|MP 7.03.12||Islet Transplantation|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/5:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Autologous islet transplantation, performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of insulin-dependent diabetes. Moreover, allogeneic islet cell transplantation is being investigated as a treatment or cure for patients with type 1 diabetes.
In autologous islet transplantation, during the pancreatectomy procedure, islet cells are isolated from the resected pancreas using enzymes, and a suspension of the cells is injected into the portal vein of the patient’s liver. Once implanted, the beta cells in these islets begin to make and release insulin. In the case of allogeneic islet cell transplantation, cells are harvested from the deceased donor’s pancreas, processed, and injected into the recipient’s portal vein. Up to 3 donor pancreas transplants may be required to achieve insulin independence. Allogeneic transplantation may be performed in the radiology department.
Primary risk factors for chronic pancreatitis include toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive (the TIGAR-O classification system). 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 transplantation has been investigated as a technique to prevent this serious morbidity.
Type 1 diabetes
Allogeneic islet transplantation has been used for type 1 diabetes to restore normoglycemia and, ultimately, reduce or eliminate the long-term complications of diabetes such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. However, a limitation of islet transplantation is that 2 or more donor organs are usually required for successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole-organ transplant is typically used for islet transplantation. Therefore, islet transplantation has generally been reserved for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin-based management.
In 2000, a modified immunosuppression regimen increased the success of allogeneic islet transplantation. This regimen was developed in Edmonton, Canada and is known as the "Edmonton protocol".
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 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 submitted a biologics license application.
Autologous pancreas islet transplantation may be considered medically necessary as an adjunct to a total or near total pancreatectomy in patients with chronic pancreatitis.
Allogeneic islet transplantation is considered investigational for the treatment of type 1 diabetes.
Islet transplantation is considered investigational in all other situations.
CPT code 48160 explicitly describes autologous pancreas islet cell transplantation.
Effective October 1, 2004, there are 3 HCPCS codes specific to these procedures:
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
Between 2006 and 2012, there were 3 category III CPT codes specific to these procedures:
0141T Pancreatic islet cell transplantation through portal vein, percutaneous
0142T Pancreatic islet cell transplantation through portal vein, open
0143T Laparoscopy, surgical, pancreatic islet cell transplantation through portal vein
CPT now instructs the use of code 48999 (unlisted procedure, pancreas) for these procedures.
BlueCard/National Account Issues
Islet transplantation is a specialized procedure that may require referral to an out of network facility.
The policy was created in 2001 and was updated regularly with searches of the MEDLINE database. The most recent literature search was for period April 2012 through March 26, 2014. Following is a summary of the key literature to date on islet cell transplantation.
In 2012, Bramis and colleagues published a systematic review of studies on islet transplantation after total pancreatectomy in patients with chronic pancreatitis. (1) The investigators searched for studies reporting on patients who had been treated with total, subtotal or completion pancreatectomy followed by islet autotransplantation. Case series were included if they included more than 5 individuals and reported outcomes for consecutive patients. A total of 72 full-text articles were reviewed, and 5 studies were found to meet inclusion criteria. The postoperative insulin independence rate in the 5 studies ranged from 10% (mean follow-up=8 years) to 46% (mean follow-up=5 years). In the study with the longest follow-up, the insulin independence rate was 28% at 10 years. Two studies reported postoperative morphine use. In one study, patients reported a mean post-operative decrease in morphine use of 116 mg and in the other, a mean decrease of 55 mg of morphine was reported.
An earlier systematic review of studies on islet transplantation after pancreatectomy was published in 2011 by Dong and colleagues. (2) Studies were included regardless of design or sample size. After reviewing 84 studies, 15 observational studies were found to meet eligibility criteria. There were 11 studies of total pancreatectomy, 2 studies of partial pancreatectomy, and 2 studies that included both types of surgery. Sample sizes in individual studies ranged from 3 to 173 patients. Thirteen studies included patients with chronic pancreatitis, and 2 included patients with benign pancreatic tumors. The pooled 30-day mortality was 5% (95% confidence interval [CI]: 2 to 10%), and the cumulative mortality at 1 year (reported by 10 studies) was 4.9% (95% CI: 2.6 to 7.3%) In a pooled analysis of data from 14 studies, the rate of insulin dependence at last follow-up was 4.6 per 100 person years (95% CI: 1.53 to 7.62). The pooled rate of insulin independence at 1 year (5 studies) was 27% (95% CI: 21-33%) and at 2 years (3 studies) was 21% (95% CI: 16-27%).
Representative studies included in the systematic reviews or published more recently are described next:
A large single center series was reported by Sutherland and colleagues in 2012. (3) The study included 409 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation between February 1977 and September 2011. Fifty-three of the 409 patients (13%) were children between the ages of 5 and 18 years. Actuarial survival post-surgery was 96% in adults and 98% in children after 1 year and 89% in adults and 98% in children after 5 years. A total of 15.9% of patients experienced surgical complications requiring reoperation during the initial admission. The most common reason for reoperation was bleeding, occurring in 9.5% of patients. At 3 years, 30% of patients were insulin-independent (25% of adults and 55% of children). A survey of quality-of-life outcomes was initiated in October 2008; responses were available for 102 patients. At baseline, all 102 patients reported using narcotics for pain. At 12 months, the proportion of patients on narcotics decreased to 56% (n=32), and at 24 months, 41% of respondents (n=21) reported using narcotics.
A 2014 study by Chinnakotla et al included 484 patients with chronic pancreatitis.(4) Patients underwent total pancreatectomy and immediate islet auto transplantation. Using a Kaplan-Meier analysis method, 10-year survival was 84%. Patient survival at 5 years was 90.3% in the 80 patients with hereditary/genetic pancreatitis and 89.7% in the 404 patients with nonhereditary pancreatitis; the difference between groups was not statistically significant. Pancreatitis pain decreased significantly after the procedures, and there was no statistically significant difference in the rate of pancreatitis pain between the groups with and without genetic/hereditary disease.
In 2008, Webb et al reported on 46 patients who had total pancreatectomy with immediate islet auto transplantation. Twelve had periods of insulin independence for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent.(5) Insulin requirements increased over the 10-year follow-up, as have HbA1c levels; however, all patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide positive values recorded at 10 years after transplantation suggest significant graft function in the long term.
Type 1 Diabetes
In April 2004, 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 (AHRQ). (6) The evidence report found that published data on clinical outcomes of islet-alone transplantation were limited by small patient numbers, few transplant centers, short duration of follow-up, and lack of standardized methods of reporting clinical outcomes. Rare, serious adverse events have occurred in patients given islet transplants; 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 2008 report from the Collaborative Islet Transplant Registry (CITR), which collects and monitors data on allogeneic islet transplantation in North America, Europe, and Australia, had 325 adult recipients in their registry as of April 2008.(7) Three years after first infusion, 23% of islet-alone recipients were insulin independent (defined as insulin independent 2 or more weeks), 29% were insulin dependent with detectable C-peptide, 26% had lost function, and 22% had missing data. Seventy percent achieved insulin independence at least once, 71% of whom were still insulin independent 1 year later and 52% at 2 years. Factors that favored primary outcomes were higher number of islet infusions, greater number of total islet equivalents infused, lower pretransplant HbA1c levels, processing centers related to the transplant center, and larger islet size. The CITR published an updated report in 2012; the focus of the article was changes in outcomes over time. (8) The number of patients receiving islet transplants was 214 during 1999-2002, 255 between mid-2003-2006 and 208 from 2007-2010. A total of 575 of the 677 (85%) islet transplant recipients received islets only; the remainder underwent simultaneous kidney and islet transplants. In the 1999-2002 group, rates of insulin independence were 51% after 1 year, 36% after 2 years, and 27% after 3 years. Rates for the 2007-2010 group were 66%, 55% and 44%, respectively. The incidence of clinically reportable adverse events in the first year after infusion decreased from 50% to 53% in 1999-2006 to 38% in 2007-2010. The rates of peritoneal hemorrhage or gallbladder infusion were 5.4% in 1999-2003 and 3.1% in 2007-2010. The authors did not report findings separately for the subset of patients who underwent islet-only transplants.
In 2011, Thompson et al in Canada published findings from a prospective crossover study of intensive medical therapy (pretransplant) versus islet cell transplantation in patients with type 1 diabetes.(9) The article reported on 45 patients; at the time of data analysis, 32 had received islet cell transplants. Median follow-up was 47 months pretransplant and 66 months posttransplant. The overall mean HbA1c was 7.8% pretransplant and 6.7% posttransplant; this difference was statistically significant (p<0.001). In the 16 patients for whom sufficient data pre- and posttransplant were available on renal outcomes, the median decline in glomular filtration rate (mL/min/mo) was -6.7 pretransplant and -1.3 posttransplant (p=0.01). Retinopathy was assessed using the International Scale, which categorizes nonproliferative diabetic retinopathy as mild, moderate, or severe. Retinopathy progressed in 10 of 82 (12%) eyes pretransplant versus 0 of 51 posttransplant (p<0.01). (The numbers of patients in the retinopathy analyses were not reported). The rate of change in nerve conduction velocity did not differ significantly between groups (exact numbers not reported). The authors noted that their finding of reduced microvascular complications after islet transplantation may be due, in part, to their choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil.
Several case series have also been published. These series tend to have small sample sizes and relatively short-term follow-up. Representative series are described next. In 2013, Rickels et al reported on 12 patients with type 1 diabetes and severe hypoglycemia who had islet transplantation.(10) Mean glycosylated hemoglobin decreased from 7.0%±0.3% before the procedure to 5.6%±0.1% after 6 to 7 months (p<0.01). All of the insulin sensitivity measures were significantly less than normal before islet transplantation and not significantly different from normal after transplantation.Adverse events were not discussed.
In 2013, O’Connell et al reported on 17 patients with type 1 diabetes and severe hypoglycemia who underwent islet transplantation in Australia.(11) The primary end point was the proportion of patients who had had an HbA1c less than 7% and no severe hypoglycemic events 2 months after the initial transplant. (Patients could have 1 or 2 infusions.) Fourteen of the 17 (82%) patients achieved the primary end point. Nine (53%) patients attained insulin independence for a median of 26 months. At the time of data analysis for this publication, 6 patients remained insulin independent. Most adverse events related to immunosuppression. Seven of the 17 (41%) patients developed mild lymphopenia and 1 developed Clostridium difficile colitis; these all responded to treatment. Eight patients developed anemia shortly after transplant and 1 required a blood transfusion. Procedure-related complications included 1 partial portal vein thrombosis and 3 postoperative bleeds; 2 of the bleeds required transfusion. Patients were followed for different amounts of time; long-term follow-up data were not available for a consistent length of time.
In 2012, Vantyghem et al reported on 23 patients with type 1 diabetes who underwent islet transplantation; 14 had islet-only transplants, and 9 had islet after kidney transplants.(12) Median HbA1c was 8.3% at baseline and 6.7% at 3 years. Ten of the 23 patients (43%) were insulin independent 3 years after islet transplantation. Findings were not reported separately for the islet-only transplant recipients.
Recent papers have highlighted research in the areas of islet cell regenerative therapy including stem-cell technology, encapsulating islets to protect them from the host immune system by a semipermeable capsule, transplantation site, and xenotransplantation.(13-17) In addition, novel immunosuppressive regimens using biologics have been discussed.(18)
Ongoing Clinical Trials
A comparison of strict glucose control with usual care at the time of islet cell transplantation (NCT01123122)(19): This is a single-center randomized controlled trial comparing the impact of strict glucose control versus usual care before islet cell transplantation on outcomes in patients with type 1 diabetes. The primary study outcome is islet cell function 3 months posttransplantation. The estimated enrollment is 32 patients, and the estimated study completion date is September 2015.
Trial Comparing Metabolic Efficiency of Islet Graft to Intensive Insulin Therapy for Type 1 Diabetes's Treatment (TRIMECO) (NCT01148680)(20): This randomized controlled trial is comparing islet transplantation to intensive insulin therapy in patients with type 1 diabetes. The estimated enrollment is 40 patients, and the estimated study completion date is December 2014.
Autologous islet transplantation is proposed in conjunction with pancreatectomy for patients with chronic pancreatitis. Although the published experience with autologous islet cell transplantation is limited, the procedure appears to significantly decrease the incidence of diabetes after total or near total pancreatectomy in patients with chronic pancreatitis. In addition, this procedure is not associated with serious complications itself and is performed as an adjunct to the pancreatectomy procedure. Thus, this may be considered medically necessary.
The techniques for allogeneic islet cell transplants are evolving, and the impact on the net health outcome is still uncertain. Moreover, longer follow-up with larger numbers of patients is needed before conclusions can be drawn about the safety of allogeneic islet transplantation and its impact on diabetes mellitus and associated complications. Thus, this technology is considered investigational for patients with diabetes type 1.
Practice Guidelines and Position Statements
Guidance from the National Institute for Clinical Excellence, published in 2008, states that the evidence on allogeneic pancreatic islet cell transplantation for type 1 diabetes mellitus shows short-term efficacy with some evidence of long-term efficacy.(21) Evidence on safety shows that serious complications may occur, and the long-term immunosuppression required is also associated with risk of adverse events. The
procedure is particularly indicated for patients with hypoglycemia unawareness or those already on immunosuppressive therapy because of renal transplantation. A 2008 update of guidance on autologous islet cell transplantation for improved glycemic control after pancreatectomy states that studies show some short-term efficacy, although most patients require insulin therapy in the long term. Complications mainly result from the major surgery involved in pancreatectomy rather than from the islet cell transplantation.(22)
Medicare National Coverage
Effective October 1, 2004, Medicare will cover pancreatic islet transplantation in patients with type 1 diabetes participating in the context of a clinical trial sponsored by the National Institutes of Health. (23) Partial pancreatic tissue transplantation or islet transplantation performed outside the context of a clinical trial will continue to not be covered.
- Bramis K, Gordon-Weeks AN, Friend PJ et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012; 99(6):761-6.
- Dong M, Parsaik AK, Erwin PJ et al. Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes. Clin Endocrinol (Oxf) 2011; 75(6):771-9.
- Sutherland DE, Radosevich DM, Bellin MD et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 2012; 214(4):409-24.
- Chinnakotla S, Radosevich DM, Dunn TB et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for hereditary/genetic pancreatitis. J Am Coll Surg 2014; 218(4):530-43.
- Webb MA, Illouz SC, Pollard CA et al. Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function. Pancreas 2008; 37(3):282-7.
- Piper M, Seidenfeld J, Aronson N. Islet transplantation in patients with type 1 diabetes mellitus. Evid Rep Technol Assess (Summ) 2004; (98):1-6.
- Alejandro R, Barton FB, Hering BJ et al. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation 2008; 86(12):1783-8.
- Barton FB, Rickels MR, Alejandro R et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012; 35(7):1436-45.
- Thompson DM, Meloche M, Ao Z et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011;91(3):373-8.
- Rickels MR, Kong SM, Fuller C et al. Improvement in insulin sensitivity after human islet transplantation for type 1 diabetes. J Clin Endocrinol Metab 2013; 98(11):E1780-5.
- O'Connell PJ, Holmes-Walker DJ, Goodman D et al. Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. Am J Transplant 2013; 13(7):1850-8.
- Vantyghem MC, Raverdy V, Balavoine AS et al. Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab 2012; 97(11):E2078-83.
- Ekser B, Cooper DK. Overcoming the barriers to xenotransplantation: prospects for the future. Expert Rev Clin Immunol 2010; 6(2):219-30.
- van der Windt DJ, Bottino R, Kumar G et al. Clinical islet xenotransplantation: how close are we? Diabetes 2012; 61(12):3046-55.
- Aguayo-Mazzucato C, Bonner-Weir S. Stem cell therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 2010; 6(3):139-48.
- de Vos P, Spasojevic M, Faas MM. Treatment of diabetes with encapsulated islets. Adv Exp Med Biol 2010; 670:38-53.
- Ramesh A, Chhabra P, Brayman KL. Pancreatic islet transplantation in type 1 diabetes mellitus: an update on recent developments. Curr Diabetes Rev 2013; 9(4):294-311.
- Posselt AM, Szot GL, Frassetto LA et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 2010; 90(12):1595-601.
- Sponsored by Vancouver Coastal Health. A comparison of strict glucose control with usual care at the time of islet cell transplantation (NCT01123122) Available online at: www.clinicaltrials.gov. Last accessed March, 2014.
- Sponsored by University Hospital Grenoble. Trial Comparing Metabolic Efficiency of Islet Graft to Intensive Insulin Therapy for Type 1 Diabetes's Treatment (TRIMECO) (NCT01148680).A vailable online at: www.clinicaltrials.gov. Last accessed March, 2014.
- National Institute for Health and Clinical Excellence (NICE). Allogeneic pancreatic islet cell transplantation for type 1 diabetes mellitus. 2008. Available online at:http://www.nice.org.uk/Guidance/IPG257. Last accessed March, 2014.
- National Institute for Health and Clinical Excellence (NICE). Autologous pancreatic islet cell transplantation for improved glycemic control after pancreatectomy. 2008. Available online at:
http://www.nice.org.uk/Guidance/IPG274. Last accessed March, 2014.
- Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for
pancreas Transplants (260.3). Effective 4/26/2006. Available online at: http://www.cms.gov/medicare-coverage-database/overview-and-quick-search.aspx?clickon=search. Last accessed March, 2014.
|CPT||48160||Pancreatectomy, total or subtotal, with autologous transplantation of pancreas or pancreatic islet cells|
|ICD-9 Procedure||52.84||Autotransplantation of cells of islets of Langerhans|
|52.85||Allotransplantation of cells of islets of Langerhans|
|52.86||Transplantation of cells of islets of Langerhans, not otherwise specified|
|ICD-9 Diagnosis||577.1||Chronic pancreatitis|
|250.00 – 250.93||Diabetes mellitus coding range|
|HCPCS||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|
|S2102||Transplant, islet cell tissue, allogeneic|
|ICD-10-CM (effective 10/1/15)||K86.1||Other chronic pancreatitis|
|ICD-10-PCS (effective 10/1/15)||3E033U0||Percutaneous administration, peripheral vein, pancreatic islet cells, autologous|
|3E0J3U0||Percutaneous administration, biliary and pancreatic tract, pancreatic islet cells, autologous|
|3E0J7U0||Administration via natural or artificial opening, biliary and pancreatic tract, pancreatic islet cells, autologous|
|3E0J8U0||Endoscopic administration via natural or artificial opening, biliary and pancreatic tract, pancreatic islet cells, autologous|
|Type of Service||Surgery|
|Place of Service||Inpatient|
Allogeneic Transplantation, Islet
Autologous Transplantation, Islet Cell
Islet Cell Transplantation
Transplantation, Allogeneic Islet
Transplantation, Autologous Islet Cell
Transplantation, Pancreas, Autologous Islet Cell
|08/15/01||Add to Surgery section||New policy|
|04/29/03||Replace policy||Policy updated; no change to policy statement, reference added|
|11/9/04||Replace policy||Literature review update for the period of January 2003 through September 2004. Added information on islet transplantation for type 1 diabetes and statement that this indication is considered investigational. Added Medicare coverage policy information on islet transplantation for type 1 diabetes; removed “autologous” from the policy title. HCPCS codes updated|
|08/17/05||Replace policy||Literature review update for the period of September 2004 through June 2005; reference No. 5 added. Policy statement unchanged. Removed “cell” from title and policy when describing islet transplantation rather than “islet cell transplantation.” CPT Category III codes for 1/1/06 added|
|12/14/05||Replace policy – typographical error corrected||Date corrected in Policy Guidelines section|
|10/10/06||Replace policy||Literature review update for the period of June 2005 through September 2006; reference numbers 6 and 7 added. Policy statement unchanged.|
|02/14/08||Replace policy||Policy updated with literature review; references 8-11 added; policy statements unchanged|
|03/12/09||Replace policy||Policy updated with literature review; references 12-22 added; policy statements unchanged|
|6/10/10||Replace policy||Policy updated with literature review; rationale section extensively edited; reference numbers 16-18 added; policy statements unchanged|
|6/9/11||Replace policy||Policy updated with literature review. Reference numbers 13 and 17 added; other references renumbered or removed; policy statements unchanged.|
|06/14/12||Replace policy||Policy updated with literature review. Reference numbers 1, 2, 3 and 14 added; other references renumbered or removed; policy statements unchanged.|
|6/13/13||Replace policy||Policy updated with literature review through April 18, 2013. Reference numbers 7,9,11 and 16 added; other references renumbered or removed; policy statements unchanged.|
|5/22/14||Replace policy||Policy updated with literature review through March 26, 2014. Reference numbers 4, 10-11, and 20 added. Statement added that islet transplantation is considered investigational in all other situations.|