Medical Policy

 

Subject: Hematopoietic Stem Cell Transplantation for Diabetes Mellitus
Document #: TRANS.00034 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description/Scope

This document addresses the use of hematopoietic stem cell transplantation to reconstitute the immune system as a treatment of diabetes mellitus (DM).

Position Statement

Investigational and Not Medically Necessary:

Autologous or allogeneic (ablative and non-myeloablative) hematopoietic stem cell transplantation is considered investigational and not medically necessary as a treatment of diabetes mellitus.

Rationale

Type 1 diabetes mellitus is a result of cell-mediated autoimmune destruction of pancreatic beta cells. Many clinical trials are investigating different treatment modalities to restore and maintain sufficient glucose control to avoid the detrimental effects of inadequate glucose metabolism. Pancreas transplant and islet cell transplantation to replace insulin producing beta cells are hindered by the limited supply of organs. Additionally, transplanted islet cells frequently succumb to continued destruction by the underlying host immune system.

Animal models suggest that immune suppression in newly diagnosed type 1 diabetes prevents further loss of insulin production (Burt, 2002). Early human studies demonstrated that various immune blocking therapies (prednisone, azathioprine, cyclosporine) may produce limited and short-term improvement in C-peptide levels, but these effects were not maintained after immunosuppression was discontinued (Canadian-European Randomized Control Trial Group, 1988). In addition, the Diabetes Control and Complications Trial (DCCT, 1998) showed that individuals with a larger beta cell reserve have a slower decline in C-peptide levels and fewer microvascular complications than individuals with low or undetectable C-peptide concentrations. As a result, beta cell preservation is felt to be an important target in the management of type 1 diabetes mellitus and in the prevention of its complications.

Burt and colleagues (2002) proposed application of hematopoietic stem cell transplantation to treat diabetes as an autoimmune disorder. It was proposed that administration of immune ablative therapy might induce tolerance to auto-antigens and promote islet cell regeneration. In theory, hematopoietic stem cells would serve as progenitor cells for the immune system as well as minimizing the duration and complications of myelosuppression.

In an attempt to moderate the immune destruction of pancreatic beta cells in newly diagnosed type 1 diabetes mellitus (DM), investigators in Brazil (Voltarelli, 2007) reported a small phase I/II trial using high-dose immunosuppression followed by autologous non-myeloablative hematopoietic stem cell transplantation (AHST) in 15 subjects. Couri (2009) provided an extended report of the original participants and an additional 8 for a total of 23 participants with a mean follow-up of 29.8 months (range 7-58 months). The subjects included in this study were aged 12 to 31 years (mean 18.4 years) with a diagnosis of type 1 DM within the previous 6 weeks. In this study, hematopoietic stem cells were mobilized with cyclophosphamide (2.0g/m2) and granulocyte colony-stimulating factor. The stem cells were injected after conditioning with cyclophosphamide (200mg/kg) and rabbit antithymocyte globulin. The primary endpoints (Voltarelli, 2007) were transplant morbidity and mortality and the changes in exogenous insulin requirements. Secondary endpoints were levels of hemoglobin A1C, C-peptide levels and anti-glutamic acid decarboxylase (anti-GAD) antibody titers. Anti-GAD antibodies are auto-antibodies directed against islet cell antigen. In the extension study (Couri, 2009), the primary outcome measure was C-peptide levels during the mixed-meal tolerance test, before and at different times following transplantation. The pre-transplant mean exogenous insulin requirement for all participants was 0.38 IU/kg per day. Statistical differences in anti-GAD antibodies were noted between the pre-transplant level of 31.8 U/mL and 12.5 U/mL at 6 months following therapy. There were no significant differences in anti-GAD antibodies at other time frames (Voltarelli, 2007).

In the extension study (range 7-58 months) 12 participants attained continuous insulin freedom for a mean of 31 months. The mean pre-transplant HbA1C was 8% and decreased significantly (p<0.001) at 3, 12, 24, 36 and 48 months to 5.4%, 5.7%, 5.7%, 5.5% and 6.0%, respectively. Mean area under the curve (AUC) C-peptide levels increased from 225.0 [75.2] ng/mL per 2 hours to 785.4 [90.3] ng/mL per 2 hours (p<0.001) at 24 months, and 728.1 [144.4] ng/mL per 2 hours (p=0.001) at 36 months (Couri, 2009).

Additionally, for a mean of 17.7 months, 8 participants achieved intermittent freedom from insulin, but relapsed and resumed low-dose insulin therapy. Mean pre-transplantation (AUC) C-peptide level was 148.9 [75.2] ng/mL per 2 hours. It increased after transplantation to 546.8 [96.9] ng/mL per 2 hours (p=0.001) at 36 months and 413.9 [124.7] ng/mL per 2 hours at 48 months (Couri, 2009).

Of note, the first participant treated in this study had a low C-peptide level of 0.4 ng/mL at baseline, which did not increase after 1 year. In this participant, insulin requirements progressively increased to doses 250% more than baseline requirements. This participant was lost to follow-up at 1 year. The investigators reported the study protocol was then modified, and the initial participant’s results were not included. Three participants did not achieve any freedom from insulin, and HbA1C levels did not decrease below 7% despite increasing insulin therapy. Transplant-related complications were reported in all participants with a majority experiencing febrile neutropenia and alopecia. Two serious infectious complications (bilateral pneumonia) were recorded. There were no deaths. During long-term follow-up, 3 participants developed endocrine disorders and 9 reported oligospermia (Couri, 2009; Voltarelli, 2007).

Although this study involved a highly selected group of participants, early results suggest that islet cell tolerance may be potentially re-induced with high dose immunosuppression followed by AHST. However, the evidence at this point is insufficient to establish the long-term safety and durable efficacy of this therapy in the treatment of type 1 DM. Further study in randomized, controlled trials is needed to establish a role of this treatment in changing the natural history of type 1 DM. At this time, there is one phase I/II and one phase II clinical trial recruiting individuals for autologous hematopoietic stem cell transplantation (HSCT) for type 1 DM. For evaluation of the efficacy of autologous HSCT for type 2 DM, there is one ongoing phase II and one Phase II/III clinical trial recruiting participants.

A published study by Bhansali and colleagues (2009) provides the first prospective review of participants undergoing autologous bone marrow-derived stem cell transplantation (SCT) for type 2 DM, represented by progressive and inexorable B-cell dysfunction. The pilot trial consisted of 10 participants (8 men, 2 women, age 50-68 years) diagnosed with “type 2 DM for greater than 5 years, failure of triple oral antidiabetic drugs, currently on insulin (greater than or equal to 0.7 U/kg/day) at least for 1 year, and glutamic acid decarboxylase antibody negative were included.” Ten participants underwent SCT with a reported 7 (70%) participants achieving a reduction in insulin requirement by greater than or equal to 50%, while the remaining 3 participants were categorized as nonresponders. As a result, post SCT there was a reduction in the demand for insulin with mean 41.2 units/ day (59%) (p=0.007). The authors concluded:

This study shows that SCT is an effective and safe option of B-cell regeneration leading to reduction in insulin requirement in patients with type 2 DM requiring high doses of insulin. However, further large-scale and long-term studies are required to fully substantiate the role of SCT in the management of type 2 DM.

An updated literature search based on the MEDLINE database through September 2017 did not identify any new literature to support the use of hematopoietic stem cell transplantation to treat type 1 DM.

Background/Overview

According to the World Health Organization, there was an estimated 422 million people affected by diabetes worldwide in 2017. Diabetes mellitus, the 7th leading cause of death in the U.S., is a chronic condition marked by impaired metabolism of carbohydrate, protein and fat affecting 30.3 million (9.4 %) Americans (CDC, 2017). The underlying problem in diabetes is in the production or utilization of insulin, the hormone secreted by the pancreas that controls the level of blood sugar by regulating the transfer of glucose from the blood into the cells. Diabetes mellitus, if poorly controlled, can cause cardiovascular disease, retinal damage that could lead to blindness, damage to the peripheral nerves, and injury to the kidneys. Management of diabetes mellitus involves attempting to keep the blood sugar in normal ranges without causing potentially dangerous hypoglycemia, or low blood sugar.

There are three major types of diabetes:

Type 1 diabetes mellitus (DM) occurs as a result of an autoimmune attack on insulin producing pancreas beta cells. Type 1 diabetics are dependent on exogenous insulin to maintain control of glucose levels.

Hematopoietic stem cell transplant for diabetes includes the use of high dose chemotherapy (HDC) or immunosuppressive agents.  Bone marrow ablation is the most significant side effect of HDC. As a result, HDC is accompanied by a re-infusion of hematopoietic stem cells, which are primitive cells capable of replication and formation into mature blood cells, in order to repopulate the marrow. The potential donors of stem cells include:

  1. Autologous - Stem cells can be harvested from the individual’s own bone marrow prior to the cytotoxic therapy
  2. Allogeneic - Stem cells harvested from a histocompatible donor

Donor stem cells, either autologous or allogeneic, can be collected from either the bone marrow or the peripheral blood. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation, donors may be pretreated with a course of chemotherapy or hematopoietic growth factors, or both.

In addition, blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Although cord blood is an allogeneic source, these stem cells are antigenically "naïve" and thus, are associated with a lower incidence of rejection or graft versus host disease.

The most appropriate stem cell source for a particular individual depends upon his or her disease, treatment history, and the availability of a compatible donor. The most appropriate source of stem cells for each individual must balance the risks of graft failure in autologous procedures, the risks of graft rejection, and graft versus host disease in allogeneic procedures.

While some hematopoietic stem cell transplant protocols can be administered on an outpatient basis, an inpatient stay may be required.

While the intensity of the regimens used for conditioning in conventional HDC varies, collectively they have been termed "myeloablative." Several less intense conditioning regimens have been developed recently and rely more on immunosuppression than cytotoxic effects to permit engraftment of donor cells. These regimens, collectively termed "non-myeloablative," also vary in intensity with substantial overlap between the ranges for "myeloablative" and "non-myeloablative" regimens. Studies have shown that donor allogeneic stem cells can engraft in recipients using less-intensive conditioning regimens that are sufficiently immunosuppressive to permit graft-host tolerance. Non-myeloablative allogeneic transplants also referred to as "mini-transplant" or "reduced intensity conditioning (RIC) transplant," are thought to be potentially as effective as conventional HDC followed by an allogeneic stem cell transplantation (AlloSCT), but with decreased morbidity and mortality related to the less intense non-myeloablative chemotherapy conditioning regimen.

Definitions

Ablative: A very high dose of a treatment, calculated to kill a tumor.

Blood glucose: A sugar that is present in the bloodstream.

Bone marrow: A spongy tissue located within flat bones, including the hip and breast bones and the skull; this tissue contains stem cells, the precursors of platelets, red blood cells, and white cells.

C-peptide: A substance released by the pancreas in equal amounts as insulin.

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals; chemotherapy may vary by disease and stage.

Cytotoxic: Destructive to cells.

Glucose: A form of sugar required for proper functioning of the body.

Hemoglobin A1C: A test to measure the average blood glucose level over the previous 2-3 months; amount of glucose attached to the red blood cells.

Hematopoietic stem cells: Primitive cells capable of replication and formation into mature blood cells in order to re-populate the bone marrow.

High-dose or myeloablative chemotherapy (HDC): The administration of cytotoxic agents using doses several times greater than the standard therapeutic dose.

Hyperglycemia: Blood glucose levels that are higher than the normal range.

Hypoglycemia: Blood glucose levels that are lower than the normal range.

Insulin: A substance normally produced by the body that takes glucose from the blood and makes glucose usable by the cells of the body.

Non-myeloablative chemotherapy: A less intense chemotherapy conditioning regimens, which rely more on immunosuppression than cytotoxic effects to permit engraftment of donor cells.

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 Investigational and Not Medically Necessary:

CPT

 

38204

Management of recipient hematopoietic progenitor cell donor search and cell acquisition

38205

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous

38207-38215

Transplant preparation of hematopoietic progenitor cells [includes codes 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215]

38230

Bone marrow harvesting for transplantation; allogeneic

38232

Bone marrow harvesting for transplantation; autologous

38240

Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor

38241

Hematopoietic progenitor cell (HPC); autologous transplantation

38243

Hematopoietic progenitor cell (HPC); HPC boost

 

 

HCPCS

 

S2142

Cord blood-derived stem cell transplantation, allogeneic

S2150

Bone marrow or blood-derived peripheral stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including pheresis and cell preparation/storage, marrow ablative therapy, drugs, supplies, hospitalization with outpatient follow-up, medical/surgical, diagnostic, emergency, and rehabilitative services, and the number of days of pre- and post-transplant care in the global definition

 

 

ICD-10 Procedure

 

 

Autologous transplantation

30230G0-30243G0

Transfusion of autologous bone marrow into vein [peripheral or central, by approach; includes codes 30230G0, 30233G0, 30240G0, 30243G0]

30230Y0-30243Y0

Transfusion of autologous hematopoietic stem cells into vein [peripheral or central, by approach; includes codes 30230Y0, 30233Y0, 30240Y0, 30243Y0]

30250G0-30263G0

Transfusion of autologous bone marrow into artery [peripheral or central, by approach; includes codes 30250G0, 30253G0, 30260G0, 30263G0]

30250Y0-30263Y0

Transfusion of autologous hematopoietic stem cells into artery [peripheral or central, by approach; includes codes 30250Y0, 30253Y0, 30260Y0, 30263Y0]

 

Allogeneic transplantation

30230G2-30243G4

Transfusion of allogeneic bone marrow, related, unrelated or unspecified into peripheral or central vein [by approach; includes codes 30230G2, 30230G3, 30230G4, 30233G2, 30233G3, 30233G4, 30240G2, 30240G3, 30240G4, 30243G2, 30243G3, 30243G4]

30250G1-30263G1

Transfusion of nonautologous bone marrow into peripheral or central artery [by approach; includes codes 30250G1, 30253G1, 30260G1, 30263G1]

30230X2-30243X4

Transfusion of allogeneic cord blood stem cells, related, unrelated or unspecified into peripheral or central vein [by approach; includes codes 30230X2, 30230X3, 30230X4, 30233X2, 30233X3, 30233X4, 30240X2, 30240X3, 30240X4, 30243X2, 30243X3, 30243X4]

30250X1-30263X1

Transfusion of nonautologous cord blood stem cells into peripheral or central artery [by approach; includes codes 30250X1, 30253X1, 30260X1, 30263X1]

30230Y2-30243Y4

Transfusion of allogeneic hematopoietic stem cells, related, unrelated or unspecified into peripheral or central vein [by approach; includes codes 30230Y2, 30230Y3, 30230Y4, 30233Y2, 30233Y3, 30233Y4, 30240Y2, 30240Y3, 30240Y4, 30243Y2, 30243Y3, 30243Y4]

30250Y1-30263Y1

Transfusion of nonautologous hematopoietic stem cells into peripheral or central artery [by approach; includes codes 30250Y1, 30253Y1, 30260Y1, 30263Y1]

 

Pheresis

6A550ZV

Pheresis of hematopoietic stem cells, single

6A551ZV

Pheresis of hematopoietic stem cells, multiple

 

 

ICD-10 Diagnosis

 

E08.00-E08.9

Diabetes mellitus due to underlying condition

E09.00-E09.9

Drug or chemical induced diabetes mellitus

E10.10-E10.9

Type 1 diabetes mellitus

E11.00-E11.9

Type 2 diabetes mellitus

E13.00-E13.9

Other specified diabetes mellitus

References

Peer Reviewed Publications:

  1. Bhansali A, Upreti V, Khandelwal N, et al. Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev. 2009; 18(10):1407-1416.
  2. Burt RK, Oyama Y, Traynor A, Kenyon NS. Hematopoietic stem cell therapy for type 1 diabetes: induction of tolerance and islet cell neogenesis. Autoimmun Rev. 2002; 1(3):133-138.
  3. Canadian-European Randomized Clinical Trial Group. Cyclosporine-induced remission of IDDM after early intervention: association of 1 year cyclosporine treatment with enhanced insulin secretion. Diabetes. 1988; 37(11):1574-1582.
  4. Couri C, Oliveira M, Stracieri A, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009; 301(15):1573-1579.
  5. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the Diabetes and Control and Complications Trial. Ann Intern Med.  1998; 128(7):517-523.
  6. Voltarelli JC, Couri CE, Stracieri AB, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007; 297(14):1568-1576.
  7. Ye L, Li L, Wan B, et al. Immune response after autologous hematopoietic stem cell transplantation in type 1 diabetes mellitus. Stem Cell Res Ther. 2017. 8(1):90.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Diabetes Association. Diagnosis and classification of diabetes. Diabetes Care. 2004, 27 (Suppl 1): S5-S10.
  2. Centers for Disease Control and Prevention. National diabetes statistics report, 2017. Available at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed on September 5, 2017.
  3. National Cancer Institute. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation: Questions and Answers. Reviewed August 12, 2013. Available at: http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant. Accessed on September 5, 2017.
  4. National Library of Medicine. Clinical Trials. Available at: http://clinicaltrials.gov/. Accessed on September 5, 2017.
Websites for Additional Information
  1. American Diabetes Association available at: http://www.diabetes.org/. Accessed on September 5, 2017.
  2. Centers for Disease Control and Prevention. 2011 National diabetes fact sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed on September 5, 2017.
  3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). Diabetes in America, 3rd Edition. December 2016. Available at: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/Pages/diabetes-america-3rd-edition.aspx. Accessed on September 5, 2017.
  4. World Health Organization. Diabetes fact sheet. Revised July 2017. Available at: http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed on September 5, 2017.
Index

Diabetes
Hematopoietic Stem Cell Transplant
Mini Transplant
Non-Myeloablative Stem Cell Transplant
Peripheral Blood Stem Cell
Stem Cell Support (SCS)
Stem Cell Transplant (SCT)
Type 1 Diabetes Mellitus (DM)
Type 2 Diabetes Mellitus (DM)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background, References and Websites sections.

Reviewed

11/03/2016

MPTAC review.

Reviewed

11/02/2016

Hematology/Oncology Subcommittee review. Updated Rationale, Background, References and Websites sections.

 

10/01/2016

Updated Coding section with 10/01/2016 ICD-10-PCS procedure code changes.

Reviewed

11/05/2015

MPTAC review.

Reviewed

11/04/2015

Hematology/Oncology Subcommittee review. Updated References and Websites sections. Removed ICD-9 codes from Coding section.

Reviewed

11/13/2014

MPTAC review.

Reviewed

11/12/2014

Hematology/Oncology Subcommittee review. Updated References and Websites.

Reviewed

11/14/2013

MPTAC review.

Reviewed

11/13/2013

Hematology/Oncology Subcommittee review. Updated Rationale, Background, References and Websites.

Reviewed

11/08/2012

MPTAC review.

Reviewed

11/07/2012

Hematology/Oncology Subcommittee review. Updated Background and Websites. Updated Coding section with 01/01/2013 CPT changes.

Reviewed

11/17/2011

MPTAC review.

Reviewed

11/16/2011

Hematology/Oncology Subcommittee review. Updated Background, References and Websites.  Updated Coding section with 01/01/2012 CPT changes.

Reviewed

11/18/2010

MPTAC review.

Reviewed

11/17/2010

Hematology/Oncology Subcommittee review. Change title to: Hematopoietic Stem Cell Transplantation for Diabetes Mellitus. Updated Rationale, Definitions, Index, References and Websites.

Reviewed

11/19/2009

MPTAC review.

Reviewed

11/18/2009

Hematology/Oncology Subcommittee review. Updated rationale, references and websites.

Reviewed

11/20/2008

MPTAC review.

Reviewed

11/19/2008

Hematology/Oncology Subcommittee review. Updated rationale, references and websites.

 

10/01/2008

Updated Coding section with 10/01/2008 ICD-9 changes.

 

01/01/2008

Updated Coding section with 01/01/2008 HCPCS changes; removed HCPCS G0267 deleted 12/31/2007.

New

11/29/2007

MPTAC review.

New

11/28/2007

Hematology/Oncology Subcommittee review. Initial document development.