Description:
Performed in conjunction with pancreatectomy, autologous islet transplantation 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.

For individuals with chronic pancreatitis undergoing total or near total pancreatectomy who receive autologous pancreas islet transplantation, the evidence includes case series and systematic reviews. Relevant outcomes are overall survival, change in disease status, medication use, resource utilization, and treatment-related morbidity. Autologous islet transplants are performed in the context of total or near total pancreatectomies to treat intractable pain for chronic pancreatitis. The procedure appears to significantly decrease the incidence of diabetes after total or near total pancreatectomy in patients with chronic pancreatitis. Also, this procedure itself is not associated with serious complications and is performed in patients who are already undergoing a pancreatectomy procedure. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with Type 1 diabetes who receive allogeneic pancreas islet transplantation, the evidence includes case series and systematic reviews. Relevant outcomes are overall survival, change in disease status, medication use, resource utilization, and treatment-related morbidity. A wide range of insulin independence has been reported in case series. There is conflicting evidence whether allogeneic islet transplantation reduces long-term diabetic complications. Long-term comparative studies are required to determine the effects of allogeneic islet transplantation in Type 1 diabetics. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
ISLET TRANSPLANTATION
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.

Allogeneic islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. In the case of allogeneic islet cell transplantation, cells are harvested from a deceased donor's pancreas, processed, and injected into the recipient's portal vein. Up to three donor pancreas transplants may be required to achieve insulin independence. However, a limitation of islet transplantation is that two 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. Allogeneic transplantation may be performed in the radiology department.

In 2000, a modified immunosuppression regimen increased the success of allogeneic islet transplantation. This regimen is known as the "Edmonton protocol."

Regulatory Status
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Allogeneic islet cells are included in these regulations. No allogeneic islet cell product is currently approved in the United States, but a biologic license application is currently under consideration by the FDA, and the Cellular, Tissue and Gene Therapies Advisory Committee voted in favor of approving the product (donislecel, purified allogeneic deceased donor pancreatic islet cells) in April 2021.^1,2

Related Policies
20143 Chronic Intermittent Intravenous Insulin Therapy (CIIIT)
70302 Allogeneic Pancreas Transplant

Policy:
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 investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of Type 1 diabetes.

Islet transplantation is investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARY in all other situations.

Policy Guidelines
None

Benefit Application
BlueCard/National Account Issues
Islet transplantation is a specialized procedure that may require referral to an out-of-network facility.

Rationale
The evidence review was created in August 2001 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 17, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Chronic Pancreatitis
Clinical Context and Therapy Purpose
The purpose of autologous pancreas islet transplantation for patients with chronic pancreatitis who are undergoing total or near-total pancreatectomy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does autologous pancreas islet transplantation improve the net health outcome in individuals who have chronic pancreatitis who are undergoing total or near-total pancreatectomy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have chronic pancreatitis who are undergoing total or near-total pancreatectomy. Primary risk factors for chronic pancreatitis may be categorized as the following: toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute, or obstructive (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.

Interventions
The therapy being considered is autologous pancreas islet transplantation.

Comparators
The following practice is currently being used to make decisions about managing chronic pancreatitis: medical management, which may include medications or endoscopy.

Outcomes
The general outcomes of interest are overall survival (OS), insulin independence, change in disease status, medication use, resource utilization, and treatment-related morbidity.

Short-term follow-up (30 days) is required to monitor for transplant-related complications; long-term follow-up — 1 to 3, 5, or even 10 years — is required to establish the durability of glucose control.³

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
There are several systematic reviews of the literature on chronic pancreatitis patients. Zhang et al. (2020) published a systematic review and meta-analysis of 17 studies that reported clinical outcomes following total pancreatectomy with islet transplant in patients with chronic pancreatitis.⁴ Most studies were single-center, small case series from the United States. The median age was 53 years. Insulin independence was 33.29% (95% CI, 27.77% to 39.05%; I2 = 32.3%) at 1 year (8 studies). Mortality at 30 days was 1.32% (95% CI, 0.68% to 2.16%; I2 = 0.0%) and mortality at 1 year was 2.54% (95% CI, 1.32% to 4.16%; I2 = 17.6%).

Kempeneers et al. (2019) published a systematic review of studies examining pain, endocrine function, or quality of life outcomes in patients with chronic pancreatitis undergoing total pancreatectomy with islet transplantation.5, A total of 15 studies met the inclusion criteria. All included studies were retrospective and observational. The median age was 41 years. Pooled insulin free rate was 30% (95% CI, 20% to 43%) at 1 year (4 studies). The pooled mortality rate was 2% (95% CI, 1% to 4%) at 30 days (11 studies) and 4% at 1 year (6 studies). At 1 year, 63% (95% CI, 46% to 77%, I2 = 89%) of patients were opioid free (6 studies, 657 patients). An analysis revealed a high risk for publication bias among the included studies, which could have led to an overestimation of the true effect.

Wu et al. (2015) published a systematic review of studies on islet transplantation after total pancreatectomy for chronic pancreatitis.⁶ Studies could use any design type but had to include at least 5 patients or have a median follow-up of at least 6 months. Twelve studies (N = 677 patients) met reviewers' inclusion criteria. The mean age was 38 years and the mean duration of pancreatitis was 6.6 years. A meta-analysis of the insulin-independence rate at 1 year (5 studies, 362 patients) was 28.4% (95% CI, 15.7% to 46.0%). At 2 years, the pooled insulin-independence rate (3 studies, 297 patients) was 19.7% (95% CI, 5.1% to 52.6%). The pooled 30-day mortality rate (11 studies) was 2.1% (95% CI, 1.2% to 3.8%). Long-term mortality data were not pooled.

Dong et al. (2011) published a systematic review that included studies irrespective of design or sample size.⁷ After reviewing 84 studies, 15 observational studies met eligibility criteria. Eleven studies assessed total pancreatectomy, 2 studies evaluated partial pancreatectomy, and 2 studies 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 rate was 5% (95% 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 was 27% (95% CI, 21% to 33%) at 1 year (5 studies) and 21% (95% CI, 16% to 27%) at 2 years (3 studies).

Table 1 provides a crosswalk of studies included in the systematic reviews discussed. Tables 2 and 3 provide the characteristics and results of these systematic reviews.

Table 1. Comparison of Studies Included in Systematic Reviews Assessing Autologous Pancreas Islet Transplants

Table 2. Characteristics of Systematic Reviews Assessing Autologous Pancreas Islet Transplants

Table 3. Results of Systematic Reviews Assessing Autologous Pancreas Islet Transplants

CI: confidence interval; NR: not reported

Nonrandomized Studies
Wilson et al. (2014) reported on 166 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation at a single-center.²⁹ Actutimes survival rate at 5 years was 94.6%. Five or more years of data were available for 112 (67%) patients. At 1 year, 38% of patients were insulin-independent and that declined to 27% at the 5-year follow-up. Daily insulin requirement, however, remained stable over the 5 years. Fifty-five percent of patients were independent of opioid analgesics at 1 year and this improved to 73% at 5 years.

Chinnakotla et al. (2014) included 484 patients with chronic pancreatitis who underwent total pancreatectomy and immediate islet autotransplantation.³ The 10-year survival rate 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.

Sutherland et al. (2012) reported on 409 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation at a single-center.²⁴ Fifty-three (13%) of the 409 patients were children between the ages of 5 and 18 years. Actutimes survival postsurgery 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, 55% of children). A survey of quality of life outcomes was initiated in 2008; responses were available for 102 patients. At baseline, all 102 patients reported using opioid analgesia for pain control. 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.

Tables 4 and 5 provide the characteristics and results of the nonrandomized studies assessed.

Table 4. Summary of Key Nonrandomized Study Characteristics

FU: follow-up; NR: not reported.

Table 5. Summary of Key Nonrandomized Study Results

NR: not reported.

Section Summary: Chronic Pancreatitis
Autologous islet transplantation is frequently performed as an adjunct to a total or near-total pancreatectomy for chronic pancreatitis. Evidence from nonrandomized studies and systematic reviews has demonstrated that autologous islet transplantation decreases the incidence of diabetes in the setting of pancreatectomies for the treatment of chronic pancreatitis.

Type 1 Diabetes
Clinical Context and Therapy Purpose
The purpose of allogeneic pancreas islet transplantation for patients who have type 1 diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does allogeneic pancreas islet transplantation improve the net health outcome in individuals with type 1 diabetes?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with type 1 diabetes.

Glucose control is a challenge for individuals with type 1 diabetes. Failure to prevent disease progression can lead to long-term complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disease.⁴¹

Interventions
The therapy being considered is allogeneic pancreas islet transplantation.

Comparators
The following practice is currently being used to make decisions about managing type 1 diabetes: medical management, which generally includes daily insulin injections as well as diet and lifestyle changes.

Outcomes
The general outcomes of interest are OS, insulin independence, change in disease status, medication use, resource utilization, and treatment-related morbidity.

According to U.S. Food and Drug Administration (2009) industry guidance on evaluating allogeneic pancreatic islet cell products, single-arm trials with historical controls may be acceptable alternatives to RCTs for evaluating the safety and efficacy of islet cell products in patients with metabolically unstable type 1 diabetes.⁴² Attainment of a normal hemoglobin A1c (HbA1c) range (i.e., ≤ 6.5%) and elimination of hypoglycemia are acceptable primary endpoints. To assess the durability of the islet cell procedure, primary endpoints should be measured at least 12 months after the final infusion. Other key clinical outcomes include insulin independence, measures of glucose metabolic control such as fasting plasma glucose level, and loss of hypoglycemia unawareness.

Short-term (30 days) follow-up is required to monitor for transplant-related complications; the long-term follow-up to assess the durability of glucose control and monitor immunosuppression is lifelong.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review by Health Quality Ontario (2015) reported on islet transplantation for patients with type 1 diabetes.⁴³ Case series derived from single-centers constitutes most of the evidence. For nonuremic patients, rates of insulin independence ranged from 30% to 70% from observational case series at 1 year after islet transplantation. For uremic patients, reported insulin-independence rates ranged from 20% to 67%. Evidence of changes in secondary complications such as diabetic retinopathy and nephropathy were conflicting across different studies.

A TEC Assessment (2004) evaluated the evidence on islet cell transplantation in type 1 diabetes.⁴⁴ The Assessment found that published data on clinical outcomes of islet-alone transplantation were limited by small sample sizes (i.e., ≤ 35 enrolled patients), few transplant centers, short duration of follow-up, and lack of standardized methods of reporting clinical outcomes. Also, rare, serious adverse events have occurred in patients given islet transplants, although recent procedure modifications reportedly minimized risks of these adverse events. No procedure-related deaths, cytomegalovirus infection, or posttransplantation lymphoproliferative disease have been reported for islet-alone transplantation.

Randomized Controlled Trials
Lablanche et al. (2018) published a multicenter, open-label, RCT (TRIMECO trial) evaluating patients who had type 1 diabetes with severe hypoglycemia or after kidney transplantation.⁴⁵ Patients received immediate islet transplantation (n = 25) or intensive insulin therapy followed by delayed islet transplantation (n = 22). Median follow-up was 6 months for both groups. The primary endpoint was a composite score (β score), which has not been validated and which reflected fasting glucose, HbA1c level, C-peptide, and insulin independence. At 6 months, 16 of 25 patients in the immediate transplantation group and none of 22 patients in the control group had a modified β score of 6 or higher (p < .001). Of note, few patients in the insulin group used continuous glucose monitoring or other technologies to monitor for hypoglycemia. At 6 months, insulin independence was achieved in 44% of patients in the immediate transplantation group (n = 25; p < .001). After the entire cohort received islet transplantation, the 1-year insulin independence rate was 59% (n = 46; p < .001). Subsequent to islet transplantation, 6% of patients had bleeding complications. Trial limitations included possible bias from open-label design as well as an inadequate follow-up period to demonstrate transplant durability.

Registry Studies
LaBlanche et al. (2021) reported 10-year outcomes from the Swiss-French GRAIL Network of 44 patients who received islet transplant for type 1 diabetes between 2003 and 2010.⁴⁶ Thirty one patients were still being followed at 10 years; 6 patients died between years 1 and 10 posttransplant. Median HbA1c levels were 7.2% (range, 6.2% to 8.0%) after 10 years compared to 8.0% pretransplant (p < .001). One patient was insulin independent at 10 years and 73.9% were free of severe hypoglycemia. Insulin requirements were significantly lower posttransplant (0.3 units/kg/day vs. 0.5 units/kg/day; p < .001). Islet graft survival was 51.9% at 10 years.

In a report from the Collaborative Islet Transplant Registry, which collects and monitors data on allogeneic islet transplantation in North America, Europe, and Australia, Alejandro et al. (2008) assessed data on 325 adult recipients.⁴⁷ Three years after the first cell infusions, 23% of islet-alone recipients were insulin-independent (defined as insulin-independent ≥ 2 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 a higher number of islet infusions, a greater number of total islet equivalents infused, lower pretransplant HbA1c levels, processing centers related to the transplant center, and larger islet size.

Barton et al. (2012) updated the Collaborative Islet Transplant Registry report, which focused on changes in outcomes over time.⁴⁸ The number of patients receiving islet transplants was 214 from 1999 to 2002, 255 between mid-2003 and 2006, and 208 from 2007 to 2010. A total of 575 (85%) of the 677 islet transplant recipients received islets only; the remainder underwent simultaneous kidney and islet transplants. In the 1999 to 2002 group, rates of insulin independence were 51% after 1 year, 36% after 2 years, and 27% after 3 years. Rates for the 2007 to 2010 group were 66%, 55%, and 44%, respectively. The incidence of clinically reportable adverse events in the first year after infusion decreased from a range of 50% to 53% in 1999 to 2006 to 38% in 2007 to 2010. The rates of peritoneal hemorrhage or gallbladder infusion were 5.4% in 1999 to 2003 and 3.1% in 2007 to 2010. The authors did not report findings separately for the subset of patients who underwent islet-only transplants.

Prospective Trials
Two prospective, Phase 3, single-arm, open-label, multicenter trials of purified human pancreatic islet cell transplant have been conducted in North America under the guidance of the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium.^49,50 Hering et al. (2016) studied 48 patients with type 1 diabetes, hypoglycemic unawareness, and a history of experiencing severe hypoglycemic events (Protocol CIT07).⁴⁹ The primary outcome (HbA1c level ≤ 7% and freedom from severe hypoglycemia after 1 year) was achieved in 87.5% and 71% of patients at 1 and 2 years. Median HbA1c level decreased from 7.2% at baseline to 5.6% at 1 and 2 years (both p < .001). Only 2 patients experienced severe hypoglycemia in the first year posttransplant. Insulin independence was achieved in 52.1% of patients at 1 year, and median insulin use decreased from 0.49 units/kg/day at baseline to 0 units/kg/day at 1 year (p < .0003). Glomerular filtration rate decreased posttransplant (p < .0008 vs. baseline) due to adverse effects of immunosuppression. Twenty-two serious adverse events during the first year were attributed to the procedure or subsequent immunosuppression.

Markmann et al. (2021) conducted a similar trial in 24 patients with type 1 diabetes and hypoglycemic unawareness who had previously received a kidney transplant (Protocol CIT06).⁵⁰ The primary outcome (HbA1c level ≤ 6.5% or a reduction in HbA1c level of at least 1% and freedom from severe hypoglycemia after 1 year) was achieved by 62.5% of patients. At 2 and 3 years, 58.3% and 45.8% had achieved these glycemic targets. Severe hypoglycemia was eliminated in 79.2% of patients at 1 year, 75% at 2 years, and 62.5% at 3 years. Median insulin requirements decreased from 0.5 units/kg/day at baseline to 0 units/kg/day at 1, 2, and 3 years (p < .001, p < .001, and p = .002, respectively). Kidney function remained stable throughout follow-up. Thirteen serious adverse events were considered related or possibly related to islet transplant or immunosuppression.

Thompson et al. (2011) in Canada published findings from a prospective crossover study of intensive medical therapy (pretransplant) versus islet cell transplantation in patients with type 1 diabetes.⁴¹ 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 level was 7.8% pretransplant and 6.7% posttransplant (p < .001). In the 16 patients for whom sufficient pre- and posttransplant data were available on renal outcomes, the median decline in glomerular filtration rate was -6.7 mL/min/1.73 m2/year pretransplant and -1.3 mL/min/1.73 m2/year posttransplant (p = .01). Retinopathy was assessed using a scale that categorized nonproliferative diabetic retinopathy as mild, moderate, or severe. Retinopathy progressed in 10 (12%) of 82 eyes pretransplant versus 0 of 51 posttransplant (p < .01). (The numbers of patients in the retinopathy analyses were not reported.) The authors noted that their finding of reduced microvascular complications after islet transplantation might have been due, in part, to their choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil.

Case Series
Other small case series have reported some success and also adverse events.^51,52,53,54 Lemos et al. (2021) reported 20-year results for a retrospective series of 49 patients with type 1 diabetes, hypoglycemic unawareness, and severe hypoglycemia who underwent islet transplant.⁵⁴ Median follow-up time after transplant was 13.8 years. Median duration of graft function while on immunosuppression was 4.4 years (interquartile range, 1.3 to 12.2 years). Kaplan-Meier survival analysis showed cumulative survival of > 80% at 20 years; 2 patients died during follow-up, 1 from myocardial infarction and 1 from suspected hypoglycemia.

In another case series , O'Connell et al. (2013) reported on 17 patients with type 1 diabetes and severe hypoglycemia who underwent islet transplantation in Australia.⁵² Fourteen (82%) patients attained the primary endpoint, which was an HbA1c level of less than 7% and no severe hypoglycemic events 2 months after the initial transplant. Nine (53%) patients attained insulin independence for a median of 26 months. Most adverse events were related to immunosuppression. Seven (41%) of the 17 patients developed mild lymphopenia and 1 developed Clostridium difficile colitis; 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.

Section Summary: Type 1 Diabetes
Allogeneic islet transplantation has been investigated in the treatment of type 1 diabetes. One RCT found that quality of life was significantly improved after islet transplantation; however, the short length of follow-up limits these conclusions. Evidence from registry studies, single-arm prospective studies, and systematic reviews has demonstrated varying ranges of insulin independence posttransplantation. There is conflicting evidence that allogeneic islet transplantation reduces long-term diabetic complications. Long-term comparative studies are required to determine the effects of allogeneic islet transplantation in type 1 diabetics and posttransplant immunosuppression.

Summary of Evidence
For individuals with chronic pancreatitis undergoing total or near-total pancreatectomy who receive autologous pancreas islet transplantation, the evidence includes nonrandomized studies and systematic reviews. Relevant outcomes are OS, change in disease status, medication use, resource utilization, and treatment-related morbidity. Autologous islet transplants are performed in the context of total or near-total pancreatectomies to treat intractable pain from chronic pancreatitis. The procedure appears to decrease significantly the incidence of diabetes after total or near-total pancreatectomy in patients with chronic pancreatitis. Also, this islet procedure is not associated with serious complications and is performed in patients who are already undergoing a pancreatectomy procedure. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with type 1 diabetes who receive allogeneic pancreas islet transplantation, the evidence includes an RCT, single-arm prospective studies, registry studies, and systematic reviews. Relevant outcomes are OS, change in disease status, medication use, resource utilization, and treatment-related morbidity. Results of a 2018 randomized trial have suggested some reduction in the number of severe hypoglycemic incidence annually, but limited follow-up and other trial limitations reduce the certainty in conclusions drawn. A wide range of insulin independence has been reported in single-arm prospective studies and case series. There is conflicting evidence on whether allogeneic islet transplantation reduces long-term diabetic complications. Long-term comparative studies are required to determine the effects of allogeneic islet transplantation in patients with type 1 diabetes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in "Supplemental Information" if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute for Health and Care Excellence
In 2008, NICE published guidance indicating the evidence on allogeneic pancreatic islet cell transplantation for type 1 diabetes has shown that serious procedure-related complications may occur, and the long-term immunosuppression required is associated with risk of adverse events.⁵⁵ A related 2008 guidance addressed autologous islet cell transplantation for improved glycemic control after pancreatectomy and stated that studies have shown "some short-term efficacy, although most patients require insulin therapy in the long term... complications result mainly from the major surgery involved in pancreatectomy (rather than from the islet cell transplantation)."⁵⁶

American Diabetes Association
In 2022, the American Diabetes Association standards of medical care recommended autologous islet cell transplantation be considered in patients undergoing total pancreatectomy for chronic pancreatitis to prevent postsurgical diabetes.⁵⁷ The standards of care note that islet cell transplantation may have a role in type 1 diabetes; however, it is considered experimentaland improved blood glucose monitoring technology may be a better alternative.⁵⁸ Because of the need for immunosuppressive agents posttransplantation, the guideline notes that transplantation in type 1 diabetes should be reserved for patients also undergoing renal transplantation or experiencing recurrent ketoacidosis with severe hypoglycemia despite intensive management.

International Consensus Guidelines for Chronic Pancreatitis
In 2020, the International Consensus Guidelines for Chronic Pancreatitis panel released a statement on the role of total pancreatectomy and islet transplant in patients with chronic pancreatitis.⁵⁹ The panel stated that islet transplant should be considered for patients undergoing total pancreatectomy due to the potential for insulin independence and better long-term glycemic outcomes compared to pancreatectomy alone (weak recommendation based on low quality evidence). However, there is not enough information to definitively conclude when transplant should be performed relative to other interventions. Major indications for pancreatectomy with islet transplant include debilitating pain or recurrent pancreatitis episodes that diminish quality of life (strong recommendation based on low quality evidence). Contraindications to pancreatectomy with islet transplant include active alcoholism, pancreatic cancer, end-stage systemic illness, or psychiatric illness or socioeconomic status that would hinder either the procedure itself or posttransplant care (strong recommendation based on low quality evidence). Pancreatectomy with islet transplant improves quality of life, opioid use, and pancreatic pain in this population, but evidence about the effect on healthcare utilization is limited.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT: national clinical trial.

References   

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15. Oberholzer J, Triponez F, Mage R, et al. Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations. Transplantation. Mar 27 2000; 69(6): 1115-23. PMID 10762216
16. Berney T, Mathe Z, Bucher P, et al. Islet autotransplantation for the prevention of surgical diabetes after extended pancreatectomy for the resection of benign tumors of the pancreas. Transplant Proc. May 2004; 36(4): 1123-4. PMID 15194391
17. Ahmad SA, Lowy AM, Wray CJ, et al. Factors associated with insulin and narcotic independence after islet autotransplantation in patients with severe chronic pancreatitis. J Am Coll Surg. Nov 2005; 201(5): 680-7. PMID 16256909
18. Argo JL, Contreras JL, Wesley MM, et al. Pancreatic resection with islet cell autotransplant for the treatment of severe chronic pancreatitis. Am Surg. Jun 2008; 74(6): 530-6; discussion 536-7. PMID 18556996
19. Dixon J, DeLegge M, Morgan KA, et al. Impact of total pancreatectomy with islet cell transplant on chronic pancreatitis management at a disease-based center. Am Surg. Aug 2008; 74(8): 735-8. PMID 18705576
20. Sutherland DE, Gruessner AC, Carlson AM, et al. Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes. Transplantation. Dec 27 2008; 86(12): 1799-802. PMID 19104425
21. Webb MA, Illouz SC, Pollard CA, et al. Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function. Pancreas. Oct 2008; 37(3): 282-7. PMID 18815550
22. Jung HS, Choi SH, Kim SJ, et al. Delayed improvement of insulin secretion after autologous islet transplantation in partially pancreatectomized patients. Metabolism. Nov 2009; 58(11): 1629-35. PMID 19604519
23. Takita M, Naziruddin B, Matsumoto S, et al. Variables associated with islet yield in autologous islet cell transplantation for chronic pancreatitis. Proc (Bayl Univ Med Cent). Apr 2010; 23(2): 115-20. PMID 20396418
24. Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg. Apr 2012; 214(4): 409-24; discussion 424-6. PMID 22397977
25. Walsh RM, Saavedra JR, Lentz G, et al. Improved quality of life following total pancreatectomy and auto-islet transplantation for chronic pancreatitis. J Gastrointest Surg. Aug 2012; 16(8): 1469-77. PMID 22673773
26. Dorlon M, Owczarski S, Wang H, et al. Increase in postoperative insulin requirements does not lead to decreased quality of life after total pancreatectomy with islet cell autotransplantation for chronic pancreatitis. Am Surg. Jul 2013; 79(7): 676-80. PMID 23815999
27. Garcea G, Pollard CA, Illouz S, et al. Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatitis. Pancreas. Mar 2013; 42(2): 322-8. PMID 23407482
28. Gruessner RW, Cercone R, Galvani C, et al. Results of open and robot-assisted pancreatectomies with autologous islet transplantations: treating chronic pancreatitis and preventing surgically induced diabetes. Transplant Proc. Jul-Aug 2014; 46(6): 1978-9. PMID 25131087
29. Wilson GC, Sutton JM, Abbott DE, et al. Long-term outcomes after total pancreatectomy and islet cell autotransplantation: is it a durable operation?. Ann Surg. Oct 2014; 260(4): 659-65; discussion 665-7. PMID 25203883
30. Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors Predicting Outcomes After a Total Pancreatectomy and Islet Autotransplantation Lessons Learned From Over 500 Cases. Ann Surg. Oct 2015; 262(4): 610-22. PMID 26366540
31. Georgiev G, Beltran del Rio M, Gruessner A, et al. Patient quality of life and pain improve after autologous islet transplantation (AIT) for treatment of chronic pancreatitis: 53 patient series at the University of Arizona. Pancreatology. Jan-Feb 2015; 15(1): 40-5. PMID 25455347
32. Takita M, Lara LF, Naziruddin B, et al. Effect of the Duration of Chronic Pancreatitis on Pancreas Islet Yield and Metabolic Outcome Following Islet Autotransplantation. J Gastrointest Surg. Jul 2015; 19(7): 1236-46. PMID 25933581
33. Tai DS, Shen N, Szot GL, et al. Autologous islet transplantation with remote islet isolation after pancreas resection for chronic pancreatitis. JAMA Surg. Feb 2015; 150(2): 118-24. PMID 25494212
34. Wilson GC, Sutton JM, Smith MT, et al. Completion pancreatectomy and islet cell autotransplantation as salvage therapy for patients failing previous operative interventions for chronic pancreatitis. Surgery. Oct 2015; 158(4): 872-8; discussion 879-80. PMID 26173686
35. Mokadem M, Noureddine L, Howard T, et al. Total pancreatectomy with islet cell transplantation vs intrathecal narcotic pump infusion for pain control in chronic pancreatitis. World J Gastroenterol. Apr 28 2016; 22(16): 4160-7. PMID 27122666
36. Shahbazov R, Yoshimatsu G, Haque WZ, et al. Clinical effectiveness of a pylorus-preserving procedure on total pancreatectomy with islet autotransplantation. Am J Surg. Jun 2017; 213(6): 1065-1071. PMID 27760705
37. Fan CJ, Hirose K, Walsh CM, et al. Laparoscopic Total Pancreatectomy With Islet Autotransplantation and Intraoperative Islet Separation as a Treatment for Patients With Chronic Pancreatitis. JAMA Surg. Jun 01 2017; 152(6): 550-556. PMID 28241234
38. Quartuccio M, Hall E, Singh V, et al. Glycemic Predictors of Insulin Independence After Total Pancreatectomy With Islet Autotransplantation. J Clin Endocrinol Metab. Mar 01 2017; 102(3): 801-809. PMID 27870552
39. Solomina J, Golebiewska J, Kijek MR, et al. Pain Control, Glucose Control, and Quality of Life in Patients With Chronic Pancreatitis After Total Pancreatectomy With Islet Autotransplantation: A Preliminary Report. Transplant Proc. Dec 2017; 49(10): 2333-2339. PMID 29198673
40. Morgan KA, Lancaster WP, Owczarski SM, et al. Patient Selection for Total Pancreatectomy with Islet Autotransplantation in the Surgical Management of Chronic Pancreatitis. J Am Coll Surg. Apr 2018; 226(4): 446-451. PMID 29289751
41. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. Feb 15 2011; 91(3): 373-8. PMID 21258272
42. Food and Drug Administration (FDA). Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products. 2009; https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/ CellularandGeneTherapy/UCM182441.pdf. Accessed June 17, 2022.
43. Health Quality Ontario. Pancreas Islet Transplantation for Patients With Type 1 Diabetes Mellitus: A Clinical Evidence Review. Ont Health Technol Assess Ser. 2015; 15(16): 1-84. PMID 26644812
44. Piper M, Seidenfeld J, Aronson N. Islet transplantation in patients with type 1 diabetes mellitus. Evid Rep Technol Assess (Summ). Jul 2004; (98): 1-6. PMID 15366369
45. Lablanche S, Vantyghem MC, Kessler L, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. Jul 2018; 6(7): 527-537. PMID 29776895
46. Lablanche S, Borot S, Wojtusciszyn A, et al. Ten-year outcomes of islet transplantation in patients with type 1 diabetes: Data from the Swiss-French GRAGIL network. Am J Transplant. Nov 2021; 21(11): 3725-3733. PMID 33961335
47. Alejandro R, Barton FB, Hering BJ, et al. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation. Dec 27 2008; 86(12): 1783-8. PMID 19104422
48. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. Jul 2012; 35(7): 1436-45. PMID 22723582
49. Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. Jul 2016; 39(7): 1230-40. PMID 27208344
50. Markmann JF, Rickels MR, Eggerman TL, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Am J Transplant. Apr 2021; 21(4): 1477-1492. PMID 32627352
51. Caiazzo R, Vantyghem MC, Raverdi V, et al. Impact of Procedure-Related Complications on Long-term Islet Transplantation Outcome. Transplantation. May 2015; 99(5): 979-84. PMID 25393157
52. O'Connell PJ, Holmes-Walker DJ, Goodman D, et al. Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. Am J Transplant. Jul 2013; 13(7): 1850-8. PMID 23668890
53. Rickels MR, Kong SM, Fuller C, et al. Improvement in insulin sensitivity after human islet transplantation for type 1 diabetes. J Clin Endocrinol Metab. Nov 2013; 98(11): E1780-5. PMID 24085506
54. Lemos JRN, Baidal DA, Ricordi C, et al. Survival After Islet Transplantation in Subjects With Type 1 Diabetes: Twenty-Year Follow-Up. Diabetes Care. Apr 2021; 44(4): e67-e68. PMID 33579716
55. National Institute for Health and Care Excellence (NICE). Allogenic pancreatic islet cell transplantation for type 1 diabetes mellitus [IPG257]. 2008; https://www.nice.org.uk/Guidance/IPG257. Accessed June 17, 2022.
56. National Institute for Health and Care Excellence (NICE). Autologous pancreatic islet cell transplantation for improved glycaemic control after pancreatectomy [IPG274]. 2008; https://www.nice.org.uk/Guidance/IPG274. Accessed June 16, 2022.
57. Draznin B, Aroda VR, Bakris G, et al. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes-2022. Diabetes Care. Jan 01 2022; 45(Suppl 1): S46-S59. PMID 34964869
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59. Abu-El-Haija M, Anazawa T, Beilman GJ, et al. The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis. Pancreatology. Jun 2020; 20(4): 762-771. PMID 32327370
60. Centers for Medicare & Medicaid. National Coverage Determination (NCD) for ISLET CELL Transplantation in the Context of a Clinical Trial (260.3.1). 2004; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=286&ncdver=1&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyW ord=islet+cell&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAA&. Accessed June 17, 2022.

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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