BlueCross and BlueShield of Montana Medical Policy/Codes
Pancreas and Related Organ Tissue Transplantation
Chapter: Transplant
Current Effective Date: December 27, 2013
Original Effective Date: August 17, 2012
Publish Date: September 27, 2013
Revised Dates: April 16, 2012; August 17/2012; September 9, 2013
Description

Pancreas Transplantation

Transplantation of a normal pancreas is a treatment method for patients with insulin-dependent diabetes mellitus (IDDM). Pancreas transplantation can restore glucose control and is intended to prevent, halt, or reverse the secondary complications from diabetes mellitus.

Background

Achievement of insulin independence with resultant decreased morbidity and increased quality of life is the primary health outcome of pancreas transplantation. While pancreas transplantation is generally not considered a life-saving treatment, in a small subset of patients who experience life-threatening complications from diabetes mellitus, pancreas transplantation could be considered life-saving. Pancreas transplant alone (PTA) has also been investigated in patients following total pancreatectomy for chronic pancreatitis. In addition to the immune rejection issues common to all allograft transplants, autoimmune destruction of beta cells has been observed in the transplanted pancreas, presumably from the same mechanism responsible for type 1 diabetes mellitus. (1)

Pancreas transplantation occurs in several different scenarios such as a:

  1. Diabetic patient with renal failure who may receive a cadaveric combined (frequently known as simultaneous) pancreas-kidney transplant (CPK or SPK);
  2. Diabetic patient who may receive a cadaveric or living-related pancreas transplant after a kidney transplantation (pancreas after kidney, i.e., PAK); 
  3. Non-uremic diabetic patient with specific severely disabling and potentially life-threatening diabetic problems who may receive a PTA; or
  4. Segmental pancreas transplantation from a living related donor (LRD) has also been performed. The early rationale for LRD pancreas transplant was to reduce the rejection rate. LRD represents a very small proportion of all pancreas transplants.

The total number of adult pancreas transplants (pancreas and pancreas-kidney) in the U.S. peaked at 1,484 in 2004; the number has since declined. (2) In 2011, there were 287 pancreas transplants and 795 pancreas-kidney transplants in the U.S.

According to International Registry data, the proportion of pancreas transplant recipients worldwide who have type 2 diabetes mellitus has increased over time, from 2% in 1995 to 7% in 2010. (3) In 2010, approximately 8% of SPK, 5% of PAK, and 1% of PTA were performed in patients with type 2 diabetes mellitus.

The approach to retransplantation varies according to the cause of failure. Surgical/technical complications such as venous thrombosis are the leading cause of pancreatic graft loss among diabetic patients. Graft loss from chronic rejection may result in sensitization, increasing both the difficulty of finding a cross-matched donor and the risk of rejection of a subsequent transplant. Each center has its own guidelines based on experience; some transplant centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol.

Potential contraindications subject to the judgment of the transplant center:

  1. Known current malignancy, including metastatic cancer,
  2. Recent malignancy with high risk of recurrence,
  3. Untreated systemic infection making immunosuppression unsafe, including chronic infection,
  4. Other irreversible end-stage disease not attributed to kidney disease,
  5. History of cancer with a moderate risk of recurrence,
  6. Systemic disease that could be exacerbated by immunosuppression,
  7. Psychosocial conditions or chemical dependency affecting ability to adhere to therapy.

In addition, the vast majority of pancreas transplant patients will have type 1 diabetes mellitus. Those transplant candidates with type 2 diabetes mellitus, in addition to being insulin-dependent, should also not be obese (body mass index [BMI] should be 32 or less). According to International Registry data, in 2010, 7% of pancreas transplant recipients had type 2 diabetes mellitus. (3)

Islet Cell Transplantation

Transplantation of pancreatic islet cells is defined as removing isolated islet cells from a donor pancreas to the recipient. In autologous transplantation, the donor and recipient is the same individual. For allogeneic transplantation, the donor and the recipient are not the same individual, but matched as closely as possible to promote islet cell engraftment. Autologous islet transplantation, performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of IDDM. Moreover, allogeneic islet cell transplantation is being investigated as a treatment or cure for patients with type 1 diabetes mellitus.

Background

In autologous islet transplantation, during the pancreatectomy procedure, islet cells are isolated from the resected pancreas using enzymes, and a suspension of the cells is injected into the portal vein of the patient’s liver. Once implanted, the beta cells in these islets begin to make and release insulin.

In the case of allogeneic islet cell transplantation, cells are harvested from the deceased donor’s pancreas, processed, and injected into the recipient’s portal vein. Up to 3 donor pancreas transplants may be required to achieve insulin independence. Allogeneic transplantation may be performed in the radiology department.

Chronic pancreatitis: Primary risk factors for chronic pancreatitis include toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive (the TIGAR-O classification system). Patients with chronic pancreatitis may experience intractable pain that can only be relieved with a total or near total pancreatectomy. However, the pain relief must be balanced against the certainty that the patient will be rendered an insulin-dependent diabetic. Autologous islet transplantation has been investigated as a technique to prevent this serious morbidity.

Type 1 diabetes mellitus: Allogeneic islet transplantation has been used for type 1 diabetes mellitus to restore normoglycemia and, ultimately, reduce or eliminate the long-term complications of diabetes mellitus such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. However, a limitation of islet transplantation is that 2 or more donor organs are usually required for successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole-organ transplant is typically used for islet transplantation. Therefore, islet transplantation has generally been reserved for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin-based management.

Regulatory Status

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

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan or contract, the benefit plan or contract will govern.

Coverage

Pancreas Transplantation

The following individual pancreatic transplantation procedures may be considered medically necessary when following specific indications or criteria are met:

  • A pancreas transplant alone (PTA) for patients with severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and labile diabetes that persists in spite of optimal medical management (refer to NOTE below);
  • A combined (or simultaneous) pancreas-kidney transplant (CPK) for insulin dependent diabetic mellitus (IDDM) patients with uremia;
  • A pancreas transplant, after a prior kidney transplant (PAK) for patients with insulin dependent diabetes mellitus (IDDM); or
  • Pancreatic retransplantation (PR), after a failed primary pancreas transplant.

NOTE: Candidates for a pancreas transplant alone should meet ONE of the following severities of illness criteria:

  • Documentation of severe hypoglycemia unawareness as evidenced by chart notes or emergency room visits; or
  • Documentation of potentially life threatening labile diabetes mellitus as evidenced by chart notes or hospitalization for diabetic ketoacidosis.

NOTE:  For kidney transplantation, see policy SUR703.007, Kidney Transplants.

The following individual pancreatic transplantation procedures are considered experimental, investigational and unproven:

  • Pancreatic retransplantation (PR) after two or more failed pancreas transplants;
  • Transplantation of a segment of a pancreas from a living related donor (i.e., head or tail sections).

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.

Allogeneic pancreas islet cell transplantation is considered experimental, investigational and unproven.

Policy Guidelines

Between 2006 and 2012, there were 3 category III CPT codes specific to islet cell transplantation (0141T, 0142T, and 0143T). As of 1/2012, these codes have been deleted. CPT now instructs the use of code 48999 (unlisted procedure, pancreas) for these procedures.

Rationale

The most recent search was performed for the period up through August 2013. Much of the published literature consists of case series reported by single centers and registry data. The extant randomized controlled trials (RCTs) compare immunosuppression regimens and surgical techniques and therefore do not address the comparison of pancreas transplantation to insulin therapy, combined (or simultaneous) pancreas-kidney (CPK or SPK) transplant to insulin therapy and hemodialysis, or islet cell transplantation to insulin therapy.

Pancreas Transplantation

This policy is based in part on a 1998 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, which focused on pancreas graft survival and health outcomes associated with both pancreas transplant alone (PTA) and pancreas after kidney transplant (PAK). (4) A 2001 BCBSA TEC Assessment focused on the issue of pancreas retransplant. (5) The assessments and subsequent evidence offer the following observations and conclusions:

Pancreas Transplant Alone (PTA)

PTA graft survival has improved in recent years. According to International Registry data 1-year graft function increased from 51.5% in 1987-1993 to 77.8% in 2006-2010 (p<0.0001). (3) One-year immunologic graft loss remains higher (6%) after PTA than pancreas after kidney (PAK) (3.7%) or combined pancreas-kidney (SPK) (1.8%). In carefully selected patients with insulin dependent diabetes mellitus (IDDM) and severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and labile diabetes mellitus that persists despite optimal medical management, the benefits of PTA were judged to outweigh the risk of performing pancreas transplantation with subsequent immunosuppression.

The majority of patients undergoing PTA are those with either hypoglycemic unawareness or labile diabetes mellitus. However, other exceptional circumstances may exist where nonuremic IDDM patients have significant morbidity risks due to secondary complications of diabetes mellitus (i.e., peripheral neuropathy) that exceed those of the transplant surgery and subsequent chronic immunosuppression. Because there is virtually no published evidence regarding outcomes of medical management in this very small group of exceptional diabetic patients, it is not possible to generalize about which circumstances represent appropriate indications for pancreas transplantation alone. Case-by-case consideration of each patient’s clinical situation may be the best option for determining the balance of risks and benefits.

Noting that nephrotoxic immunosuppression may exacerbate diabetic renal injury after PTA, in 2008 Scalea et al. reported a single institutional review of 123 patients who received 131 PTA for development of renal failure. (6) Mean graft survival was 3.3 years (range, 0–11.3), and 21 patients were lost to follow-up. Mean estimated glomerular filtration rate (eGFR) was 88.9 pre-transplantation versus 55.6 post-transplantation, with mean follow-up of 3.7 years. All but 16 patients had a decrease in eGFR, and mean decrement was 32.1 mg/min/1.73. Thirteen developed end-stage renal disease, which required kidney transplantation at a mean of 4.4 years. The authors suggested that patients should be made aware of the risk and only the most appropriate patients offered PTA.

Pancreas after Kidney (PAK) Transplant

PAK transplantation allows the uremic patient the benefits of a living-related kidney graft, if available and the benefits of a subsequent pancreas transplant that is likely to result in improved quality of life compared to a kidney transplant alone. Uremic patients for whom a cadaveric kidney graft is available, but a pancreas graft is not simultaneously available benefit similarly from a later pancreas transplant. Based on International Pancreas Registry data, at 5 years post-transplant, the patient survival rate after PAK is 83%. (3)

In 2009, Fridell and colleagues reported a retrospective review (n=203) of a single center’s experience with PAK and SPK since 2003, when current induction or tacrolimus immunosuppressive strategies became standard. (7) Of the cases studied, 61 (30%) were PAK and 142 (70%) were SPK. One-year patient survival rates were 98% and 95% (PAK and SPK, respectively; p=0.44). Pancreas graft survival rates at 1 year were observed to be 95% and 90%, respectively (p=0.28). The authors concluded that in the modern immunosuppressive era, PAK should be considered as an acceptable alternative to SPK in candidates with an available living kidney donor.

In 2012, Bazarbachi and colleagues reviewed a single center’s experience with PAK and SPK. (8) Between 2002 and 2010, 172 pancreas transplants were performed in diabetic patients; 123 SPK and 49 PAK. The median length of time between kidney and pancreas transplantation in the PAK group was 4.8 years. Graft and patient survival rates were similar in the 2 groups. Death-censored pancreas graft survival rates for SPK and PAK were 94% and 90% at 1 year, 92% and 90% at 3 years, and 85% and 85% at 5 years (all respectively, p=0.93). Patient survival rates (calculated beginning at the time of pancreas transplantation) in the SPK versus PAK groups were 98.3% and 100% after 1 year, 96.4% and 100% after 3 years, and 94.2% and 100% after 5 years (all respectively, p=0.09).

Kleinclauss and colleagues retrospectively examined data from diabetic kidney transplant recipients (n=307) from a single center and compared renal graft survival rates in those who subsequently received a pancreatic transplant to those who did not. (9) The comparative group was analyzed separately depending on whether they were medically eligible (kidney transplant alone [KTA]-E) for pancreas transplant, but chose not to proceed for financial or personal reasons, or were ineligible (KTA-I) for medical reasons. The KTA-I (n=57) group differed significantly at baseline from both the PAK group (n=175) and the KTA-E group (n=75) with respect to age, type of diabetes mellitus, and dialysis experience; kidney graft survival rates were lower than either of the other groups, with 1-, 5-, and 10-year rates of 75%, 54%, and 22%, respectively (p<0.0001). The PAK and KTA-E groups were similar in age, race, type of diabetes mellitus, and dialysis experience. The authors compared 1--, 5-, and 10-year kidney graft survival rates in PAK patients with those in the KTA-E group: 98%, 82%, and 67% versus 100%, 84%, and 62%, respectively, and concluded that the subsequent transplant of a pancreas after a living donor kidney transplant does not adversely affect patient or kidney graft survival rates.

Combined (or Simultaneous) Pancreas-Kidney (CPK or SPK) Transplant

According to International Registry data through 2005, recent 5-year graft survival rates for SPK transplants are 72% for the pancreas and 80% for the kidney. (10) Ten-year graft survival rates have reached almost 60% for SPK transplants.

In 2010, Mora and colleagues described the long-term outcome of 12 patients 15 years following SPK transplant. (11) Metabolic measures of glucose control were measured at 1, 5, 10, and 15 years following the procedure. Of this subset of patients, 6 (50%) had non-diabetic glucose challenge tests. Basal serum insulin levels declined over this period as well, from 24 mU/L to 16 mU/L at 1 and 15 years, respectively. The authors conclude that in a select group of patients whose pancreatic graft continued to function after 15 years, some glycemic control continued, albeit in a diminished fashion. It should be noted that this represents a small fraction of the 367 patients receiving the SPK transplant at this single center (12 of 367 SPK; 3.3%). The number of allograft survivals at 5 or more, and 10 or more years in this study was 43 (11.7%) and 28 (7.6%), respectively.

The improved glycemic control that may occur in SPK transplant patients, principally in those with labile disease while on medical therapy alone, is purported to reduce risk of complications from the diabetic disease. In 2009, Davenport and colleagues published results of a registry review (n=58) on cardiovascular risk factors in an Irish study of SPK transplant recipients. (12) Glycosylated hemoglobin values fell from a mean of 8.1 to 5.2 (p<0.0001) from pre-transplant levels. Similar statistically significant declines were seen in total cholesterol, triglycerides, and creatinine. Systolic and diastolic blood pressures were likewise improved but with a greater range of pre- and post-transplant variability. These endpoints are commonly accepted as surrogates for cardiovascular risk. The authors compared both a surgical method (bladder vs. enteric drainage) and mode of immunosuppression (cyclosporine vs. tacrolimus) on changes to blood pressure and cholesterol. No significant differences were found in either measure based on surgical drainage method, nor did immunosuppressive therapy have an impact on blood pressure reduction. Cholesterol reduction was greater in the cyclosporine than the tacrolimus group (-1.3 to -0.2, respectively), favoring the less contemporary strategy. The authors note that this is in contrast to other recently published studies favoring both enteric drainage and tacrolimus. While this single-arm study suggests beneficial cardiovascular effects from transplant, other factors such as rejection rates are more likely to influence the conditions under which transplantations take place, and this study’s data do not lead to conclusions that would change the policy statement.

In 2011, Sampaio and colleagues published an analysis of data from the United Network for Organ Sharing (UNOS) database. (13) The investigators compared outcomes in 6,141 patients with type 1 diabetes mellitus and 582 patients with type 2 diabetes mellitus who underwent SPK between 2000 and 2007. In adjusted analyses, outcomes were similar in the 2 groups. After adjusting for other factors such as body weight; dialysis time; and cardiovascular comorbidities, type 2 diabetes mellitus was not associated with an increased risk of pancreas or kidney graft survival, or mortality compared to type 1 diabetes mellitus.

Pancreas Retransplantation

The U.S.-based Organ Procurement Transfer Network (OPTN) reported data on transplants performed between 1997 and 2004. (2) Patient survival rates after repeat transplants were similar to survival rates after primary transplants. For example, the 1-year survival rate was 94.0% (95% confidence interval [CI]: 92.6 to 95.3%) after a primary pancreas transplant and 95.6% (95% CI: 92.7 to 98.5%) after a repeat pancreas transplant. The numbers of patients transplanted was not reported, but the OPTN data stated that 1,217 patients were alive 1 year after primary transplant and 255 after repeat transplants. Three-year patient survival rates were 89.5% (95% CI: 87.8 to 91.2%) after primary transplants and 89.7% (95% CI: 85.9 to 93.5) after repeat transplants. One-year graft survival rates were 78.2% (95% CI: 76.0 to 80.5%) after primary pancreas transplants and 70.4% (95% CI: 64.8 to 76.0%) after repeat transplants.

Data are similar for patients receiving SPK transplants, but follow-up data are only available on a small number of patients who had repeat kidney/pancreas transplants so estimates of survival rates in this group are imprecise. Three-year patient survival rates were 90.0% (95% CI: 89.0 to 91.0%) after primary combined transplant and 79.9% (95% CI: 63.8 to 95.9%) after a repeat combined transplant. The number of patients who were living 3 years after transplant was 2,907 after a primary combined procedure and 26 after a repeat combined procedure.

In 2013, Buron and colleagues reported on their experience with pancreas retransplantation in France and Geneva. (14) Between 1976 and 2008, 568 pancreas transplants were performed at 2 centers, including 37 repeat transplants. Patient survival after a repeat pancreas transplant was 100% after 1 year and 89% after 5 years. Graft survival was 64% at 1 year and 46% at 5 years. Among the 17 patients who underwent a second transplant in a later time period i.e., between 1995 and 2007, graft survival was 71% at 1 year and 59% at 5 years. In this more recently transplanted group, graft survival rates were similar to primary pancreas transplants, which was 79% at 1 year and 69% at 5 years.

Immunosuppressive Regimen

Pancreas transplantation requires T cell autoantibody induction, which most solid organ transplantations do not. As a consequence, a variety of studies, including RCTs, have examined various immunosuppressive regimens. (15-20) This high-quality evidence adds to our understanding of transplant management but does not compare pancreas transplant to alternatives and therefore does not contribute to the evidence base for this policy.

HIV+ Transplant Recipients

The Organ Procurement Transfer Network (OPTN) policy on Identification of Transmissible Diseases in Organ Recipients states: “Potential candidate for organ transplantation whose test for HIV [human immunodeficiency virus] is positive should not be excluded from candidacy for organ transplantation unless there is a documented contraindication to transplantation based on local policy.” (21)

In 2006, the British HIV Association and the British Transplantation Society Standards Committee published guidelines for kidney transplantation in patients with HIV disease. (22) As described above, these criteria may be extrapolated to other organs. The guidelines recommend that any patient with end-stage organ disease with a life expectancy of at least 5 years is considered appropriate for transplantation under the following conditions:

  • CD4 count greater than 200 cells/microliter for at least 6 months
  • Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months
  • Demonstrable adherence and a stable HAART [highly active antiretroviral therapy] regimen for at least 6 months
  • Absence of AIDS [acquired immunodeficiency syndrome]-defining illness following successful immune reconstitution after HAART.

Age

Several 2011 studies addressed pancreas transplantation in individuals 50 years of age or older. A study by Afaneh and colleagues reviewed data on 17 individuals at least 50 years-old and 119 individuals younger than 50 years who had a pancreas transplant at a single institution in the U.S. (23) The 2 groups had similar rates of surgical complications, acute rejection and non-surgical infections. Overall patient survival was similar. Three- and 5-year survival rates were 93% and 90% in the younger group and 92% and 82%, all consecutively, in the older group. Schenker and colleagues in Germany compared outcomes in 69 individuals at least 50 years-old and 329 individuals younger than 50 years who had received a pancreas transplant. (24) Mean duration of follow-up was 7.7 years. One-, 5-, and 10-year patient and graft survival rates were similar in the 2 groups. For example, the 5-year patient survival rate was 89% in both groups. The 5-year pancreas grant survival rate was 76% in the older group and 72% in the younger group. The authors of both studies, as well as the authors of a commentary accompanying the Schenker article, (25) agreed that individuals age 50 years and older are suitable candidates for pancreas transplantation.

Practice Guidelines and Position Statements

In 2010, the Board of Directors of OPTN/UNOS approved changes to address concerns related to local variations in the allocation system for pancreas transplant. (26) The policy changes attempt to reduce the discarding of pancreas donations that have been declined in the context of PTA but which may have been utilized if offered in the setting of SPK. The effect of the policy changes on availability of pancreas donations for transplant alone or in combination with kidney transplants is unknown.

A technology assessment was produced by the Canadian Agency for Drugs and Technology in Health in 2007. (27) The authors did not identify any studies that would contribute additional evidence to this policy. The assessment states: “Given that pancreas transplantation has been widely disseminated for years, it is unlikely that well-designed RCTs that examine pancreas transplantation will occur because ethical and logical complications will prevent this…Pancreas transplantation is an accepted treatment for patients with type I diabetes and end-stage renal disease (ESRD). This has occurred despite the absence of high quality, robust evidence.”

Summary for Pancreas Transplantation

The literature, consisting primarily of case series and registry data, demonstrate graft survival rates comparable to other solid organ transplants, as well as attendant risks associated with the immunosuppressive therapy necessary to prevent allograft rejection. No RCTs have compared any form of pancreas transplant to insulin therapy. Pancreas transplant may be considered medically necessary in patients who are undergoing, or have undergone, kidney transplantation for renal failure. It may also be considered medically necessary as a stand-alone treatment in patients with hypoglycemia unawareness and labile diabetes mellitus despite optimal medical therapy and in whom severe complications have developed.

Islet Cell Transplantation

This section of the current policy has been substantially revised. Following is a summary of the key literature to date.

Autologous Islet Cell Transplantation for Chronic Pancreatitis

In 2012, Bramis and colleagues published a systematic review of studies on islet transplantation after total pancreatectomy in patients with chronic pancreatitis. (29) The investigators searched for studies reporting on patients who had been treated with total, subtotal or completion pancreatectomy followed by islet autotransplantation. Case series were included if they included more than 5 individuals and reported outcomes for consecutive patients. A total of 72 full-text articles were reviewed, and 5 studies were found to meet inclusion criteria. The postoperative insulin independence rate in the 5 studies ranged from 10% (mean follow-up=8 years) to 46% (mean follow-up=5 years). In the study with the longest follow-up, the insulin independence rate was 28% at 10 years. Two studies reported postoperative morphine use. In one study, patients reported a mean post-operative decrease in morphine use of 116 mg and in the other, a mean decrease of 55 mg of morphine was reported.

An earlier systematic review of studies on islet transplantation after pancreatectomy was published in 2011 by Dong and colleagues. (30) Studies were included regardless of design or sample size. After reviewing 84 studies, 15 observational studies were found to meet eligibility criteria. There were 11 studies of total pancreatectomy, 2 studies of partial pancreatectomy, and 2 studies that included both types of surgery. Sample sizes in individual studies ranged from 3 to 173 patients. Thirteen studies included patients with chronic pancreatitis, and 2 included patients with benign pancreatic tumors. The pooled 30-day mortality was 5% (95% confidence interval [CI]: 2 to 10%), and the cumulative mortality at 1 year (reported by 10 studies) was 4.9% (95% CI: 2.6 to 7.3%) In a pooled analysis of data from 14 studies, the rate of insulin dependence at last follow-up was 4.6 per 100 person years (95% CI: 1.53 to 7.62). The pooled rate of insulin independence at 1 year (5 studies) was 27% (95% CI: 21-33%) and at 2 years (3 studies) was 21% (95% CI: 16-27%).

Representative studies included in the systematic reviews or published more recently are described below:

  • A large single center series was reported by Sutherland and colleagues in 2012. (31) The study included 409 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation between February 1977 and September 2011. Fifty-three of the 409 patients (13%) were children between the ages of 5 and 18 years. Actuarial survival post-surgery was 96% in adults and 98% in children after 1 year and 89% in adults and 98% in children after 5 years. A total of 15.9% of patients experienced surgical complications requiring reoperation during the initial admission. The most common reason for reoperation was bleeding, occurring in 9.5% of patients. At 3 years, 30% of patients were IDDM (25% of adults and 55% of children). A survey of quality-of-life outcomes was initiated in October 2008; responses were available for 102 patients. At baseline, all 102 patients reported using narcotics for pain. At 12 months, the proportion of patients on narcotics decreased to 56% (n=32), and at 24 months, 41% of respondents (n=21) reported using narcotics.
  • In 2008, Webb and colleagues reported on 46 patients who had total pancreatectomy with immediate islet cell autologous transplant. (32) Twelve had periods of insulin independence for a median of 16.5 months (range, 2–63 months), and 5 remain insulin-independent. (32) Insulin requirements increased over the 10-year follow-up, as have HgA1c levels; however, all patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide positive values recorded at 10 years after transplantation suggest significant graft function in the long term.

Allogeneic Islet Cell Transplantation for Type 1 Diabetes Mellitus

In April 2004, BCBSA TEC completed an evidence report on islet cell transplantation in type 1 diabetes in its capacity as an Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). (33) The evidence report found that published data on clinical outcomes of islet-alone transplantation were limited by small patient numbers, few transplant centers, short duration of follow-up, and lack of standardized methods of reporting clinical outcomes. Rare, serious adverse events have occurred in patients given islet transplants; recent procedure modifications reportedly minimize risks of these adverse events. No procedure-related deaths, cytomegalovirus (CMV) infection, or post-transplantation lymphoproliferative disease (PTL) have been reported for islet-alone transplantation.

The 2008 report from the Collaborative Islet Transplant Registry (CITR), which collects and monitors data on allogeneic islet transplantation in North America, Europe, and Australia, had 325 adult recipients in their registry as of April 2008. (34) Three years after first infusion, 23% of islet-alone recipients were insulin-independent (defined as insulin-independent 2 or more weeks), 29% were insulin-dependent with detectable C-peptide, 26% had lost function, and 22% had missing data. Seventy percent achieved insulin independence at least once, 71% of whom were still insulin-independent 1 year later and 52% at 2 years. Factors that favored primary outcomes were higher number of islet infusions, greater number of total islet equivalents infused, lower pretransplant HbA1c levels, processing centers related to the transplant center, and larger islet size. The CITR published an updated report in 2012; the focus of the article was changes in outcomes over time. (35) The number of patients receiving islet transplants was 214 during 1999-2002, 255 between mid-2003-2006 and 208 from 2007-2010. A total of 575 of the 677 (85%) islet transplant recipients received islets only; the remainder underwent simultaneous kidney and islet transplants. In the 1999-2002 group, rates of insulin independence were 51% after 1 year, 36% after 2 years and 27% after 3 years. Rates for the 2007-2010 group were 66%, 55% and 44%, respectively. The incidence of clinically reportable adverse events in the first year after infusion decreased from 50-53% in 1999-2006 to 38% in 2007-2010. The rates of peritoneal hemorrhage or gallbladder infusion were 5.4% in 1999-2003 and 3.1% in 2007-2010. The authors did not report findings separately for the subset of patients who underwent islet-only transplants. Additionally to the fewer adverse effects reported, the authors concluded there were fewer islet infusions as the eras progressed from 1999-2002, through mid-2003-2006, and finally 2007-2010. Overall, the authors reported the CITR data represented 81% of all islet transplants performed in North America and European/Australian centers. The authors await further investigation to efficacy and safety standardization.

In 2011, Thompson and colleagues in Canada published findings from a prospective cross-over study of intensive medical therapy (pretransplant) versus islet cell transplantation in patients with type 1 diabetes mellitus. (36) The article reported on 45 patients; at the time of data analysis, 32 had received islet cell transplants. Median follow-up was 47 months pre-transplant and 66 months post-transplant. The overall mean HbA1c was 7.8% pretransplant and 6.7% post-transplant; this difference was statistically significant, p<0.001. In the 16 patients for whom sufficient data pre- and post-transplant were available on renal outcomes, the median decline in glomular filtration rate (GFR, mL/min/month) was -6.7 pretransplant and -1.3 post-transplant (p=0.01). Retinopathy was assessed using the International Scale, which categorizes nonproliferative diabetic retinopathy as mild, moderate, or severe. Retinopathy progressed in 10 of 82 (12%) eyes pretransplant versus 0 of 51 post-transplant (p<0.01). (The numbers of patients in the retinopathy analyses was not reported). The rate of change in nerve conduction velocity did not differ significantly between groups (exact numbers not reported). The authors noted that their finding of reduced microvascular complications after islet transplantation may be due, in part, to their choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil (MMF).

In 2012, Vantyghem and colleagues reported on 23 patients with type 1 diabetes mellitus who underwent islet transplantation; 14 had islet-only transplants and 9 had islet after kidney transplants. (37) Median HbA1c was 8.3% at baseline and 6.7% at 3 years. Ten of the 23 patients (43%) were insulin independent 3 years after islet transplantation. Findings were not reported separately for the islet-only transplant recipients.

Recent papers have highlighted research in the areas of islet cell regenerative therapy including stem-cell technology, encapsulating islets to protect them from the host immune system by a semipermeable capsule, and xenotransplantation. (38-42) In addition, novel immunosuppressive regimens using biologics have been discussed. (43-44)

Ongoing Clinical Trials

A comparison of strict glucose control with usual care at the time of islet cell transplantation (NCT01123122) (45): This is a single-center randomized controlled trial (RCT) comparing the impact of strict glucose control versus usual care prior to islet cell transplantation on outcomes in patients with type 1 diabetes mellitus. The primary study outcome is islet cell function 3 months post-transplantation. The estimated enrollment is 32 patients, and the estimated study completion date is September 2015.

A comparison of islet cell transplantation with medical therapy on the risk of progression of diabetic retinopathy and diabetic macular edema (NCT00853424) (46): This RCT is comparing islet cell transplantation to standard medical therapy in patients with diabetic eye disease. The primary outcome is progression of diabetic retinopathy or moderate visual loss. The estimated enrollment is 40 patients, and the estimated study completion date is June 2015.

Practice Guidelines and Position Statements

Guidance from the National Institute for Clinical Excellence (NICE), published in 2008, states that the evidence on allogeneic pancreatic islet cell transplantation for type 1 diabetes mellitus shows short-term efficacy with some evidence of long-term efficacy. (47) Evidence on safety shows that serious complications may occur, and the long-term immunosuppression required is also associated with risk of adverse events. The procedure is particularly indicated for patients with hypoglycemia unawareness or those already on immunosuppressive therapy because of renal transplantation. A 2008 update of guidance on autologous islet cell transplantation for improved glycemic control after pancreatectomy states that studies show some short-term efficacy, although most patients require insulin therapy in the long term. Complications mainly result from the major surgery involved in pancreatectomy rather than from the islet cell transplantation. (48)

Summary for Islet Cell Transplantation

Autologous islet transplantation is proposed in conjunction with pancreatectomy for patients with chronic pancreatitis. Although the published experience with autologous islet cell transplantation is limited, the procedure appears to significantly decrease the incidence of diabetes mellitus after total or near total pancreatectomy in patients with chronic pancreatitis. In addition, this procedure is not associated with serious complications itself and is performed as an adjunct to the pancreatectomy procedure. Thus, this may be considered medically necessary.

The techniques for allogeneic islet cell transplants are evolving, and the impact on the net health outcome is still uncertain. Moreover, longer follow-up with larger numbers of patients is needed before conclusions can be drawn about the safety of allogeneic islet transplantation and its impact on diabetes mellitus and associated complications. Thus, this technology is considered experimental, investigational and unproven for patients with diabetes mellitus type 1.

Coding

Disclaimer for coding information on Medical Policies           

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.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

52.59, 52.6, 52.80, 52.81, 52.82, 52.83, 52.84, 52.85, 52.86, 52.99, 55.51, 55.53, 55.61, 55.69, 250.01 - 250.93, 577.1, 996.86

ICD-10 Codes

E10.10-E10.11, E10.21-E10.29,  E10.641-E10.649, E10.69, E10.8, K86.1, T86.890-T86.899, Z90.5, 3E033U0, 3E0J3U0, 3E0J7U0, 3E0J8U0, 0FYG0Z0, 0FYG0Z1, 0FSG0ZZ, 0FSG4ZZ

Procedural Codes: 48160, 48550, 48551, 48552, 48554, 48556, 48999, 50300, 50320, 50323, 50325, 50327, 50328, 50329, 50340, 50360, 50365, 50370, 50380, G0341, G0342, G0343, S2054, S2055, S2065, S2102, S2152
References

Pancreas Transplantation (1-28); Islet Cell Transplantation (29-50)

  1. Hirshberg B. The cardinal features of recurrent autoimmunity in simultaneous pancreas-kidney transplant recipients. Curr Diab Rep 2010; 10(5):321-2.
  2. Organ Procurement and Transplantation Network (OPTN). Available online at: http://optn.transplant.hrsa.gov. Last accessed 2013 January.
  3. Gruessner AC. 2011 update on pancreas transplantation: Comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry. Rev Diabet Stud 2011; 8(1):6-16.
  4. Pancreas Transplantation. Chicago, Illinois: Blue Cross Blue Shield Assocation – Technology Evaluation Center Assessment Program (1998 May) 15 (7):1-31.
  5. Pancreas Retransplantation. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program. (2002 April) 16 (25):1-31.
  6. Scalea JR, Butler CC, Munivenkatappa RB et al. Pancreas transplant alone as an independent risk factor for the development of renal failure: a retrospective study. Transplantation 2008; 86(12):1789-94.
  7. Fridell JA, Mangus RS, Hollinger EF et al. The case for pancreas after kidney transplantation. Clin Transplant 2009; 23(4):447-53.
  8. Bazerbachi F, Selzner M, Marquez MA et al. Pancreas-After-Kidney Versus Synchronous Pancreas-Kidney Transplantation: Comparison of Intermediate-Term Results. Transplantation 2012.
  9. Kleinclauss F, Fauda M, Sutherland DE et al. Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transplant 2009; 23(4):437-46.
  10. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant 2012; 17(1):100-5.
  11. Mora M, Ricart MJ, Casamitjana R et al. Pancreas and kidney transplantation: long-term endocrine function. Clin Transplant 2010; 24(6):E236-40.
  12. Davenport C, Hamid N, O'Sullivan EP et al. The impact of pancreas and kidney transplant on cardiovascular risk factors (analyzed by mode of immunosuppression and exocrine drainage). Clin Transplant 2009; 23(5):616-20.
  13. Sampaio MS, Kuo HT, Bunnapradist S. Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic patients. Clin J Am Soc Nephrol 2011; 6(5):1198-206.
  14. Buron F, Thaunat O, Demuylder-Mischler S et al. Pancreas Retransplantation: A Second Chance for Diabetic Patients? Transplantation 2013; 95(2):347-52.
  15. Girman P, Lipar K, Koznarova R et al. Similar early complication rate in simultaneous pancreas and kidney recipients on tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus immunosuppressive regimens. Transplant Proc 2010; 42(6):1999-2002.
  16. Kaufman DB, Iii GW, Bruce DS et al. Prospective, randomized, multi-center trial of antibody induction therapy in simultaneous pancreas-kidney transplantation. Am J Transplant 2003; 3(7):855-64.
  17. Knight RJ, Kerman RH, Zela S et al. Thymoglobulin, sirolimus, and reduced-dose cyclosporine provides excellent rejection prophylaxis for pancreas transplantation. Transplantation 2003; 75(8):1301-6.
  18. Reddy KS, Stablein D, Taranto S et al. Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J Kidney Dis 2003; 41(2):464-70.
  19. Stratta RJ, Alloway RR, Lo A et al. Two-dose daclizumab regimen in simultaneous kidney-pancreas transplant recipients: primary endpoint analysis of a multicenter, randomized study. Transplantation 2003; 75(8):1260-6.
  20. Cantarovich D, Vistoli F. Minimization protocols in pancreas transplantation. Transpl Int 2009; 22(1):61-8.
  21. Organ Procurement and Transplantation Network (OPTN). Identification of Transmissible Diseases in Organ Recipients. Available online at: http://optn.transplant.hrsa.gov. Last accessed 2013 January.
  22. Bhagani S, Sweny P, Brook G. Guidelines for kidney transplantation in patients with HIV disease. HIV Med 2006; 7(3):133-9.
  23. Afaneh C, Rich BS, Aull MJ et al. Pancreas transplantation: does age increase morbidity? J Transplant 2011; 2011:596801.
  24. Schenker P, Vonend O, Kruger B et al. Long-term results of pancreas transplantation in patients older than 50 years. Transplant Int 2011; 24(2):136-42.
  25. Gruessner AC, Sutherland DE. Access to pancreas transplantation should not be restricted because of age. Transplant Int 2011; 24(2):134-35.
  26. Organ Procurement and Transplantation Network (OPTN). Policies and Bylaws: Allocation of Deceased Kidneys. Available online at: http://optn.transplant.hrsa.gov. Last accessed 2013 January.
  27. Canadian Agency for Drugs and Technology in Health. Pancreas Transplantation to Restore Glucose Control: Review of Clinical and Economic Evidence. 2007. Available online at: http://cadth.ca. Last accessed 2013 January.
  28. Allogeneic Pancreas Transplant. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual. (2013 February). Surgery: 7.03.02.
  29. Bramis K, Gordon-Weeks AN, Friend PJ et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012; 99(6):761-6.
  30. Dong M, Parsaik AK, Erwin PJ et al. Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes. Clin Endocrinol (Oxf) 2011; 75(6):771-9.
  31. Sutherland DE, Radosevich DM, Bellin MD et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 2012; 214(4):409-24.
  32. Webb MA, Illouz SC, Pollard CA et al. Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function. Pancreas 2008; 37(3):282-7.
  33. Piper MA, Seidenfeld J, Aronson N. Islet transplantation in type 1 diabetes, Prepared for Agency for Healthcare Research and Qualtiy by the Blue Cross Blue Shield Association Technology Evaluation Center. Contract No. 290-02-0026. 2005. Available online at: http://archive.ahrq.gov. Last accessed 2013 May.
  34. Alejandro R, Barton FB, Hering BJ et al. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation 2008; 86(12):1783-8.
  35. Barton FB, Rickels MR, Alejandro R et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012; 35(7):1436-45.
  36. Thompson DM, Meloche M, Ao Z et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011; 91(3):373-8.
  37. Vantyghem MC, Raverdy V, Balavoine AS et al. Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab 2012; 97(11):E2078-83.
  38. Ekser B, Cooper DK. Overcoming the barriers to xenotransplantation: prospects for the future. Expert Rev Clin Immunol 2010; 6(2):219-30.
  39. van der Windt DJ, Bottino R, Kumar G et al. Clinical islet xenotransplantation: how close are we? Diabetes 2012; 61(12):3046-55.
  40. Aguayo-Mazzucato C, Bonner-Weir S. Stem cell therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 2010; 6(3):139-48.
  41. de Vos P, Spasojevic M, Faas MM. Treatment of diabetes with encapsulated islets. Adv Exp Med Biol 2010; 670:38-53.
  42. McCall, M., and A.M. James Shapiro. Update on islet transplantation. Cold Spring Harbor Perspectives in Medicine (2013 July 17) 2:a007823.
  43. Posselt AM, Szot GL, Frassetto LA et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 2010; 90(12):1595-601.
  44. Bellin, M.D., Barton, F.B., et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. American Journal of Transplantation (2012) 12:1576-83.
  45. Sponsored by Vancouver Coastal Health. A comparison of strict glucose control with usual care at the time of islet cell transplantation (NCT01123122) Available online at: www.clinicaltrials.gov. Last accessed 2013 April.
  46. Sponsored by University of British Columbia. A Comparison of Islet Cell Transplantation With Medical Therapy on the Risk of Progression of Diabetic Retinopathy and Diabetic Macular Edema (NCT00853424) Available online at: www.clinicaltrials.gov. Last accessed 2013 April.
  47. National Institute for Health and Clinical Excellence. Allogenic pancreatic islet cell transplantation for type 1 diabetes mellitus. 2008. Available online at: http://www.nice.org.uk. Last accessed 2013 April.
  48. National Institute for Health and Clinical Excellence. Autologous pancreatic islet cell transplantation for improved glycemic control after pancreatectomy. 2008. Available online at: http://www.nice.org.uk. Last accessed 2013 April.
  49. Islet Transplantation. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual. (2013 June) Surgery: 7.03.12.
  50. ECRI Institute. Indications and contraindications for islet cell transplantation for treating type 1 diabetes. Plymouth Meeting (PA): ECRI Institute; 2012 Nov. 12 p. (Hotline Response).
History
April 2012 Policy updated with literature review. Reference numbers 13 and 17 added; other references renumbered or removed; policy statement changed from Not Medically Necessary to Investigational.
August 2012 Policy updated with literature review. Reference numbers 1, 2, 3 and 14 added; other references renumbered or removed; policy statements unchanged.
September 2013 Policy formatting and language revised.  Title changed from "Islet Transplantation" to "Pancreas and Related Organ Tissue Transplantation".  Coverage criteria expanded to include multiple pancreas transplant procedures.
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Pancreas and Related Organ Tissue Transplantation