket approval. Islet cells also meet the definition of a drug under the federal Food, Drug, and Cosmetic Act. Clinical studies to determine safety and effectiveness outcomes of allogeneic islet cell transplantation must be conducted under FDA investigational new drug (IND) regulation. While at least 35 IND applications have been submitted to the FDA, no center has yet to submit a biologics license application.

While most of the published research to date involves the transplantation of allogeneic islet cells, there is also interest in xenotransplantation, using porcine islet cells.

Policy/Criteria

Autologous pancreas islet cell transplantation may be considered medically necessary as an adjunct to a total or near total pancreatectomy in patients with chronic pancreatitis.

Allogeneic and xeno islet cell transplantation, for any diagnosis, are considered investigational.

Scientific Background

Autologous Islet Cell Transplant as an Adjunct to Pancreatectomy

Autologous islet cell transplantation as an adjunct to pancreatectomy or near total pancreatectomy has been investigated since 1977. Since then the experience has grown slowly with incremental improvements in the islet cell isolation process. Researchers at the University of Minnesota have reported the largest experience, summarizing the results in 48 patients undergoing the procedure between 1977 and 1995. (2) Of the 39 patients available for evaluation, 51% were insulin independent for at least one month, with the probability of sustained insulin independence dropping to 34% after two years. However, of the 18 patients who received an autotransplant with islets prepared with the most recent techniques in islet cell isolation, the long-term success rate was 55%. The most powerful predictor of insulin independence was the number of islet cells infused, which in turn is inversely related to the degree of fibrosis of the pancreas. In a small longitudinal study of 6 patients, Robertson and colleagues reported 5 patients remained free of insulin treatment for up to 13 (6.2 +/-1.7) years after intrahepatic islet autotransplantation. (3) This study also reported a correlation between the number of islets transplanted to insulin response. Unfortunately, there is currently no way to predict preoperatively the number of islet cells isolated, although patients with long-standing pancreatitis and prior surgical procedures are more likely to have a fibrotic pancreas. There have been no reports of significant morbidity or mortality associated with this procedure.  Although the published experience with this procedure is limited, autologous islet cell transplantation appears to significantly decrease the incidence of diabetes after total or near total pancreatectomy. In addition, this procedure is not associated with serious complications itself and is performed as an adjunct to the pancreatectomy procedure.

Allogeneic Islet Cell Transplant

Islet cell transplantation has also been investigated as a treatment for type I diabetes, particularly in patients with poor glucose control despite insulin therapy. In the past, attempts to achieve insulin independence and stabilization of the secondary complications of diabetes have been complicated by difficulty in isolating sufficient numbers of islets and by immunosuppression regimens with diabetogenic side effects. More recently, isolation techniques have advanced, and new immunosuppressive strategies have been developed which provide greater immunologic protection without diabetogenic side effects.  In a landmark study, known as the Edmonton Protocol, seven consecutive patients achieved insulin independence following islet cell transplants from two to four donors; a glucocorticoid-free immunosuppressive regimen was instituted in this protocol. (4)  Research is currently underway, attempting to reproduce this experience.  With greater experience in more patients, further improvements in islet isolation and handling have been documented.  Also reported to be more common than originally thought are complications and side effects, related to both immunosuppression and the procedure itself. (9)  Finally, the experience of the transplant center itself has a demonstrated effect on patient outcomes, with the more experienced centers reporting higher success rates. (9)

In April 2004, the BlueCross BlueShield Association Technology Evaluation Center (TEC) completed an evidence report on islet cell transplantation in type 1 diabetes in its capacity as an Evidence-based Practice Center for the Agency for Healthcare Research and Quality. (5) The evidence report found published data on clinical outcomes of islet alone transplantation are limited by small patient numbers, few transplant centers, short duration of follow-up, and lack of standardized methods for reporting clinical outcomes. Efforts are ongoing to update and expand long-term transplant results, disseminate protocols to additional centers, and standardize reporting of outcomes. The following statements from the report summarize available outcomes for patients highly selected for islet alone transplantation based on a history of severe labile diabetes and/or hypoglycemia unawareness.

The published technical success rate for islet alone transplantation is high: 94% of transplanted patients achieved insulin independence over the 3-month post transplant period. Clinical outcomes from presently available published data can be summarized as follows:

• The published insulin independence rate at one year is 76% (37 patients; 3 centers). Recent abstracts report rates of 50%-90% (104 patients; 4 centers).
• The two-year insulin independence rate is approximately 64% based on published and supplemental data from one center (15 patients with 2 or more years of follow-up; 48 total).
• In all insulin independent patients, hypoglycemic episodes were completely abated and mean HbA1c decreased from greater than 7% to less than 6.5%.
• Patients who did not achieve or who lost insulin independence tended to use 25%-75% of pre-transplant insulin doses, continued to produce C-peptide, and were free of hypoglycemic episodes.
• Eighty-three percent of 23 patients from two institutions were euglycemic at one year, without hypoglycemic episodes, and were free of or receiving reduced insulin.

Rare, serious adverse events have occurred in patients given islet cell transplants; however, recent procedure modifications reportedly minimize risks of these adverse events. No procedure-related deaths, cytomegalovirus (CMV) infection, or post-transplantation lymphoproliferative disease (PTL) have been reported for islet alone transplantation.

The report concluded the evidence is insufficient for reaching conclusions regarding the following:

• Long-term complications of diabetes
• Quality of life outcomes
• Long-term consequences of immunosuppression
• Long-term effects of the islet graft
• The potential need for and consequences of supplemental islet transplants
• Islet-kidney transplants

After publication of the AHRQ report, the first Collaborative Islet Transplant Registry (CITR) Annual Report was published in 2004, followed annually by an updated report.  The 2006 CITR report included data from 23 islet transplant centers, reporting data on 225 islet transplant recipients. (6)  Analysis of registry data found that 56.7% of patients at 6 months and 51.4% of patients at 12 months were insulin-independent after the last infusion (patients included in the analysis received from 1 to 3 infusions). These results are  decreased from the 2005 CITR report which found 67% of patients at six months and 58% of patients at 12 months were insulin independent after the last infusion.  Islet graft failure occurred  in 32 participants (26.4%).  For these patients, on average, the complete graft loss occurred in 506 days after receiving the first islet infusion.  At one year following the last infusion procedure, participants who ever achieved insulin independence have a mean fasting blood glucose of 111.5 mg/dL (SD 30.4), a basal C-peptide of 1.1ng/mL (SD 0.065) and an HbA1C of 6.0% (SD 0.8). As previously noted in the 2005 report, there continues to be a “striking” decrease in the number of severe hypoglycemic events. Over 85% of participants experienced one or more severe hypoglycemic events prior to their first infusion.  This decreased to 2.6% up to 30 days post their first infusion and then to 3.8% in months one to six and 4.0% in months six to twelve post last infusion.  All participants that experienced a severe hypoglycemic event during follow-up were on insulin at the time of the event.“ Data contained in this summary must be interpreted cautiously.  Even with the efforts of the 23 participating centers, the total number of reports is still small.  As with any  registry, a number of potential biases may exist, including selective reporting and differences in clinical care and decision-making.” In addition, this registry data is not reflective of the complete North American experience with islet transplants; therefore, there may be inherent bias in the data.  The report also focuses on intermediate outcomes and does not provide long-term health outcomes as follow-up was limited.

One clinical trial published in late 2004, retrospectively compared isolated islet transplantation (IIT) with whole-organ pancreas transplantation (WOP). (7)  The authors reported that IIT patients encountered fewer and less severe complications than WOP recipients.  However, although IIT was as reliable as WOP in the initial reversal of diabetes, IIT was likely to be associated with a shorter duration of complete insulin independence.  For the 26 WOP grafts, the insulin-free survival rate remained at 100% after two years, whereas the 11 islet recipients experienced decreasing insulin-free survival rates over time, with a rate of 56% reported at 12 months.  In addition, insulin reserve and glucose control in IIT patients were inferior to that observed in whole organ recipients, even in the short term.

In addition to the above study, Bretzel and colleagues reported on data collected from the  International Islet Transplant Registry. (8)  Data were available for 705 human islet cell transplantations.  At one year post transplant, patient survival was 97%, islet grafts were functioning in 54% of the cases, and insulin independence was achieved in 20% of the cases.

In 2005, Ryan and colleagues reported 5- year outcomes from the first patients transplanted under the Edmonton protocol. (10)  Despite persistent graft survival as measured by C-peptide positivity (~80%), the rate of insulin independence at 5 years decreased over time to approximately 10%, with the majority of patients resuming insulin therapy in order to maintain good glycemic control.  The authors noted that problems with glycemic lability and hypoglycemia, the primary indications for transplant, were corrected; however, no clear advantages for the chronic complications of diabetes (e.g., peripheral neuropathy) were evident.  Chronic complications related to standard immunosuppressive therapy led to the need to alter the protocol in 23% of patients, thus leading the authors to conclude that “safer immunosuppression associated with fewer side effects is needed.”  Froud and colleagues randomized 16 type one diabetes mellitus patients to evaluate cultured islet transplantation with or without tumor necrosis factor (TNF-alpha) blockade using Infliximab just prior to islet infusion( 11)  Insulin independence was achieved in 14 patients after one to two infusions and was maintained in eleven patients after one year and in six patients at 18 and 336 months without additional infusions.  The authors reported no identifiable clinical benefit with the use of Infliximab but concluded cultured human islet allografts produced results comparable to freshly transplanted islets including normalization of HBA1c.  Further  research is needed to explore different immunosuppressive regimens.

In 2006, Shapiro reported on 36 patients with type one diabetes mellitus who had islet transplantation.(12) While short-term results were promising, insulin independence was generally not sustainable; five patients were insulin-independent at two years.

In summary, the data published to date are inconclusive with respect to the role of and final health outcomes associated with islet cell transplantation in the treatment of type 1 diabetes.  Research is ongoing, investigating different immunosuppression regimens, potential renewable sources of islets, and modified engraftment conditions.  Finally, the FDA has not yet granted full market approval for islet cell transplantation.  An updated search of the MEDLINE database through May 29, 2008 failed to identify any clinical trials that  would alter the above conclusions concerning allogeneic islet cell transplantation.

Xenotransplantation

Although there is research interest in porcine islets as an alternative and potentially unlimited source of islet cells, an updated search of the MEDLINE database through May 29, 2008 failed to identify data from human clinical trials that allows conclusions concerning the effects of this procedure on health outcomes. Problems related to xenograft rejection and xeno-zoonosis (transmission of animal disease to humans) are still unresolved.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 7.03.12
2. Wahoff DC, Papalois BE, Najarian JS et al. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995;222:562-579
3. Robertson RP, Lanz KJ, Sutherland De et al. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001;50(1):47-50
4. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343(4):230-8
5. Piper  MA, Seidenfeld J, Aronson N.  Islet Transplantation in Type 1 Diabetes Mellitus.  Evidence Report/Technology Assessment No. 98 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026).  AHRQ Publication No. 04-E017-2.  Rockville, MD: Agency for Healthcare Research and Quality.  April 2004.  www.ahrq.gov/downloads/pub/evidence/pdf/islet/islet.pdf  (Verified 05/29/08)
6. Collaborative Islet Transplant Registry (CITR) Annual Report.  CITR Coordinating Center.  The EMMES Corporation, Rockville, MD. August 10, 2007.
   (Verified 05/29/08)
7. Frank A, Deng S, Haung X et al.  Transplantation for type 1 diabetes.  Comparison of vascularized whole-organ pancreas with isolated pancreatic islets.  Ann Surg  2004;240(4):631-40
8. Bretzel RG, Eckhard M, Brendel MD.  Pancreatic islet and stem cell transplantation: new strategies in cell therapy of diabetes mellitus.  Panminerva Med  2004;46(1):25-42
9. Gaglia JL, Shapiro AM, Weir GC.  Islet transplantation: progress and challenge.  Arch Med Res 2005;36(3):273-80
10. Ryan EA, Paty BW, Senior PA et al.  Five-year follow-up after clinical islet transplantation.  Diabetes 2005;54(7):2060-9
11. Froud T, Ricordi C, Baidal DA et al. Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression:  Miami experience. Am J Transplant 2005;5(8):2037-46
12. Shapiro AM, Ricordi C, Hering BJ et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355(13):1318-30

Cross References

Pancreas Transplant, TRG Medical Policy Manual, Transplant, Policy No. 6

Transplant Section Table of Contents