Populations	Interventions	Comparators	Outcomes
Individuals: With insulin-dependent diabetes	Interventions of interest are: Pancreas transplant after a kidney transplant	Comparators of interest are: Insulin therapy	Relevant outcomes include: Overall survival Change in disease status Treatment-related mortality Treatment-related morbidity
Individuals: With insulin-dependent diabetes with uremia	Interventions of interest are: Simultaneous pancreas and kidney transplants	Comparators of interest are: Insulin therapy	Relevant outcomes include: Overall survival Change in disease status Treatment-related mortality Treatment-related morbidity
Individuals: With insulin-dependent diabetes and severe complications	Interventions of interest are: Pancreas transplant alone	Comparators of interest are: Insulin therapy	Relevant outcomes include: Overall survival Change in disease status Treatment-related mortality Treatment-related morbidity
Individuals: With a prior pancreas transplant who still meet criteria for a pancreas transplant	Interventions of interest are: Pancreas retransplant	Comparators of interest are: Insulin therapy	Relevant outcomes include: Overall survival Change in disease status Treatment-related mortality Treatment-related morbidity

Background

Pancreas transplantation occurs in several different scenarios such as (1) a diabetic patient with renal failure who may receive a simultaneous cadaveric pancreas plus kidney transplants; (2) a diabetic patient who may receive a cadaveric or living-related pancreas transplant after a kidney transplantation (pancreas after kidney); or (3) a nonuremic diabetic patient with specific severely disabling and potentially life-threatening diabetic problems who may receive a pancreas transplant alone. The total number of adult pancreas transplants (pancreas and pancreas plus kidney) in the U. S. peaked at 1484 in 2004 and has since steadily declined.^1, In 2017, 213 received a pancreas transplant alone and 789 simultaneous pancreas plus kidneys were performed in the U. S.^1,

According to the International Pancreas Transplant Registry data, the proportion of pancreas transplant recipients worldwide who have type 2 diabetes has increased over time, from 2% in 1995 to 7% in 2010.^2, In 2010, approximately 8% of simultaneous pancreas plus kidney transplants, 5% of pancreas transplant after kidney transplant, and 1% of a pancreas transplant alone were performed in patients with type 2 diabetes.

Regulatory Status

Small bowel/liver and multivisceral transplantation are surgical procedures and, as such, are not subject to regulation by the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration 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. Pancreas transplants are included in these regulations.

Related Policies

• Artificial Pancreas Device System (Policy #045 in the DME Section)
• Kidney Transplant (Policy #087 in the Surgery Section)
• Islet Transplantation (Policy #091 in the Surgery Section)

1. Pancreas transplant after a prior kidney transplant is considered medically necessary in members with insulin-dependent diabetes.

2. A combined pancreas and kidney transplant is considered medically necessary in insulin-dependent diabetic members with uremia.

3. Pancreas transplant alone is considered medically necessary in members with severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and labile insulin-dependent diabetes that persists despite of optimal medical management.

4. Pancreas retransplant after a failed primary pancreas transplant is considered medically necessary in members who meet criteria for pancreas transplantation.

5. Pancreas transplant is considered investigational in all other situations.

Policy Guidelines: (Information to guide in medical necessity determination but should not be utilized as absolute criteria.)

General Criteria
Potential contraindications for solid organ transplant are subject to the judgment of the transplant center include the following:

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 the ability to adhere to therapy.

· Documentation of severe hypoglycemia unawareness as evidenced by chart notes or emergency department visits or
· Documentation of potentially life-threatening labile diabetes, as evidenced by chart notes or hospitalization for diabetic ketoacidosis.

Multiple Transplant Criteria
Although there are no standard guidelines for multiple pancreas transplants, the following information may aid in case review:

· If there is early graft loss resulting from technical factors (e.g., venous thrombosis), a retransplant may generally be performed without substantial additional risk.
· Long-term graft losses may result from chronic rejection, which is associated with increased risk of infection following long-term immunosuppression, and sensitization, which increases the difficulty of finding a negative cross-match. Some transplant centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol.

1. PA will be limited to those facilities that are Medicare-approved for kidney transplantation.
2. Patients must have a diagnosis of type I diabetes:
· Patient with diabetes must be beta cell autoantibody positive; or
· Patient must demonstrate insulinopenia defined as a fasting C-peptide level that is less than or equal to 110% of the lower limit of normal of the laboratory's measurement method. Fasting C-peptide levels will only be considered valid with a concurrently obtained fasting glucose ≤225 mg/dL;
3. Patients must have a history of medically-uncontrollable labile (brittle) insulin-dependent diabetes mellitus with documented recurrent, severe, acutely life-threatening metabolic complications that require hospitalization. Aforementioned complications include frequent hypoglycemia unawareness or recurring severe ketoacidosis, or recurring severe hypoglycemic attacks;
4. Patients must have been optimally and intensively managed by an endocrinologist for at least 12 months with the most medically-recognized advanced insulin formulations and delivery systems;
5. Patients must have the emotional and mental capacity to understand the significant risks associated with surgery and to effectively manage the lifelong need for immunosuppression; and,
6. Patients must otherwise be a suitable candidate for transplantation.

Transplantation of partial pancreatic tissue or islet cells (except in the context of a clinical trial (see section 260.3.1 of the National Coverage Determinations Manual).

FIDE-SNP Coverage:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2009 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 10, 2019.

This policy was informed in part by a TEC Assessment (1998), which focused on pancreas graft survival and health outcomes associated with both pancreas transplant alone (PTA) and pancreas after kidney (PAK) transplants.^3, A TEC Assessment (2001) focused on pancreas retransplant.^4, The assessments and subsequent evidence offer the following observations and conclusions.

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

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

Much of the published literature consists of case series reported by single-centers and registry data. The extant randomized controlled trials compare immunosuppression regimens and surgical techniques and therefore do not compare pancreas transplantation with insulin therapy, or simultaneous pancreas and kidney (SPK) transplant with insulin therapy and hemodialysis.

Pancreas Transplant After Kidney Transplant

Clinical Context and Therapy Purpose

The purpose of a PAK transplant in patients who have insulin-dependent diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a PAK transplant improve the net health outcome in patients with insulin-dependent diabetes?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with insulin-dependent diabetes.

Interventions

The therapy being considered is a PAK transplant.

PAK transplantation permits patients with insulin-dependent diabetes to benefit from a living-related kidney graft, if available, and to benefit from a subsequent pancreas transplant that is likely to improve quality of life compared with a kidney transplant alone. Patients with insulin-dependent diabetes for whom a cadaveric kidney graft is available, but a pancreas graft is not simultaneously available, benefit similarly from a later pancreas transplant.

PAK transplant is provided in a hospital setting with specialized staff and equipment to perform the surgical procedure and provide postsurgical intensive care.

Comparators

The following therapy is currently being used to make decisions about insulin-dependent diabetes: insulin therapy.

Outcomes

The general outcomes of interest are overall survival (OS), disease progression, graft failure, and adverse events. In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended to ten years as survival improves.

Case Series

As reported by Gruessner and Gruessner (2016), according to United Network for Organ Sharing (UNOS) and International Pancreas Transplant Registry data, patient survival rates after PAK conducted from 2010 to 2014 was 97.9% after 1 year and 94.5% after 3 years.^5,This compares with 1-year (96.4%) and 3-year (93.1%) patient survival rates for transplants conducted from 2005 to 2009.

Bazarbachi et al (2013) reviewed a single center's experience with PAK and SPK.^6, Between 2002 and 2010, 172 pancreas transplants were performed in diabetic patients (123 SPK, 49 PAK). The median length of time between kidney transplant and pancreas transplant in the PAK group was 4.8 years. Graft and patient survival rates were similar for both 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 (p=0.93), all respectively. Patient survival rates (calculated from the time of pancreas transplantation) in the SPK and PAK groups were 98% and 100% after 1 year, 96% and 100% after 3 years, and 94% and 100% after 5 years (p=0.09), respectively.

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

Kleinclauss et al (2009) retrospectively reviewed data from 307 diabetic kidney transplant recipients from a single-center and compared renal graft survival rates in those who subsequently received a pancreatic transplant with those who did not.⁹ The comparative group was analyzed separately based on whether patients were medically eligible for pancreas transplant, but chose not to proceed for financial or personal reasons, or were ineligible for medical reasons. The ineligible (n=57) group differed significantly at baseline from both the PAK group (n=175) and the eligible group (n=75) with respect to age, type of diabetes, and dialysis experience; kidney graft survival rates in the eligible group were lower (1-, 5-, and 10-year rates of 75%, 54%, and 22%, respectively, p<0.001) than in the other groups (1-, 5-, and 10-year rates: for the PAK group, 98%, 82%, and 67% vs for the eligible group, 100%, 84%, and 62%). The authors concluded that the subsequent transplant of a pancreas after a living donor kidney transplant does not adversely affect patient or kidney graft survival rates.

Section Summary: PAK Transplant

Data from national and international registries have found relatively high patient survival rates after PAK (e.g., a 3-year survival rate of 93%). A 2013 analysis of data from a single-center found similar patient survival and death-censored pancreas graft survival rates after PAK (and SPK) transplants.

Simultaneous Pancreas Plus Kidney Transplants for Patients with Uremia

Clinical Context and Therapy Purpose

The purpose of a SPK transplant in patients who have insulin-dependent diabetes with uremia is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does an SPK transplant improve the net health outcome in patients who have insulin-dependent diabetes with uremia?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals who have insulin-dependent diabetes with uremia.

Interventions

The therapy being considered is an SPK transplant.

SPK transplant is provided in a hospital setting with specialized staff and equipment to perform the surgical procedure and provide postsurgical intensive care.

Comparators

The following therapy is currently being used to make decisions about insulin-dependent diabetes with uremia: insulin therapy.

Outcomes

The general outcomes of interest are OS, disease progression, graft failure, and adverse events. In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended to ten years as survival improves.

Case Series

The U.S.-based Organ Procurement and Transplant Network (OPTN) has reported a 1-year patient survival rate of 97.5% (95% confidence interval [CI], 96.9% to 98.0%) for SPK procedures performed between 2008 and 2015.^1, Three- and 5-year patient survival rates were 94.7% (95% CI, 93.9% to 95.5%) and 88.6% (95% CI, 87.5% to 89.7%), respectively.

Analysis of a U.K. registry data by Barlow et al (2017) compared outcomes in patients with type 1 diabetes and end-stage renal disease who had SPK transplants (n=1739) with live donor kidney transplants (n=370).^8, In multivariate analysis, there was no significant association between type of transplant and patient survival (hazard ratio, 0.71; 95% CI, 0.47 to 1.06; p=0.095). SPK recipients with a functioning pancreas graft had significantly better OS than those with a living donor kidney transplant (p<0.001).

SPK transplants have been found to reduce mortality in patients with type 1 diabetes. Van Dellen et al (2013) in the U.K. reported on a retrospective analysis of data for 148 SPK patients and a wait-list control group of 120 patients.^9, All patients had type 1 (insulin-dependent) diabetes. (The study also included 33 patients who had PAK and 11 patients who had PTA.) Overall mortality (mortality at any time point) was 30% (30/120) for the waiting list and 9% (20/193) for transplanted patients; the difference between groups was statistically significant (p<0.001). The 1-year mortality rate was 13% (n=16) for the waiting list and 4% (n=8) for the transplant group (p<0.001).

Sampaio et al (2011) published an analysis of data from the UNOS database.^10, Outcomes for 6141 patients with type 1 diabetes and 582 patients with type 2 diabetes who underwent SPK were similar for both groups in adjusted analyses. After adjusting for other factors (e.g., bodyweight; dialysis time; cardiovascular comorbidities), type 2 diabetes was not associated with an increased risk of pancreas or kidney graft failure or mortality compared with type 1 diabetes.

Section Summary: SPK Transplants for Patients with Uremia

Data from national and international registries have found relatively high patient survival rates after SPK transplants (e.g., a 3-year survival rate of 95%). A retrospective analysis found a higher survival rate in patients with type 1 diabetes who had an SPK transplant than in those on a waiting list.

Pancreas Transplant Alone for Patients with Severe Complications

Clinical Context and Therapy Purpose

The purpose of a pancreas transplant in patients who have insulin-dependent diabetes with severe diabetic complications is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a pancreas transplant improve the net health outcome in patients who have insulin-dependent diabetes with severe diabetic complications?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals who have insulin-dependent diabetes with severe diabetic complications.

Although pancreas transplantation is generally not considered a life-saving treatment for individuals with insulin-dependent diabetes, in a small subset of patients who experience life-threatening complications from diabetes, pancreas transplantation could be considered life-saving. 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.[1]

Most patients undergoing PTA are those with either hypoglycemic unawareness or labile diabetes. However, other exceptional circumstances may exist where nonuremic type 1 diabetes patients have significant morbidity risks due to secondary complications of diabetes (e.g., peripheral neuropathy) that exceed those of the transplant surgery and subsequent chronic immunosuppression. Because virtually no published evidence addresses 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 PTA. Case-by-case consideration of each patient's clinical situation may be the best option for determining the balance of risks and benefits.

Interventions

The therapy being considered is a pancreas transplant. A pancreas transplant is provided in a hospital setting with specialized staff and equipment to perform the surgical procedure and provide postsurgical intensive care.

Comparators

The following therapy is currently being used to make decisions about insulin-dependent diabetes with severe diabetic complications: insulin therapy.

Outcomes

The general outcomes of interest are OS, disease progression (e.g., end-stage renal disease), graft failure, and adverse events (e.g., hypoglycemia, labile diabetes). In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended to five years as survival improves.

Registry Studies and Case Series

PTA graft survival has improved over time. According to International Pancreas Transplant Registry data, 1-year graft function increased from 51.5% for 1987 to 1993 to 77.8% for 2006 to 2010 (p<0.001).^2, One-year immunologic graft loss remained higher (6%) after PTA than after PAK (3.7%) or SPK (1.8%). According to UNOS and the International Pancreas Transplant Registry data, for the period from 2010 to 2014, the patient survival rate for PTA was 96.3% after 1 year and 94.9% after 3 years.^5,This compares with 1-year and 3-year patient survival rates of 97.5% and 93.3% for 2005 to 2009, respectively. According to Gruessner (2011), in carefully selected patients with type 1 diabetes and severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and persistent labile diabetes despite optimal medical management, the benefits of PTA were judged to outweigh the risk of performing pancreas transplantation with subsequent immunosuppression.^2,

Noting that nephrotoxic immunosuppression may exacerbate diabetic renal injury after PTA, Scalea et al (2008) reported on a single institutional review of 123 patients who received 131 PTA for the development of renal failure.^11, Mean graft survival was 3.3 years (range, 0-11.3 years), and 21 patients were lost to follow-up. At a mean follow-up of 3.7 years, the mean estimated glomerular filtration rate was 88.9 mL/min/1.73 m² pretransplantation and 55.6 mL/min/1.73 m² posttransplantation. All but 16 patients had a decrease in estimated glomerular filtration rate. Thirteen developed end-stage renal diseases, 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.

Section Summary: PTA for Patients with Severe Complications

Data from international and national registries have found that graft and patient survival rates after PTA have improved over time. For the period of 2010 to 2014, 1- and 3-year survival rates had improved to 96% and 95%, respectively.

Pancreas Retransplantation

Clinical Context and Therapy Purpose

The purpose of a pancreas retransplant in patients who have had a prior pancreas transplant and still meet criteria for a pancreas transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a pancreas retransplant improve the net health outcome in patients who have had a prior pancreas transplant and still meet criteria for a pancreas transplant?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals who have had a prior pancreas transplant and still meet criteria for a pancreas transplant.

Interventions

The therapy being considered is a pancreas retransplant.

The approach to retransplantation varies by cause of failure. Surgical and 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 transplant center has guidelines based on experience; some centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol.

Pancreas retransplant is provided in a hospital setting with specialized staff and equipment to perform the surgical procedure and provide postsurgical intensive care.

Comparators

The following therapy is currently being used to make decisions about a failed pancreas transplant: insulin therapy.

Outcomes

The general outcomes of interest are OS, graft progression, transplant failure, and adverse events.In the short-term (post-surgery), follow-up monitors for graft failure. Long-term follow-up has extended over time to five years as survival improves.

Case Series

The retrospective observational study by Gasteiger at al (2018) assessed the outcomes of pancreas retransplantation for patients with pancreas graft failure (defined as a return to insulin dependence).^12, The study evaluated pancreas retransplantations performed between 1997 and 2013 at a single Austrian medical university. Fifty-two pancreas retransplantations were identified, and the median follow-up was 65.0 (range 0.8-174.3) months. At 5 years, the overall patient survival rate was 89%; the survival rate for patients who underwent simultaneous kidney-pancreas retransplantation was 90% (18/20), and the survival rate for those who received only a pancreas retransplantation was 88% (28/32). Graft survival rates were 79% at 1 year and 69% at 5 years. The 5-year graft survival rate was higher following simultaneous kidney-pancreas retransplantation than pancreas retransplantation alone: 80% for simultaneous kidney-pancreas (16/20) vs 63% (20/32) for pancreas alone (P = 0.226). During the entire follow-up, 42% (22/52) of the grafts were lost. Two factors significantly associated with long-term graft survival were early surgical complications (odds ratio = 3.29; 95% CI, 1.09 to 9.99; P = 0.035) and acute rejection (odds ratio = 4.49; 95% CI, 1.59 to 12.68; P = 0.005). The authors note that because pancreas transplantation is not a life-saving operation, the risks and benefits of the procedure must be carefully considered.

The OPTN has reported data on transplants performed between 1997 and 2004.^1, Patient survival rates after repeat transplants were similar to survival rates after primary transplants. For example, the 1-year survival rate was 94% (95% CI, 93% to 95%) after a primary pancreas transplant and 96% (95% CI, 93% to 99%) after a repeat pancreas transplant. The numbers of patients transplanted were not reported, but OPTN data stated that 1217 patients were alive 1 year after primary transplant and 256 after repeat transplants. The 3-year patient survival rate was 90% (95% CI, 88% to 91%) after primary transplants and 90% (95% CI, 86% to 94%) after repeat transplants. The 1-year graft survival rate was 78% (95% CI, 76% to 81%) after primary pancreas transplant and 70% (95% CI, 65% to 76%) after repeat transplant.

Data are similar for patients receiving SPK transplants, but follow-up data are only available on a small number of patients who had repeat SPK transplants, so estimates of survival rates in this group are imprecise. Three-year patient survival rate was 90% (95% CI, 89% to 91%) after primary SPK transplant and 80% (95% CI, 64% to 96%) after a repeat SPK transplant. The number of patients living 3 years after transplant was 2907 after a primary combined procedure and 26 after a repeat combined procedure.

Several centers have published outcomes after pancreas retransplantation and generally reported comparable graft and patient survival rates after initial transplants and retransplants.^13,14,15,16, For example, Fridell et al (2015) reported on 441 initial transplants and 20 late transplants.^14, One-year graft survival rates were 92% after initial transplant and 90% after retransplant (p=0.48). Similarly, 1-year patient survival rates were 96% after initial transplants and 95% after retransplants (p=0.53). However, Rudolph et al (2015), who assessed the largest number of patients, reported higher graft survival rates, but not patient survival rates, after primary transplant.^16, A total of 2145 pancreas transplants were performed, 415 (19%) of which were retransplants. The death-censored graft survival rate at 1 year was 88.2% in initial transplants and 75% in retransplants (p<0.001). Patient survival rates at 1 year were 91% after initial transplants and 88% after retransplants (p=0.06).

Section Summary: Pancreas Retransplantation

National and international data reported from specific transplant centers have generally reported similar graft and patient survival rates after pancreas retransplantation compared with initial transplantation.

Potential Contraindications (Applies to all Indications Above)

Pancreas Transplant in Human Immunodeficiency Virus-Positive Transplant Recipients

Current OPTN policy permits HIV-positive transplant candidates.^17,

The British HIV Association and the British Transplantation Society (2017) updated their guidelines on kidney transplantation in patients with HIV disease.^18,These criteria may be extrapolated to other organs:

• Adherent with treatment, particularly antiretroviral therapy
• Cluster of differentiation 4 count greater than 100 cells/mL (ideally >200 cells/mL) for at least 3 months
• Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months
• No opportunistic infections for at least six months
• No history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphoma.

Recipient age older than 50 years has been considered a relative contraindication for a pancreas transplant. Several analyses of outcomes by patient age group have prompted general agreement among experts that age should not be a contraindication; however, age-related comorbidities must be considered when selecting patients for transplantation.

In the largest study of pancreas outcomes by recipient age, Siskind et al (2014) assessed data from the UNOS database.^19, Investigators included all adults who received SPK or PTA transplants between 1996 and 2012 (n=20854). This included 3160 patients between the ages of 50 and 59 years, and 280 patients, 60 years or older. Overall, Kaplan-Meier survival analysis found statistically significant differences in patient survival (p<0.001) and graft survival (p<0.001) by age category. Graft survival was lowest in the 18-to-29 age group at 1, 5, and 10 years, which the authors noted might be due to early immunologic graft rejection as a result of more robust immune responses. However, 10- and 15-year graft survival was lowest in the 60 and older age group. Patient survival rates decreased with increasing age, and the differential between survival in older and younger ages increased with longer follow-up intervals. Lower survival rates in patients 50 and older could be due in part to comorbidities at the time of transplantation. Also, as patients age, they are more likely to die from other causes. Still, patient survival rates at five and ten years are relatively high, as shown in Table 1.

Table 1. Patient Survival by Age Group

Years After Transplant	Age 18-29, %	Age 30-39, %	Age 40-49, %	Age 50-59, %	Age 60+, %
1 year	95.4	96.0	94.9	93.3	91.0
5 years	86.3	87.8	85.7	81.6	71.4
10 years	73.5	76.8	71.8	61.5	42.5

Adapted from Siskind et al (2014).^19,

Among previous studies on pancreas outcomes in older patients, Shah et al (2013) reviewed data on 405 patients who underwent PTA transplants between 2003 and 2011.²¹ One-year patient survival was 100% for patients younger than age 30 years, 98% for patients aged 30 to 39 years, 94% for patients aged 40 to 49 years, 95% for patients aged 50 to 59 years, and 93% for patients age 60 or older. There was no statistically significant difference in patient survival by age group (p=0.38). Findings were similar for one-year graft survival; there was no statistically significant difference in outcomes by age of transplant recipients (p=0.10).

A study by Afaneh et al (2011) 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.^20, The two groups had similar rates of surgical complications, acute rejection, and nonsurgical infections. Overall patient survival was similar. Three- and 5-year survival rates were 93% and 90%, respectively, in the younger group, and 92% and 82%, respectively, in the older group. Schenker et al (2011) compared outcomes in 69 individuals at least 50 years old with 329 individuals younger than 50 years who had received pancreas transplants.^21, Mean duration of follow-up was 7.7 years. One-, 5-, and 10-year patient and graft survival rates were similar for the groups. For example, the 5-year patient survival rate was 89% in both groups. The 5-year pancreas graft 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 et al (2011) article,^22, agreed that individuals age 50 years and older are suitable candidates for pancreas transplantation.

Summary of Evidence

For individuals who have insulin-dependent diabetes who receive a PAK transplant, the evidence includes case series and registry studies. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Data from national and international registries have found relatively high patient survival rates with a PAK transplant (e.g., a 3-year survival rate of 93%). A 2012 analysis of data from a single-center found similar patient survival and death-censored pancreas graft survival rates with a PAK transplant or an SPK transplant. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have insulin-dependent diabetes with uremia who receive SPK transplants, the evidence includes registry studies. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Data from national and international registries have found relatively high patient survival rates after SPK transplant. A retrospective analysis found a higher survival rate in patients with type 1 diabetes who had an SPK transplant vs those on a waiting list. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have insulin-dependent diabetes and severe complications who receive PTA, the evidence includes registry studies. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Data from international and national registries have found that graft and patient survival rates after PTA have improved over time (e.g., 3-year survival of 95%). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have had a prior pancreas transplant who still meet criteria for a pancreas transplant who receive pancreas retransplantation, the evidence includes case series and registry studies. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. National data and specific transplant center data have generally found similar graft and patient survival rates after pancreas retransplantation compared with initial transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

Organ Procurement and Transplantation Network

The Organ Procurement and Transplantation Network updated its comprehensive list of transplant-related policies, most recently in May 2019.^23,

For pancreas registration:

"Each candidate registered on the pancreas waiting list must meet one of the following requirements:

• Be diagnosed with diabetes
• Have pancreatic exocrine insufficiency
• Require the procurement or transplantation of a pancreas as part of a multiple organ transplant for technical reasons."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01047865	Type 1 Diabetes Recurrence in Pancreas Transplants	400	May 2020
NCT01957696	A Prospective, Observational Study in Pancreatic Allograft Recipients: The Effect of Risk Factors, Immunosuppressive Level and the Benefits of Scheduled Biopsies - on Surgical Complications, Rejections, and Graft Survival	80	Oct 2028
NCT00238693	Transplant Registry: Patients Who May Require Transplantation and Those Who Have Undergone Transplantation of Liver, Kidney and/or Pancreas	13,767	Jan 2018

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Allogeneic Pancreas Transplant
Pancreas Transplant
Pancreas Transplantation
Transplant, Pancreas
Transplantation, Pancreas

References:
1. Organ Procurement and Transplantation Network (OPTN). National Data. n.d.; https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/. Accessed August 29, 2019.

2. 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 (IPTR). Rev Diabet Stud. Spring 2011;8(1):6-16. PMID 21720668.

3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Pancreas Transplantation. TEC Assessments. 1998;Volume 13, Tab 7.

4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Pancreas Retransplantation. TEC Assessments. 2001;Volume 16, Tab 23.

5. Gruessner AC, Gruessner RW. Pancreas Transplantation of US and Non-US Cases from 2005 to 2014 as Reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. Spring 2016;13(1):35-58. PMID 26982345.

6. Bazerbachi F, Selzner M, Marquez MA, et al. Pancreas-after-kidney versus synchronous pancreas-kidney transplantation: comparison of intermediate-term results. Transplantation. Feb 15 2013;95(3):489-494. PMID 23183776.

7. Fridell JA, Mangus RS, Hollinger EF, et al. The case for pancreas after kidney transplantation. Clin Transplant. Aug-Sep 2009;23(4):447-453. PMID 19453642.

8. Barlow AD, Saeb-Parsy K, Watson CJE. An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK Transplant Registry study. Transpl Int. Sep 2017;30(9):884-892. PMID 28319322.

9. van Dellen D, Worthington J, Mitu-Pretorian OM, et al. Mortality in diabetes: pancreas transplantation is associated with significant survival benefit. Nephrol Dial Transplant. May 2013;28(5):1315-1322. PMID 23512107.

10. Sampaio MS, Kuo HT, Bunnapradist S. Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients. Clin J Am Soc Nephrol. May 2011;6(5):1198-1206. PMID 21441123.

11. 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. Dec 27 2008;86(12):1789-1794. PMID 19104423.

12. Gasteiger S, Cardini B, Göbel G, et al. Outcomes of pancreas retransplantation in patients with pancreas graft failure. Br J Surg. 2018 Dec;105(13):1816-1824. PMID: 30007018.

13. Buron F, Thaunat O, Demuylder-Mischler S, et al. Pancreas retransplantation: a second chance for diabetic patients? Transplantation. Jan 27 2013;95(2):347-352. PMID 23222920.

14. Fridell JA, Mangus RS, Chen JM, et al. Late pancreas retransplantation. Clin Transplant. Jan 2015;29(1):1-8. PMID 25284041.

15. Seal J, Selzner M, Laurence J, et al. Outcomes of pancreas retransplantation after simultaneous kidney- pancreas transplantation are comparable to pancreas after kidney transplantation alone. Transplantation. Mar 2015;99(3):623-628. PMID 25148379.

16. Rudolph EN, Finger EB, Chandolias N, et al. Outcomes of pancreas retransplantation. Transplantation. Feb 2015;99(2):367-374. PMID 25594555.

17. Organ Procurement and Transplantation Network (OPTN). Organ Procurement and Transplantation Network Policies. 2018; https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. August 29, 2019.

18. Working Party of the British Transplantation Society. Kidney and Pancreas Transplantation in Patients with HIV. Second Edition (Revised). British Transplantation Society Guidelines. Macclesfield, UK: British Transplantation Society; 2017.

19. Siskind E, Maloney C, Akerman M, et al. An analysis of pancreas transplantation outcomes based on age groupings--an update of the UNOS database. Clin Transplant. Sep 2014;28(9):990-994. PMID 24954160.

20. Afaneh C, Rich BS, Aull MJ, et al. Pancreas transplantation: does age increase morbidity? J Transplant. 2011;2011:596801. PMID 21766007.

21. Schenker P, Vonend O, Kruger B, et al. Long-term results of pancreas transplantation in patients older than 50 years. Transpl Int. Feb 2011;24(2):136-142. PMID 21039944.

22. Gruessner AC, Sutherland DE. Access to pancreas transplantation should not be restricted because of age: invited commentary on Schenker et al [commentary]. Transpl Int. Feb 2011;24(2):134-135. PMID 21208293.

23. Organ Procurement and Transplantation Network. Organ Procurement and Transplantation Network (OPTN) Policies. Effective May 23, 2019. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf ,Accessed July 1, 2019.

24. Centers for Medicare & Medicaid Services (CMS). Medicare-approved transplant programs. 2018; https://www.cms.gov/Medicare/Provider-Enrollment-and- Certification/CertificationandComplianc/downloads/ApprovedTransplantPrograms.pdf. Accessed August 29, 2019.

25. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for pancreas Transplants (260.3). 2006; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?ncdid=107&ver=3. Accessed August 29, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

48550
48551
48552
48554

S2065