Medical Policy: 07.03.01 

Original Effective Date: October 2004 

Reviewed: October 2020 

Revised: October 2018 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Autologous islet cell transplantation performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of insulin-dependent diabetes. Allogeneic islet cell transplantation is also being investigated as a treatment or cure for patients with type 1 diabetes.

 

The islet cells come from the patient (autologous transplant) or from a cadaveric donor (allogeneic transplant). Islet cell transplantation may benefit an individual who is without a functioning pancreas. Currently, only individuals with either chronic pancreatitis or type 1 diabetes mellitus have been subject to clinical investigations.

 

Islet Transplantation

Autologous islet cell transplantation is generally performed during the pancreatectomy procedure, and the 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. Because the body recognizes these islet cells as its own, there is no rejection of these cells by the patient’s body.

 

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 3 donor pancreas transplants may be required to achieve insulin dependence. However, a limitation of islet transplantation is that 2 or more donor organs are usually required for a successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole organ transplant is typically used for allogeneic islet transplantation. Therefore, allogeneic 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. A modified immunosuppression regimen has increased the success of allogeneic islet transplantation, this regimen is known as the “Edmonton protocol” (sirolimus, tacrolimus and monoclonal antibody daclizumab).

 

Chronic Pancreatitis

Chronic pancreatitis is inflammation of the pancreas that does not heal or improve, it gets worse over time and leads to permanent damage. Chronic pancreatitis eventually impairs an individual’s ability to digest food and make pancreatic hormones. Individuals with chronic pancreatitis can 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 individual will be rendered an insulin-dependent diabetic.

 

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.

 

Islet transplantation is provided in a hospital setting with specialized staff who are equipped to perform the interventional radiology procedure and manage post-transplant care.

 

Patients

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. Islet transplantation is provided in a hospital setting with specialized staff who are equipped to perform the cell isolation and re-infusion procedures and manage post-transplant care.

 

Comparators

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

 

Outcomes

Outcomes of interest include overall survival, insulin independence, change in disease status, medication use, resource utilization and treatment-related morbidity.

 

Short-term follow-up is required to monitor for treatment related complications and long-term follow-up 1 to 3, 5 or even 10 years is required to establish durability of glucose control.  

 

Systematic Reviews

There are several systematic reviews of the literature on chronic pancreatitis patients.

 

In 2019, Kempeneers et. al. published a systematic review of studies examining pain, endocrine function, or quality of life (QOL) outcomes in patients with chronic pancreatitis undergoing total pancreatectomy with islet transplantation. The review included 15 observational studies evaluating 1,255 patients, of whom 28% had had endoscopic and 23% operative therapy. One year after total pancreatectomy with islet cell auto-transplantation, the opioid-free rate had improved from between 0% and 15% to 63% (95% CI 46-77), and the insulin-free rate had decreased from between 89.5% and 100% to 30% (95% CI 20-43). An alcoholic etiology was associated with a lesser insulin-free rate after total pancreatectomy with islet cell auto-transplantation. Quality of life improved statistically after total pancreatectomy with islet cell auto-transplantation. Publication bias was present for both opioid and insulin outcomes. The authors concluded in selected patients with painful, treatment refractory, chronic pancreatitis, evidence shows that total pancreatectomy with islet cell auto-transplantation is effective for pain control in almost two-thirds of patients, whereas the insulin-free rate is relatively low.

 

In 2015, Wu et. al. published a systematic review and meta-analysis of studies on islet transplantation after total pancreatectomy (TP) for chronic pancreatitis (CP). Twelve studies reporting the outcomes of 677 patients were included in this review. The insulin independent rate for islet autologous transplant (IAT) after total pancreatectomy (TP) at last follow-up was 3.72 per 100 person-years (95% CI: 1.00-6.44). The 30-day mortality was 2.1% (95% CI: 1.2-3.8%). The mortality at last follow-up was 1.09 per 100 person-years (95% CI: 0.21-1.97). Factors associated with incidence density of insulin independence in univariate meta-regression analyses included islet equivalents per kg body weight (IEQ/kgBW) (P=0.026). Our systematic review suggests that IAT is a safe modality for patients with CP need to undergo TP. A significant number of patients will achieve insulin independence for a long time after receiving enough IEQ/kgBW.

 

Nonrandomized Studies

In 2014, Wilson et. al. reported on 166 patients with chronic pancreatitis (CP) who underwent total pancreatectomy and islet autologous transplantation at a single center.  Actuarial 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 improved to 73% at 5 years.

 

Chinnakotla et. al. (2014) reviewed a prospectively maintained database of 484 patients with chronic pancreatitis who underwent a total pancreatectomy (TP) and immediate islet autologous transplantation (IAT) at a single center. The outcomes (e.g., pain relief, narcotic use, β-cell function, health-related quality of life measures) of patients who received TP-IAT for hereditary/genetic pancreatitis (HGP) (protease trypsin 1, n = 38; serine protease inhibitor Kazal type 1, n = 9; cystic fibrosis transmembrane conductance regulator, n = 14; and familial, n = 19) were evaluated and compared with those with non-hereditary/nongenetic causes. All 80 patients with HGP were narcotic dependent and failed endoscopic management or direct pancreatic surgery. Post TP-IAT, 90% of the patients were pancreatitis pain free with sustained pain relief; >65% had partial or full β-cell function. Compared with nonhereditary causes, HGP patients were younger (22 years old vs 38 years old; p ≤ 0.001), had pancreatitis pain of longer duration (11.6 ± 1.1 years vs 9.0 ± 0.4 years; p = 0.016), had a higher pancreas fibrosis score (7 ± 0.2 vs 4.8 ± 0.1; p ≤ 0.001), and trended toward lower islet yield (3,435 ± 361 islet cell equivalent vs 3,850 ± 128 islet cell equivalent; p = 0.28). Using multivariate logistic regression, patients with non-HGP causes (p = 0.019); lower severity of pancreas fibrosis (p < 0.001); shorter duration of years with pancreatitis (p = 0.008); and higher transplant islet cell equivalent per kilogram body weight (p ≤ 0.001) were more likely to achieve insulin independence (p < 0.001). There was a significant improvement in health-related quality of life from baseline by RAND 36-Item Short Form Health Survey and in physical and mental component health-related quality of life scores (p < 0.001). None of the patients in the entire cohort had cancer of pancreatic origin in the liver or elsewhere develop during 2,936 person-years of follow-up. The authors concluded, total pancreatectomy and islet autologous transplantation in patients with chronic pancreatitis due to hereditary/genetic pancreatitis (HGP) cause provide long-term pain relief (90%) and preservation of β-cell function. Patients with chronic painful pancreatitis due to HGP with a high lifetime risk of pancreatic cancer should be considered earlier for total pancreatectomy (TP) and islet autologous transplantation (IAT) before pancreatic inflammation results in a higher degree of pancreatic fibrosis and islet function loss.

 

In 2017, Solomina et. al. analyzed results in 20 patients who underwent TP-IAT at The University of Chicago. The median observation period was 28 months. Data were collected prospectively then analyzed retrospectively. The number of patients requiring opioids daily for pain control decreased from 16 (80%) prior to surgery to 2 (13%) 1 year after, with only 1 (6.5%) patient experiencing persistent phantom pancreatic pain. Opioid requirements decreased from a median 56.3 (0-240) morphine equivalent dose to 5 (0-130) on day 75 and to 0 (0-30) at 1-year follow up. Five patients (25%) completely stopped insulin support prior to day 75 while maintaining hemoglobin A1c of 5.9% (5-6.3). Eight (53%) patients were insulin free at 1 year with A1c of 6% (5.5-6.8) and a similar rate persisted in next 2 years. For the remaining patients, the more islet function that was preserved, the less insulin they required and A1c was closer to optimal. Quality of Life (QoL) measured by SF36 Physical (PCS) and Mental (MCS) Component Score improved on day 75 (P < .001) and maintained improvement later on. Both PCS and MCS improved regardless of whether patient requires insulin support or not. The authors concluded improvements of QoL with pain resolution and good glucose control can be achieved after TP-IAT in properly selected patients with chronic pancreatitis (CP) and intractable pain, regardless of patient insulin support status.

 

In 2018, Morgan et. al. studied patient selection for total pancreatectomy with islet auto-transplantation (TPIAT) in the surgical management of chronic pancreatitis. A prospectively maintained database of patients undergoing TPIAT was reviewed. Islet function was inferred from daily insulin requirement. Pain relief was evaluated by healthcare use and narcotic use. Quality of life (QOL) was measured with the RAND 12-Item Short Form Survey. One hundred and ninety-five patients (141 women, aged 40.3 years, BMI 26.5 kg/m2) underwent TPIAT. Mean duration of disease before operation was 8.1 years. Fifty-six (29%) patients had pancreatic operations before TPIAT, 37 (19%) patients were diabetic preoperatively, and 52 (27%) patients were smokers. A mean of 3,253 islet equivalents transplanted/kg were harvested. Insulin independence was achieved in 29%, 28%, and 23% of patients at 1, 2, and 5 years postoperative. Nonsmokers with a shorter duration of chronic pancreatitis and no earlier pancreas operation were more likely to be insulin free. Median number of preoperative emergency department visits and hospitalizations were 6.6 and 4.3 annually, respectively, compared with 0 at 1, 2, and 5 years postoperative. Median oral morphine equivalents were 214 mg/kg preoperation and 60, 64, 69, at 1, 2, 5 years postoperative. Preoperative, 1, 2, 5 years postoperative QOL scores were 29, 36, 34, and 33 (physical; p < 0.01) and 39, 44, 42, and 42 (mental health; p < 0.02). Genetic pancreatitis patients were more often narcotic free and had better QOL than patients with pancreatitis of other causes. At 5 years, overall survival was 92.3%. The authors concluded total pancreatectomy with islet auto-transplantation is a durable operation, with islet function, pain relief, and QOL improvements persisting to 5 years postoperative. Patients with genetic pancreatitis, short duration of disease, and nonsmokers have superior outcomes.

 

Summary

Autologous islet transplantation is frequently performed as an adjunct to total or near total pancreatectomies 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 I Diabetes

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

 

Clinical Context and Therapy Purpose

The purpose of allogeneic pancreas islet transplantation for patient who have type I diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

 

Patients

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

 

Interventions

The therapy being considered is allogeneic pancreas islet transplantation. Islet transplantation is provided in a hospital setting with specialized staff who are equipped to perform the cell isolation and re-infusion procedures and manage post-transplant care.

 

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

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

 

According to U.S. Food and Drug Administration industry guidance on evaluating allogeneic pancreatic islet cell products, single-arm trials with historical controls may be acceptable alternatives to randomized controlled trials (RCTs) for evaluating the safety and efficacy of islet cell products in patients with metabolically unstable type I diabetes. Attainment of a normal hemoglobin A1C (HbA1C) range (i.e. < 6.5%) and elimination of hypoglycemia are acceptable primary end points. To assess the durability of the islet cell procedure, primary end points should be measured at 12 months after the final infusion. Other key clinical outcomes include insulin independence, measures of glucose metabolic control such as fasting plasma glucose levels 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. 

 

Systematic Reviews

A systematic review by Health Quality Ontario (2015) reported on allogeneic islet transplantation for patients with type I diabetes. The search yielded 1,354 citations. One health technology assessment, 11 additional observational studies to update the health technology assessment, one registry report, and four guidelines were included; the observational studies examined islet transplantation alone, islet-after-kidney transplantation, and simultaneous islet-kidney transplantation. In general, low to very low quality of evidence exists for islet transplantation in patients with type 1 diabetes with difficult-to-control blood glucose levels, with or without kidney disease, for these outcomes: health-related quality of life, secondary complications of diabetes, glycemic control, and adverse events. However, high quality of evidence exists for the specific glycemic control outcome of insulin independence compared with intensive insulin therapy. For patients without kidney disease, islet transplantation improves glycemic control and diabetic complications for patients with type 1 diabetes when compared with intensive insulin therapy. However, results for health-related quality of life outcomes were mixed, and adverse events were increased compared with intensive insulin therapy. For patients with type 1 diabetes with kidney disease, islet-after-kidney transplantation or simultaneous islet-kidney transplantation also improved glycemic control and secondary diabetic complications, although the evidence was more limited for this patient group. Compared with intensive insulin therapy, adverse events for islet-after-kidney transplantation or simultaneous islet-kidney transplantation were increased, but were in general less severe than with whole pancreas transplantation. The authors concluded, for patients with type 1 diabetes with difficult-to-control blood glucose levels, islet transplantation may be a beneficial β-cell replacement therapy to improve glycemic control and secondary complications of diabetes. However, there is uncertainty in the estimates of effectiveness because of the generally low to very low quality of evidence for all outcomes of interest. Additional long-term comparative studies are required for better understanding of continuing effects of transplanted islets and the immunosuppression protocols used.

 

Randomized Controlled Trials

In 2018, Leblanche et. al. published a multicenter, open-label, randomized controlled trial (TRIMECO trial) evaluating patients with type I diabetes with severe hypoglycemia or poorly controlled glycaemia after kidney transplantation. Patients with type I diabetes were randomly assigned (1:1) at 15 university hospital to receive immediate allogeneic islet transplantation or intensive insulin therapy (followed by delayed islet transplantation). Eligible patients were aged 18-65 years and had severe hypoglycemia or hypoglycemia unawareness, or kidney grafts with poor glycaemic control. We used computer-generated randomization, stratified by center and type of patient. Islet recipients were scheduled to receive 11,000 islet equivalents per kg bodyweight in one to three infusions. The primary outcome was proportion of patients with a modified β-score (in which an overall score of 0 was not allocated when stimulated C-peptide was negative) of 6 or higher at 6 months after first islet infusion in the immediate transplantation group or 6 months after randomization in the insulin group. The primary analysis included all patients who received the allocated intervention; safety was assessed in all patients who received islet infusions. This trial is registered with ClinicalTrials.gov, number NCT01148680, and is completed. Between July 8, 2010, and July 29, 2013, 50 patients were randomly assigned to immediate islet transplantation (n=26) or insulin treatment (n=24), of whom three (one in the immediate islet transplantation group and two in the insulin therapy group) did not receive the allocated intervention. Median follow-up was 184 days (IQR 181-186) in the immediate transplantation group and 185 days (172-201) in the insulin therapy group. At 6 months, 16 (64% [95% CI 43-82]) of 25 patients in the immediate islet transplantation group had a modified β-score of 6 or higher versus none (0% [0-15]) of the 22 patients in the insulin group (p<0·0001). At 12 months after first infusion, bleeding complications had occurred in four (7% [2-18]) of 55 infusions, and a decrease in median glomerular filtration rate from 90·5 mL/min (IQR 76·6-94·0) to 71·8 mL/min (59·0-89·0) was observed in islet recipients who had not previously received a kidney graft and from 63·0 mL/min (55·0-71·0) to 57·0 mL/min (45·5-65·1) in islet recipients who had previously received a kidney graft. Trial limitations include possible bias from open-label design as well as an inadequate follow-up period to demonstrate transplant durability. The authors concluded for the indications assessed in this study, islet transplantation effectively improves metabolic outcomes. Although studies with longer-term follow-up are needed, islet transplantation seems to be a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments. However, immunosuppression can affect kidney function, necessitating careful selection of patients.

 

Registry Studies

Thompson et. al. (2011) published findings from a prospective, crossover, cohort study comparing allogeneic islet cell transplantation (ICT) with intensive medical therapy on the progression of diabetic neuropathy, retinopathy, and neuropathy. The study included 45 patients; at the time of data analysis, 32 had receive islet cell transplants. Median follow-up was 47 months pretransplant and 66 months post-transplant. The overall HbA1C level was 7.8% pretransplant and 6.7% post-transplant (p<0.001). In the 16 patients for whom sufficient pre and post-transplant data were available on renal outcomes, the median decline in glomerular filtration rate was -6.7 mL/min/1.73 m2/y pretransplant and -1.3 mL/min/1.73 m2/y posttransplant (p=0.01). 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 post-transplant (p<0.01). The authors concluded, the rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post ICT. There was a nonsignificant trend for improved nerve condition velocity post ICT. Islet cell transplantation is associated with less progression of microvascular complications than intensive medical therapy which might have been due in part to the choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil. Multicenter randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications.

 

Barton et. al. (2012) updated the Collaborative Islet Transplantation Registry (CITR) report, which focused on changes in outcomes over time. A total of 677 allogeneic islet transplant-alone or islet-after-kidney recipients with type I diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years. Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). The authors concluded the CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.

 

Other small case series have reported some success and also adverse events. For example, O’Connell et. al. (2013) reported on 17 patients with type I diabetes with severe hypoglycemia who underwent allogeneic islet transplantation. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation. Most adverse events were related to immunosuppression. Seven (41%) of the 17 patients developed mild lymphopenia and 1 developed colistridium difficile colitis; all responded to treatment. Eight patient developed anemia shortly after transplant and one required a blood transfusion. Procedure-related complications included 1 portal vein thrombosis and 3 postoperative bleeds; 2 of the bleeds required transfusion.

 

Summary

Allogeneic islet transplantation has been investigated in the treatment of type I diabetes. One randomized controlled trial (RCT) found the quality of life (QOL) was significantly improved after islet transplantation; however, the short length of follow-up limits these conclusions. Evidence from registry studies and systematic reviews has demonstrated varying ranges of insulin independence post-transplantation. There is conflicting evidence that allogeneic islet transplantation reduces long-term diabetic complications. Long term comparative studies are needed to determine the effects of allogeneic islet transplantation in type 1 diabetic and post-transplant immunosuppression.

 

Summary of Evidence

For individuals with chronic pancreatitis undergoing total or new total pancreatectomy who receive autologous pancreas islet transplantation, the evidence includes nonrandomized studies and systematic reviews. 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, the autologous islet cell transplant procedure is not associated with serious complications itself and is performed in patients who are already undergoing a pancreatectomy procedure. The evidence is sufficient to determine autologous islet cell transplantation results in a meaningful improvement in net health outcomes.

 

For individuals with type I diabetes who receive allogeneic pancreas islet transplantation, the evidence includes a randomized controlled trial (RCT), a systematic review and registry studies. Results of the 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 dependence has been reported in the registry studies. 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 I diabetics.

 

The evidence is insufficient to determine the effects of allogeneic pancreatic islet transplantation on net health outcomes.

 

Practice Guidelines and Position Statements 

American Diabetes Association

In 2020, the American Diabetes Association updated their guidelines regarding the standards of medial care in diabetes.

 

Comprehensive Medical Evaluation and Assessment of Comorbidities
Recommendation

4.16 Islet auto-transplantation should be considered for patients requiring total pancreatectomy for medically refractory chronic pancreatitis to prevent postsurgical diabetes. (C)

 

Islet auto-transplantation should be considered for patients requiring total pancreatectomy for medically refractory chronic pancreatitis to prevent postsurgical diabetes. Approximately one-third of patients undergoing total pancreatectomy with islet auto-transplantation are insulin free 1 year postoperatively, and observational studies from different centers have demonstrated islet graft function up to a decade after the surgery in some patients. Both patient and disease factors should be carefully considered when deciding the indications and timing of this surgery. Surgeries should be performed in skilled facilities that have demonstrated expertise in islet auto-transplantation.

 

Pharmacologic Approaches to Glycemic Treatment
Surgical Treatment for Type I Diabetes

Pancreas and Islet Transplantation Successful pancreas and islet transplantation can normalize glucose levels and mitigate microvascular complications of type 1 diabetes. However, patients receiving these treatments require lifelong immunosuppression to prevent graft rejection and/or recurrence of autoimmune islet destruction. Given the potential adverse effects of immunosuppressive therapy, pancreas transplantation should be reserved for patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or for those with recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management. With the advent of improved continuous glucose monitors, closed-loop pump-sensor systems, and devices that offer alternative approaches for patients with hypoglycemia unawareness, the role of pancreas transplantation alone, as well as islet transplant, will need to be reconsidered.

 

Organ Procurement and Transplantation Network (OPTN)

Islet Registration Status

In September 2020 the following is the allocation policy of the Organ Procurement and Transplant Network (OPTN) for the allocation of islet cells.

 

A transplant hospital may register an islet candidate on the waiting list with an active status if the candidate meets either of the following requirements:

  • Is insulin dependent
  • Has a hemoglobin A1c (HcA1c) value greater than 6.5%

 

An islet candidate that does not meet either of these requirements above must have an inactive status on the waiting list. If the transplant hospital changes a candidate’s status from inactive to active, the transplant hospital must document that the candidate met one of the above requirements.

 

If a candidate’s clinical condition changes and the candidate becomes inactive, the transplant hospital must report this to the OPTN Contractor within 72 hours of the transplant hospital’s knowledge of this change. The transplant hospital must document in the candidate’s medical record when the transplant hospital learned of this change.

 

If the candidate is active and is insulin independent, then the transplant hospital must document in the candidate’s medical record the candidate’s insulin status and HbA1c value. The transplant hospital must use the most recent HbA1c test performed within the last six months when determining whether the candidate meets the criteria for active status.

 

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.

 

Prior Approval:

Not applicable

 

Policy:

  • See medical policy 07.03.09 Pancreas Transplants (including simultaneous pancreas-kidney, pancreas alone, and pancreas after kidney)

 

Autologous Pancreas Islet Cell Transplantation

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.

 

Autologous pancreas islet cell transplantation is considered investigational when the above criteria is not met and for all other indications because the safety and/or effectiveness of this procedure for all other indications can not be established based on available peer reviewed literature.

 

Allogeneic Pancreas Islet Cell Transplantation

Allogeneic pancreas islet cell transplantation is considered investigational for all indications including the treatment of type 1 diabetes.

 

Based on review of the peer reviewed medical literature results of the 2018 randomized controlled trial (RCT) have suggested some reduction in the number of severe hypoglycemic incidence annually, but limited follow-up and other trial limitation reduce the certainty in conclusions drawn. 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. The evidence is insufficient to determine the effects of allogeneic pancreatic islet transplantation on net health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 48160 Pancreatectomy, total or subtotal, with autologous transplantation of pancreas or pancreatic islet cells.
  • 48999 Unlisted procedure, pancreas (when specified as pancreatic islet cell transplantation)
  • 0584T Islet cell transplant, includes portal vein catheterization and infusion, including all imaging, including guidance, and radiological supervision and interpretation, when performed; percutaneous
  • 0585T Islet cell transplant, includes portal vein catheterization and infusion, including all imaging, including guidance, and radiological supervision and interpretation, when performed; laparoscopic
  • 0586T Islet cell transplant, includes portal vein catheterization and infusion, including all imaging, including guidance, and radiological supervision and interpretation, when performed; open
  • 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 Islet cell tissue transplant from pancreas; allogeneic

 

Selected References:

  • 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). AHRQ Publication No. 04-E017-2. Rockville, MD: Agency for Healthcare Research and Quality. April 2004.
  • Wahoff DC, Papalois BE, Najarian JS, et al. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995; 222(4):562-79.
  • Robertson RP, Lanz KJ, Sutherland DE, et al. Prevention of diabetes for up to 13 years by auto islet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001; 50(1):47-50.
  • TARGET [database online]. Plymouth Meeting (PA): ECRI; 2005 March. Islet cell transplantation for type 1 diabetes.
  • Frank A, Deng S, Huang X et al. Transplantation for type 1 diabetes: comparison of vascularized whole-organ pancreas with isolated pancreatic islets. Ann Surg 2004 Oct; 240(4):631-40.
  • Robertson RP. Islet transplantation as a treatment for diabetes-a work in progress. NEJM. 2004; 350(7):694-705.
  • TARGET [database online]. Plymouth Meeting (PA): ECRI; 2005 March. (Updated 2005 June 27) Islet cell transplantation for type 1 diabetes.
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  • Robertson RP. Islet transplantation as a treatment for diabetes-a work in progress. NEJM. 2004; 350(7):694-705.
  • ECRI. Islet cell transplantation for the treatment of Type 1 diabetes. Plymouth Meeting (PA): ECRI Health Technology Assessment Information Service; 2005 Oct. 80 p. (Windows on medical technology; no. 130).
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  • Posselt AM, Szot GL, Frassetto LA et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on R-cell adhesion or costimulation blockade. Transplantation. 2010 Dec 27;90(12):1595-601.
  • Posselt AM, Bellin MD, Tavakol M et al. Islet transplantation in type 1 diabetes using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. Am J Transplant. 2010 Aug;10(8):1870-80.
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  • Sutherland DE, Radosevich DM, Bellin MD et al. Total pancreatectomy and islet transplantation for chronic pancreatitis. J AM Coll Surg. 2012 Apr;214(4):409-24. Epub 2012 Mar 6.
  • Desai CS, Stephenson DA, Khan KM et al. Novel techniques of total pancreatectomy before autologous islet transplants in chronic pancreatitis patients. J AM Coll Surg. 2011 Dec;213(6):e29-34. Epub 2011 Oct 13.
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  • Jamiolkowski RM, Guo LY, Li YR et al. Islet transplantation in type 1 diabetes mellitus. Yale J Biol Med. 2012 Mar;85(1):37-43. Epub 2012 Mar 29.
  • ECRI Hotline response: Indications and contraindications for Islet Cell Transplantation for Treating Type 1 Diabetes ECRI Institute 2012 Nov.
  • National Institute for Health and Clinical Excellence (NICE) Autologous Pancreatic Islet Cell Transplantation for Improved Glycaemic Control after Pancreatectomy. September 2008.
  • National Institute for Health and Clinical Excellence (NICE) Allogeneic Pancreatic Islet Cell Transplantation for Type 1 Diabetes Mellitus. April 2008.
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  • CMS National Coverage Determination for Pancreas Transplants (260.3).
  • UpToDate. Pancreas and Islet Transplantation in Diabetes Mellitus. R. Paul Robertson, M.D. Topic last updated August 27, 2020.
  • UpToDate. Treatment of Chronic Pancreatitis. Steven D. Freedman, M.D., PhD. Topic last updated October 8, 2013.
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  • Medscape. Type 1 Diabetes Mellitus, updated October 21, 2014. 
  • National Institute for Health and Clinical Excellence (NICE) Type 1 Diabetes in Adults: Diagnosis and Management (NG17), August 2015.
  • Al-Adra. Gill RS, et. al. Single Donor Islet Transplantation and Long Term Insulin Dependence in Select Patients with Type 1 Diabetes Mellitus. Transplantation 2014 Nov 15:98(9):1007-12
  • Anazawa T, Saito T, et. al. Long Term Outcomes of Clinical Transplantation of Pancreatic Islets with Uncontrolled Donors after Cardiac Death: A Multicenter Experience in Japan. Transplant Proc. 2014 Jul-Aug:46(6):1980-4
  • Brooks AM, Oram R, et. al. Demonstration of an Intrinsic Relationship Between Endogenous C-Peptide Concentration and Determinats of Glycemic Control in Type 1 Diabetes Following Islet Transplantation. Diabetes Care 2015 Jan;38(1):105-12
  • Byrne ML, Hopkins D, et. al. Outcomes for Adults with Type 1 Diabetes Referred with Severe Hypoglycaemia and/or Referred for Islet Transplantation to a Specialist Hypoclycaemia Service. Horm Metab Res 2015 Jan;47(1):9-15
  • Caiazzo R, Vantyghem MC, et. al. Impact of Procedure-Related Complications on Long-Term Islet Transplantation Outcome. Transplantation 2015 May:99(5):979-84
  • Colling KP, Blondet JJ, et. al. Positive Sterility Cultures of Transplant Solutions During Pancreatic Islet Autotransplantation are Associated Infrequently with Clinical Infection. Surg Infect (Larchmt). 2015 Apr;16(2):115-23
  • Georgiey G, Beltran Del Rio M, 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 2015 Jan-Feb;15(1):40-5
  • Qi M, Kinzer K, et. al. Five Year Follow-Up of Patients with Type 1 Diabetes Transplanted with Allogeneic Islets: The UIC Experience. Acta Diabetol. 2014 Oct;51(5):833-43
  • Tai Ds, Shen N, et. al. Autologous Islet Transplantation with Remote Islet Isolation after Pancreas Resection for Chronic Pancreatitis. Jama Surg 2015 Feb;150(2):118-24
  • Thakor AS, Sangha BS. et. al. Percutaneous Autologous Pancreatic Islet Cell Transplantation for Traumatic Pancreatic Injury. J Clin Endocrinol Metab 2015 Apr;100(4):1230-3
  • American Diabetes Association Pancreas Transplantation Diabetes Care 2004 Jan;27:s105-S105.
  • 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 Nov;98(11):E1780-5. PMID 24085506
  • Wilson GC, Sutton JM, Abbott DE, et. al. Long-term outcomes after total pancreatectomy and islet cell autotransplantation: is it durable operation? Ann Surg 2014 Oct;260(4):659-65. PMID 25203883 
  • Organ Procurement and Transplant Network (OPTN) Allocation of Kidney-Pancreas and Islets. September 2020.
  • Blumberg E.A., Rogers C.C., The American Society of Transplantation Infectious Diseases Guidelines 3rd Edition, Human Immunodeficiency Virus in Solid Organ Transplantation. American Journal of Transplantation Volume 13, Issue s4 March 2013 Pages 169-178
  • ECRI. Health Technology Forecast News Brief. Islet cell transplantation may improve hypoglycemia awareness in patients with type 1 diabetes, Published April 26, 2016.
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Policy History:

  • October 2020 - Annual Review, Policy Renewed 
  • October 2019 - Annual Review, Policy Renewed 
  • October 2018 - Annual Review, Policy Revised
  • October 2017 - Annual Review, Policy Renewed 
  • October 2016 - Annual Review, Policy Renewed 
  • November 2015 - Annual Review, Policy Renewed
  • December 2014 - Annual Review, Policy Revised
  • February 2014 - Annual Review, Policy Revised
  • March 2013 - Annual Review, Policy Renewed
  • July 2012 - Annual Review, Policy Renewed
  • August 2011 - Annual Review, Policy Renewed

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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