Medicare Advantage

Medical Policy

Notification

Islet Cell Transplantation, including use of Donislecel-jujn (Lantidra)

Notification Issue Date:

This version of the policy will become effective 01/01/2020.

The following CPT codes have been

added

to this policy:

0584T (Medically Necessary), 0585T (Medically Necessary), 0586T (Medically Necessary)

Title:

Islet Cell Transplantation, including use of Donislecel-jujn (Lantidra)

Policy #:

MA11.007b

Policy

This policy uses coverage criteria primarily based on applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals and other applicable Medicare coverage documents. In the absence of fully established coverage criteria from these Medicare coverage documents for a specific medical service or item, the criterion/indication/service indicated by an asterisk below (*) is based on internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, regulatory status, and/or expert opinion.

MEDICALLY NECESSARY

Autologous islet cell transplantation is considered medically necessary and, therefore, covered as an adjunct to a total or near-total pancreatectomy in individuals with chronic pancreatitis.*(American Diabetes Association, 2026; Zhang et al., 2020; Kempeneers et al., 2019)

EXPERIMENTAL/INVESTIGATIONAL

Autologous islet cell transplantation is considered experimental/investigational and, therefore, not covered for all other indications because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.*(Zhang et al., 2020; Kempeneers et al., 2019)

Allogeneic islet cell transplantation, including US Food and Drug Administration (FDA)-approved cellular therapy donislecel-jujn (Lantidra), is considered experimental/investigational and, therefore, not covered for all indications because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature. *(American Diabetes Association, 2026; Wang et al., 2025; US FDA Clinical Memo Review, 2023)

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

This policy is consistent with Medicare's coverage determination. The Company's payment methodology may differ from Medicare.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, autologous islet cell transplantation as an adjunct to a total or near-total pancreatectomy in individuals with chronic pancreatitis is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

Subject to the terms and conditions of the applicable Evidence of Coverage, allogeneic islet cell transplantation, including US Food and Drug Administration (FDA)-approved cellular therapy

donislecel-jujn (

Lantidra), is not eligible for payment under the medical benefits of the Company’s Medicare Advantage products because the service is considered experimental/investigational and, therefore, not covered. Services that are experimental/investigational are excluded for the Company's Medicare Advantage products. Therefore, they are not eligible for reimbursement consideration.

Pancreatic islet cell transplantation for individuals with type 1 diabetes who participate in a clinical trial sponsored by the National Institutes of Health may be covered and reimbursed by the local Medicare Administrative Contractor (MAC).

Description

The pancreas is an organ located behind the lower part of the stomach. One of the major functions of the pancreas is the production of two hormones: insulin and glucagon. The production of these hormones takes place in endocrine cell clusters located on the pancreas called the islets of Langerhans. The islets of Langerhans make up approximately 1% to 2% of the total pancreas.

There are about one million islets in a healthy adult. Most islet cells are concentrated toward the tail end of the pancreas. Islets are mostly composed of two types of cells: alpha cells, which produce glucagon, a hormone that raises the level of glucose (sugar) in the blood, and beta cells, which produce insulin, a hormone that reduces the level of glucose in the blood by helping the body use glucose for energy.

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

CHRONIC PANCREATITIS

Chronic pancreatitis is a condition that destroys the pancreas and other tissues. Symptoms include severe abdominal pain, weight loss, fever, nausea, and vomiting. Individuals with chronic pancreatitis can experience intractable pain that can only be relieved with a total or near-total pancreatectomy. After a pancreatectomy, the individual will benefit from pain relief, but will become dependent on insulin (i.e., surgically induced diabetes) due to the loss of insulin-producing islet cells.

Autologous islet transplantation is a technique to prevent the serious morbidity of surgically induced diabetes due to the removal of the individual's pancreas. Although the pancreatotomy and transplant can be performed on two different days, the transplant is generally performed during the pancreatectomy procedure. During the pancreatectomy, a suspension is created by mixing plasma and the isolated islet cells collected from the individual's own resected pancreatic specimen. This suspension is then injected into the portal vein of the liver, where the cells function as a free graft. There is no risk of rejection because, unlike allogeneic organ/tissue transplants, the individual's own islet cells are used in the procedure.

Although the published literature regarding autologous islet cell transplantation is limited, this procedure has been shown to significantly decrease the occurrence of surgically induced diabetes after a total or near-total pancreatectomy. Additionally, autologous islet cell transplantation has not been associated with serious morbidity.

Conversely, the level of evidence in the literature is insufficient to demonstrate the efficacy of autologous islet cell transplantation performed for any other indication.

TYPE 1 DIABETES MELLITUS

Type 1 diabetes mellitus results from cellular autoimmune destruction of the beta cells in the islets of Langerhans in the pancreas. Islet cell autoantibodies (ICAs) are theorized to cause the individual to reject their own islet cells, leading to an absolute insulin deficiency. ICAs have been detected in many individuals with type 1 diabetes.

Allogeneic islet cell transplantation has been proposed as a treatment for type 1 diabetes in order to restore normoglycemia. By restoring normoglycemia, it is hoped that an islet cell transplant will reduce or eliminate the long-term complications of diabetes, such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Islet cell transplantation is a potential alternative to whole-organ pancreas transplantation.

Individuals with type 1 diabetes do not have viable beta cells for autologous transplantation and, therefore, cannot receive an autologous transplant. In addition to the immune system rejecting foreign tissue, the presence of ICAs is another confounding factor because ICAs add an additional rejection complication for allogeneic islet cells in individuals with type 1 diabetes mellitus. In 2000, a modified immunosuppression regimen, the Edmonton protocol, increased the success of allogeneic islet transplantation.

DONISLECEL-JUJN (LANTIDRA)

In June 2023, the US Food and Drug Administration (FDA) approved donislecel-jujn (Lantidra) for the treatment of adults with type 1 diabetes mellitus, which is characterized by the inability to approach target hemoglobin A1c (HbA1c) because of repeated episodes of severe hypoglycemia despite intensive diabetes management and education. The FDA primarily based this decision on an analysis of two trials with similar eligibility criteria: a Phase 1/2 single-arm, open-label, clinical trial (n=10) and a Phase 3 single-arm, open-label, clinical trial (n=21) for a total of 30 unique participants (one participant matriculated from the Phase 1/2 trial to the Phase 3 trial). Participants received at least one, but no more than three islet cell transplantations: 11 received one islet cell infusion, 12 received two infusions, and seven received three infusions. The FDA reported that of these 30 participants, 21 (70%) achieved at least 1 year of insulin independence from exogenous insulin while maintaining or improving glycemic control, and 10 of 30 (33%) participants had insulin independence for at least 5 years. Five participants did not achieve any days of insulin independence.

In the clinical trials, the composite primary endpoint defined success as an absence of severe hypoglycemic events (SHE) and HbA1c of 6.5% or less. Of the 30 participants, 19 (63%) achieved success, but the FDA Biologics License Application Clinical Review Memorandum on Lantidra, which analyzed the trial's raw data stated that the “FDA believes that the Applicant's proposed composite efficacy primary endpoint of HbA1c ≤ 6.5% and absence of SHE is not supported by the data provided." This is because the inclusion criteria of participants did not match the actual study population. Twenty percent of the population they studied had HbA1c levels in target range at baseline, 7.4% ± 0.94% (range, 5.8–9.5) and most participants (83%) had an absence of SHE in the year prior to their first transplantation. Consequently, the population's baseline characteristics preclude the measurement of clinically meaningful improvement after islet cell transplantation.

Additionally, enrollment criteria required that the participants' symptoms of severe hypoglycemia and reduced awareness of hypoglycemia had to persist “despite intensive insulin management efforts", but their diabetic treatments prior to transplantation were not reported. Given that the majority of these participants had HbA1c levels in target range and an absence of SHE, ostensibly, these “intensive insulin management efforts" were achieving positive health outcomes for this population without islet cell transplantation. Because this baseline demographic was not reported, there are limitations in the ability to demonstrate a clinically meaningful improvement compared to the treatment alternatives.

Acknowledging that the trials' composite primary endpoint was not supportive of efficacy, the FDA noted that 21 of 30 (70%) participants achieved at least 1 year of insulin independence and 10 of 30 (33%) participants had insulin independence for at least 5 years. The Phase 1/2 trial included an additional primary endpoint, insulin independence at the end of study participation; however, the Phase 3 trial analyzed insulin independence 1 year after transplantation as a secondary endpoint. The FDA completed its analysis based on insulin independence, which is problematic. In randomized controlled trials (RCTs), primary endpoints must be established a priori to prevent bias and reduce the risk of reporting outcomes that support a particular hypothesis, thus maintaining the study's validity. It is inappropriate to analyze and report the results for insulin independence as a primary endpoint for both trials when the Phase 3 trial analyzed it as a secondary endpoint.

Another limitation reported by the FDA is that 90% of all individuals experienced severe adverse events. These events included two deaths (7%) from multiorgan failure with sepsis (1.6 years after first infusion) and progressive confusion, global atrophy, and microischemic disease (9.7 years after first infusion); the most serious adverse reactions were attributed to immunosuppression. Infections were reported in 26 individuals (87%), totaling 211 episodes, one of which was classified as life-threatening and 22 as severe. Malignancy was reported in 11 subjects (37%), including 12 skin cancers and one each of posttransplant lymphoproliferative disease, breast cancer, and thyroid cancer. Common adverse events included but were not limited to nausea, fatigue, anemia, diarrhea, abdominal pain, asthenia, headache, and hyponatremia. Most adverse reactions were low-grade by Common Terminology Criteria for Adverse Events, version 5; the most common grade (three or more adverse events) included low density lipoprotein elevations (37%), anemia (27%), and pneumonia (17%).

Two endocrinologists on the advisory panel reported that 4 to 5 years of insulin independence would represent a clinical meaningful treatment benefit. A patient-preference study reported a congruent sentiment: islet cell transplantation individuals would prefer the greatest benefit for the lowest risk; specifically, a 5% risk of serious complications with the possibility of 5 years of insulin independence. Of the 25 participants who achieved insulin independence, four subjects (13%) were insulin independent for less than 1 year, 12 subjects (37%) for 1 to 5 years, and nine subjects (33%) for greater than 5 years.

The FDA Biologics License Application Clinical Review Memorandum reported numerous protocol deviations across the trials that limit the interpretation of both efficacy and safety data. The FDA also provided examples of missing and incongruent data and insufficient data monitoring during the study. Multiple information requests were generated by the FDA in order to achieve adequate data for a complete review. The studies were conducted at a single site, which raises concern. Moreover, other factors that might affect insulin independence occurrence or duration were not able to be elucidated from the existing studies such as cell product factors (e.g., number of cells, viability, purity, and potency) and delivery device (e.g., type of catheter).

Well-designed studies and longer follow-up are needed to establish the safety and effectiveness of donislecel-jujn (Lantidra) for type 1 diabetic individuals. The evidence is insufficient to determine an improvement in net health outcomes.

References

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Wilson L, Kwok T, Ma Y, et al. Preferences for risks and benefits of islet cell transplantation for persons with type 1 diabetes with history of episodes of severe hypoglycemia: a discrete-choice experiment to inform regulatory decisions. Transplantation. 2022;106(8):e368-e379.

Witkowski P, Philipson LH, Kaufman DB, et al. The demise of islet allotransplantation in the United States: A call for an urgent regulatory update. Am J Transplant. 2021;21(4):1365-1375.

Wu Q, Zhang M, Qin Y, et al. Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients [Review]. Endocr J. 2015;62(3):227-234.

Zhang YJ, Duan DD, Yuan H. Efficacy and safety of islet autotransplantation after total pancreatectomy in chronic pancreatitis: a systematic review and meta-analysis including 17 studies. Clin Res Hepatol Gastroenterol. 2020;44(4):598-608.

Coding

CPT Procedure Code Number(s)

0584T, 0585T, 0586T, 48160

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

K86.0 Alcohol-induced chronic pancreatitis

K86.1 Other chronic pancreatitis

Z90.410 Acquired total absence of pancreas

Z90.411 Acquired partial absence of pancreas

HCPCS Level II Code Number(s)

MEDICALLY NECESSARY

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

EXPERIMENTAL/INVESTIGATIONAL

S2102 Islet cell tissue transplant from pancreas; allogeneic

THE FOLLOWING CODES ARE USED TO REPRESENT donislecel-jujn (Lantidra):

C9399 Unclassified drugs or biologicals

J3490 Unclassified drugs

J3590 Unclassified biologics

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA11.007b:

04/01/2026	This policy has been reviewed and reissued to communicate the Company’s continuing position on islet cell transplantation, including use of donislecel-jujn (Lantidra).
03/05/2025	This policy has been reviewed and reissued to communicate the Company’s continued position on Islet Cell Transplantation.
02/26/2024	This version of the policy will become effective 02/19/2024 The following criterion has been added to this policy as experimental/investigational: donislecel-jujn (Lantidra) The following HCPCS codes have been added to this policy: C9399, J3490, J3590

Revisions From MA11.007a:

01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
03/22/2023	This policy has been reviewed and reissued to communicate the Company’s continued position on Islet Cell Transplantation.
05/18/2022	This policy has been reissued in accordance with the Company’s annual review process.
11/03/2021	This policy has been reviewed and reissued to communicate the Company’s continuing position on Islet Cell Transplantation.
11/18/2020	This policy has been reviewed and reissued to communicate the Company’s continuing position on Islet Cell Transplantation.
01/01/2020	Inclusion of a policy in a Code Update memo does not imply that a full review of the policy was completed at this time. This policy has been identified for the CPT code update, effective 01/01/2020. The following CPT codes have been added to this policy: 0584T (Medically Necessary), 0585T (Medically Necessary), 0586T (Medically Necessary)

Revisions From MA11.007:

11/06/2019	This policy has been reviewed and reissued to communicate the Company’s continuing position on Islet Cell Transplantation.
07/18/2018	As of 07/18/2018, this policy has been reviewed and reissued to communicate the Company’s continuing position on islet cell transplantation.

06/21/2017	This policy has been reissued in accordance with the Company's annual review process.
03/02/2016	The policy has been reviewed and reissued to communicate the Company’s continuing position on Islet Cell Transplantation.
01/07/2015	The policy has been reviewed and reissued to communicate the Company’s continuing position on Islet Cell Transplantation.
01/01/2015	This is a new policy.

Version Effective Date:

2/26/2024

Version Issued Date:

2/19/2024

Version Reissued Date:

4/1/2026