Medical Policy

 

Subject: Autologous and Allogeneic Pancreatic Islet Cell Transplantation
Document #: TRANS.00010 Publish Date:    03/29/2018
Status: Reviewed Last Review Date:    02/27/2018

Description/Scope

This document addresses autologous and allogeneic pancreatic islet cell transplantation. Islet cell transplantation involves the collection and infusion of isolated pancreatic islet cells into the portal vein of the liver. The goals of islet cell transplantation are to preserve endocrine function, glycemic control and to improve quality of life.

Note: For information on whole pancreas organ transplantation, please see:

Position Statement

Medically Necessary:

Autologous pancreatic islet cell transplantation is considered medically necessary as an adjunct to a total or near total pancreatectomy for individuals with chronic pancreatitis.

Investigational and Not Medically Necessary:

Autologous pancreatic islet cell transplantation is considered investigational and not medically necessary when the above criteria are not met and for all other indications.

Allogeneic pancreatic islet cell transplantation is considered investigational and not medically necessary for all indications.

Note: For multi-organ transplant requests, criteria must be met for each organ requested. In those situations, an individual may present with a concurrent medical condition which would be considered an exclusion or a comorbidity that would preclude a successful outcome, but would be treated with the other organ transplant. Such cases will be reviewed on an individual basis for coverage determination to assess the member's candidacy for transplantation.

Rationale

Chronic Pancreatitis

A total or near-total pancreatectomy can relieve pain from chronic pancreatitis, but also results in insulin dependent diabetes. Autologous islet cell transplantation as an adjunct to a total or near-total pancreatectomy is a technique used to salvage and transplant beta cells which may prevent complications of chronic diabetes.

Several systematic reviews of the literature on islet autotransplantation (IAT) after total pancreatectomy (TP) or partial pancreatectomy (PP) have been published. In 2015, Wu and colleagues performed a systematic review and meta-analysis in order to evaluate outcomes of IAT after TP. A total of 12 studies involving 677 subjects were included. The insulin independent rate for IAT after TP at last follow-up was 3.72 per 100 person-years (95% confidence interval [CI]: 1.00-6.44). The 30-day mortality was 2.1% (95% CI: 1.2-3.8%). The mortality at last follow-up was 1.09 per 100 person-years (95% CI: 0.21-1.97). Factors associated with incidence density of insulin independence in univariate meta-regression analyses included islet equivalents per kg body weight. The authors concluded that IAT is a safe modality for individuals with chronic pancreatitis who undergo TP.

Previously, a systematic review by Bramis and colleagues (2012) searched published articles through 2012, including case series with a minimum of 5 consecutive subjects and a minimum of 1 year follow-up. A total of 72 full-text articles were reviewed; 5 studies with 296 participants met inclusion criteria. Concurrent IAT with TP resulted in a reduction of insulin requirements. The rate of insulin independence was 46% at the 5-year mean follow-up and 10% at the 8-year mean follow-up. Two of the five studies reported preoperative morphine requirement and subsequent reduction of pain post IAT and TP. In one study with a mean follow-up of 1.5 years, the mean morphine use from baseline decreased by 116 mg. With a mean follow-up of 8 years, the second study had a mean decrease in morphine of 55 mg.

A 2011 systematic review and meta-analysis by Dong and colleagues focused on studies that assessed insulin independence, mortality and metabolic outcomes. A total of 15 observational studies met the review’s inclusion criteria. Of these,  10 studies involved IAT after TP, 2 studies involved IAT after PP, and 2 studies involved IAT after either TP or PP. From 13 of these studies, a total of 354 individuals with IAT post-TP for chronic pancreatitis were included. In an analysis of the pooled data, the rate of insulin dependence at last follow-up was 4.6 per 100 person-years (95% CI, 1.53-7.62). Ten studies reported transient insulin independence during studies at a rate of 8.34 per 100 person-years (95% CI, 3.32-13.37) with a duration of 15–57 months (95% CI, 10.35-20.79 months). Pooled data from 5 studies reported a 1-year rate of insulin independence was 27% (95% CI, 21-33%) and at 2 years was 21% (95% CI, 16-27%) based on 3 studies. The mortality rate at 30 days was 5% (95% CI, 2-10%) and at last follow-up the rate was 1.38 per 100 person-years (95% CI, 0.66-2.11). The cumulative mortality at 1 year (based on 10 studies) was 4.9% (95% CI, 2.6-7.3%) and at 2 years it was 6.2% (95% CI, 3.3-9.2%) which was based on 5 studies. Three studies reported mean or median HbA1c levels of 7%, 6.9% and 6.4% at 1 year. However, the data for C-peptide levels were insufficient for meta-analysis. For IAT after PP, the rate of insulin independence at last follow-up was 24.28 per 100 person-years (95% CI, 0.00-48.96). There were no events in 30 individuals at 30 days, resulting in a 30-day mortality rate of 0. At last follow-up, the cumulative mortality rate of IAT after PP was 0.70 per 100 person-years (95% CI, 0.00-1.80). The authors note this is the first systematic review and meta-analysis regarding IAT after pancreatectomy and the effect on insulin independence and mortality. The limitations of the analysis include heterogeneous methods, techniques, length of follow-up, lack of controls and the small number of events.

One of the largest series was published in 2012 by Sutherland and colleagues. The authors reported data from a single center series of 409 individuals with chronic pancreatitis who were treated between 1977 and 2011 with TP and IAT to relieve pain and preserve β-cell mass. Fifty-three of the 409 participants (13%) were children between the ages of 5 and 18 years. Post TP and IAT actuarial survival at 1 year was 96% in adults and 98% in children, and 5-year survival was 89% in adults and 98% in children. Overall, at 15 years post-surgery, two-thirds (66%) of the individuals were reported alive. Insulin independence at 3 years was noted in 30% of individuals (25% of adults and 55% of children), while partial function was reported in 33%. Surgical complications requiring reoperation during the initial admission occurred in a total of 15.9% of the individuals, with bleeding as the most common reason for reoperation experienced in 9.5%. There were a total of 5 (1.2%) in-hospital deaths, and 53 deaths following initial discharge with 3 of those deaths related to chronic pancreatitis disease processes.  Insulin independence at 6 months was observed in 25% of individuals, 33% had partial islet function and less than one-fifth were dependent on insulin. Narcotic use for pain control declined after TP and IAT. The proportion of individuals requiring narcotics were, 91%, 61%, 54% and 51% at 3, 6, 12 and 24 months, respectively. A survey of integrated quality-of-life outcomes, initiated in October 2008, had 219 participants eligible to participate and 193 completed the survey. At 1 year, 85% of the participants reported improvement compared to the prior year. The authors concluded TP alleviates pain caused by chronic pancreatitis  and IAT can help to preserve glycemic control in most individuals.

As part of their 2018 Standards of Medical Care in Diabetes (2018), the American Diabetes Association recommended that autologous islet transplantation be considered for individuals undergoing TP for refractory chronic pancreatitis to prevent postsurgical diabetes.

According to the available studies, autologous pancreatic islet cell transplantation appears to significantly decrease the incidence of diabetes and pain after total or near-total pancreatectomy for chronic pancreatitis. Additionally, this procedure is not associated with serious complications and is performed as an adjunct to the pancreatectomy procedure.

Type 1 Diabetes

Type I diabetes mellitus is a result of cell-mediated autoimmune destruction of insulin producing pancreatic beta cells. Pancreatic islet cell transplantation is currently under investigation as a therapy option proposed to restore normal glycemia levels in labile type 1 diabetes.

The 2008 update from Collaborative Islet Transplant Registry (CITR; Close, 2007), which has collected and monitored data on allogeneic islet transplantation in North America, Europe, and Australia since 1999, reported that as of April 2008, its registry was comprised of 325 adult recipients and 649 islet infusions from 712 donors. Recipients of allogeneic islet transplants all had type 1 diabetes for more than 5 years, were between 18 and 65 years of age, and had poor diabetes control. It was noted that at 3 years post first infusion only 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. A total of 70% achieved insulin independence at least once, of which 71% were still insulin independent 1 year later and 52% at 2 years. There have been seven reported deaths among allograft recipients with causes ranging from unknown reasons to viral meningitis possibly related to immunosuppressant therapy, drug toxicity and stroke.

An updated CITR report (Barton, 2012) focused on changes in outcomes over time. The number of individuals receiving islet transplants was 214 during 1999-2002, 255 between mid-2003 and 2006, and 208 from 2007 to 2010. A total of 575 of the 677 (85%) islet transplant recipients received islets only and the remainder underwent simultaneous kidney and islet transplants. In the 1999-2002 group, rates of insulin independence were 51% after 1 year, 36% after 2 years, and 27% after 3 years. Rates for the 2007-2010 group were 66%, 55% and 44%, respectively. The incidence of clinically reportable adverse events in the first year after infusion decreased from 50% to 53% in 1999-2006 to 38% in 2007-2010. The rates of peritoneal hemorrhage or gallbladder infusion were 5.4% in 1999-2003 and 3.1% in 2007-2010. Findings were not reported separately for the subset of individuals who underwent islet only transplantation. Limitations to the database updates were increasing levels of missing data from medical records and pending entry of data into the registry.

A systematic review of studies on islet cell transplantation in adults with type 1 diabetes was published by Health Quality Ontario in 2015. A total of 17 studies published through November 27, 2014 were identified. One of these was a technology assessment that included 13 case series. An additional 11 observational studies were identified as well as 4 guidelines and 1 registry report. Four observational studies compared islet transplantation alone to intensive insulin therapy in individuals without kidney disease. Three of the 4 studies found significantly greater changes in HbA1c after islet transplantation. In addition, 12 case series reported on glycemic control and found insulin independence rates ranging from 30% to 70% at 1 year post-transplantation. The review authors concluded:

From these studies, we determined that islet transplantation can improve blood sugar control and may reduce diabetic complications for patients with type 1 diabetes, with or without kidney disease. Improvements in health-related quality of life can occur; however, the results were inconsistent. Compared with insulin therapy, there were more adverse (undesired) events with islet transplantation, but these were less severe than with pancreas transplantation. The body of evidence was generally considered to be of low to very low quality.

Several studies have reported 5-year outcomes after islet transplantation in individuals with type 1 diabetes. Qi and colleagues (2014) reported a small single center 5-year follow-up of type 1 diabetics transplanted with allogeneic islets. A total of 10 individuals were enrolled in an open-label prospective trial. The first 4 subjects underwent islet transplantation with the Edmonton immunosuppressive regimen and the remaining 6 subjects received the Edmonton regimen plus etanercept and exenatide. All 10 individuals achieved insulin independence after 1-3 transplants. At 5 years of follow-up, 6 of the initial 10 subjects were free of exogenous insulin.

In 2015, LaBlanche and colleagues reported 5-year metabolic, functional and safety results of individuals with type 1 diabetes transplanted with allogeneic islet cells within a Swiss-French multicenter network between 2003 and 2010. A total of 44 subjects received islet cell transplantation of which 24 (54.5%) received islet transplantation alone (ITA) and 20 (45.5%) received islet after kidney (IAK). Thirty-four subjects completed the 5-year follow-up and 10 subjects completed the 4-year follow-up. At 1, 4, and 5 years post islet transplantation, respectively, 83%, 67%, and 58% of the ITA recipients and 80%, 70%, and 60% of the IAK transplant recipients reached HbA1c under 7% and were free of severe hypoglycemia, while none of the ITA recipients and only 10% of the IAK transplant recipients met this criterion at the preinfusion stage. Thirty-three of 44 subjects (75%) experienced insulin independence during the follow-up period, with a median duration of insulin independence of 19.25 months. A total of 55 adverse events occurred in 29 of 44 recipients. Of the adverse events, 14% were deemed mild, 9% were moderate, 67% were serious and 9% were life-threatening. Two individuals died due to a cardiovascular event at 55 and 48 months post-transplant; however, no deaths related to islet transplantation were reported during the follow-up period.

There are significant issues requiring further investigation before islet cell transplantation for treatment of diabetes could be considered outside of clinical trials. These issues include:

Studies supporting the use of allogeneic islet transplantation are limited by small numbers of recipients and significant adverse events. At this time, the level of evidence remains insufficient to substantiate the net benefit of allogeneic islet cell transplantation for type I diabetes and other indications.

Background/Overview

Islet cells are obtained from the resected pancreas by injecting a collagenase solution into the pancreas, which frees the cells from acinar tissue. The resultant dispersed pancreatic islet tissue is collected, washed and diluted in plasma. Most often the plasma is then injected slowly into the portal vein of the liver. In some cases, islet cells are transplanted elsewhere in the peritoneal cavity, for example, beneath the kidney capsule.

Three types of islet transplants have been reported: allogeneic transplants isolated from human adult islet tissue (including the use of multiple donors for one recipient in order to obtain a sufficient number of islet cells); transplants isolated from fetal human or animal tissue; and autologous transplants. A variety of tissue sources, methods of islet isolation and preservation, sites of cell implantation and immunosuppressive regimens continue to be investigated to identify improved islet cell procurement techniques, optimal selection criteria, and long-term durability of outcomes.

Chronic Pancreatitis

Chronic pancreatitis is a progressive inflammatory disease of the pancreas that results in irreversible deterioration of pancreatic structure and function. Pathological features include atrophy and fibrosis. Individuals with chronic pancreatitis may experience intractable pain that can require a total or near-total pancreatectomy. Pain relief must be balanced against the outcome of insulin-dependent diabetes. Autologous islet cell transplantation has been investigated as a technique to prevent this morbidity. During the removal of the pancreas, a suspension of isolated islet cells is created from the pancreas specimen and then injected into the portal vein of the liver, where the cells function as a free graft.

Type 1 Diabetes

Type 1 diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin to properly control blood glucose levels. Transplantation of pancreatic islet cells has been investigated as an alternative to insulin injections or pancreas transplantation. Islet cell transplantation is proposed as a treatment for type I diabetes, whether due to unknown causes or to partial or total pancreatectomy.  

The U.S. Food and Drug Administration (FDA) provided industry guidance regarding investigational new drug development (IND) for allogeneic pancreatic islet cell products. However, to date, there is no FDA approved biologic license for allogeneic pancreatic islet cell products.

Definitions

Acinar: Any secreting cell lining a gland, especially as applied to the cells of the pancreas that furnish pancreatic juice and enzymes to distinguish them from the islets of Langerhans, which secrete hormones.

Allogeneic: Derived from individual(s) other than the recipient.

Autologous: Derived from the individual’s own body.

Islet of Langerhans: Groups of cells found within the pancreas; A-cells and B-cells which secrete insulin and glucagon.

Pancreas: A glandular organ lying below and behind the stomach that secretes insulin and glucagon (both regulate blood sugar), as well as digestive enzymes.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Medically Necessary:

CPT

 

48160

Pancreatectomy, total or subtotal, with autologous transplantation of pancreas or pancreatic islet cells

 

 

ICD-10 Procedure

 

3E030U0-3E033U0

Introduction of autologous pancreatic islet cells into peripheral vein [by approach; includes codes 3E030U0, 3E033U0]

3E0J3U0-3E0J8U0

Introduction of autologous pancreatic islet cells into biliary and pancreatic tract [by approach; includes codes 3E0J3U0, 3E0J7U0, 3E0J8U0]

 

 

ICD-10 Diagnosis

 

K86.0-K86.1

Chronic pancreatitis

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary for allogeneic transplantation:

CPT

 

48999

Unlisted procedure, pancreas [when specified as pancreatic islet cell transplantation ]

 

 

HCPCS

 

G0341

Percutaneous islet cell transplant, includes portal vein catheterization and infusion

G0342

Laparoscopy for islet cell transplant, includes portal vein catheterization and infusion

G0343

Laparotomy for islet cell transplant, includes portal vein catheterization and infusion

S2102

Islet cell tissue transplant from pancreas, allogeneic

 

 

ICD-10 Procedure

 

3E030U1-3E033U1

Introduction of nonautologous pancreatic islet cells into peripheral vein [by approach; includes codes 3E030U1, 3E033U1]

3E0J3U1-3E0J8U1

Introduction of nonautologous pancreatic islet cells into biliary and pancreatic tract [by approach; includes codes 3E0J3U1, 3E0J7U1, 3E0J8U1]

 

 

ICD-10 Diagnosis

 

 

All diagnoses

References

Peer Reviewed Publications:

  1. American Diabetes Association. 3. Comprehensive Medical Evaluation and Assessment of Comorbidities. Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018; 41(Suppl 1):S28-S37.
  2. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012; 35(7):1436-1445.
  3. 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):761-766.
  4. Close N, Alejandro R, Hering B, Appel M.; CITR Investigators. Second annual analysis of the collaborative islet transplant registry. Transplant Proc. 2007; 39(1):179-182.
  5. 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):771-779.
  6. Health Quality Ontario. Pancreas islet transplantation for patients with type 1 diabetes mellitus: A clinical evidence review. Ont Health Technol Assess Ser. 2015; 15(16):1-84.
  7. Lablanche S, Borot S, Wojtusciszyn A, et al. GRAGIL Network. Five-year metabolic, functional, and safety results of patients with type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL Network. Diabetes Care. 2015; 38(9):1714-1722.
  8. Qi M, Kinzer K, Danielson KK, et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol. 2014; 51(5):833-843.
  9. Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg. 2012; 214(4):409-424.
  10. Sutherland DE, Radosevich D, Gruessner R, et al. Pushing the envelope: living donor pancreas transplantation. Curr Opin Organ Transplant. 2012; 17(1):106-115.
  11. Wu Q, Zhang M, Qin Y, et al. Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients. Endocr J. 2015; 62(3):227-234.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. U.S. Food & Drug Administration.  Guidance for Industry: considerations for allogeneic pancreatic islet cell products. September 2009. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM182441.pdf  Accessed on December 19, 2017.
Websites for Additional Information
  1. Collaborative Islet Transplant Registry (CITR). Available at: http://citregistry.org/. Accessed on December 19, 2017.
  2. National Diabetes Information Clearinghouse (NDIC) – Pancreatic Islet Transplantation. September 2013. Available at: http://diabetes.niddk.nih.gov/dm/pubs/pancreaticislet/index.aspx. Accessed on December 19, 2017.
Index

Allogeneic Islet Cell Transplant
Autologous Islet Cell Transplant
Diabetes
Islet Cell Transplant
Islet Cell Autotransplant
Pancreatectomy, Partial or Complete
Pancreatic Islet Cell Transplant
Pancreatitis

Document History

Status

Date

Action

Reviewed

02/27/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Rationale, Background, References and Index sections updated.

Reviewed

02/02/2017

MPTAC review. Rationale, References and Websites sections updated.

Reviewed

02/04/2016

MPTAC review. Rationale, Background and Reference sections updated. Removed ICD-9 codes from Coding section.

Reviewed

02/05/2015

MPTAC review. Updated Rationale, References and Websites sections.

Reviewed

02/13/2014

MPTAC review. Updated Rationale, References and Web Sites sections.

Reviewed

02/14/2013

MPTAC review. Updated Rationale, References and Web Sites sections.

Revised

02/16/2012

MPTAC review. Clarified investigational and not medically necessary Position Statements. Updated Rationale, and References sections. Added Web Sites section.

 

01/01/2012

Updated Coding section with 01/01/2012 CPT changes; removed codes 0141T, 0142T, 0143T deleted 12/31/2011.

Reviewed

02/17/2011

MPTAC review. Title, Rationale, Background, Definitions, and References updated.

Reviewed

02/25/2010

MPTAC review. Rationale and references updated.

Reviewed

02/26/2009

MPTAC review. Rationale, background and references updated.

Reviewed

02/21/2008

MPTAC review. Rationale, background and references updated. Clarified note for multi-organ requests. The phrase “investigational/not medically necessary” was clarified to read “investigational and not medically necessary.” This change was approved at the November 29, 2007 MPTAC meeting.

Reviewed

03/08/2007

MPTAC review. References and coding updated.

Reviewed

03/23/2006

MPTAC review. References and codes updated.

 

01/01/2006

Updated Coding section with 01/01/2006 CPT/HCPCS changes

 

11/18/2005

Added reference for Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD).

Revised

04/28/2005

MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.

Pre-Merger Organizations

Last Review Date

Document Number

Title

Anthem, Inc.

04/27/2004

TRANS.00010

Autologous and Allogeneic Islet Cell Transplant

WellPoint Health Networks, Inc.

12/02/2004

7.06.05

Transplantation-Autologous and Allogeneic Islet Cell