Medical Policy

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

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.

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 A_1C, 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 HbA_1C 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 HbA_1C 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.

In 2018, Gu and colleagues reported findings from a phase II prospective, parallel-assigned, non-randomized trial (NCT00807651) that evaluated the safety and efficacy of AHSCT therapy in 40 participants with type 1 diabetes (T1D), 20 of whom received AHSCT therapy and 20 who were treated with insulin injections. Of the participants enrolled, 14 (70%) of the AHSCT group became insulin-dependent for 1.5 to 48 months compared to 1 participant in the insulin group. A total of 11 AHSCT participants relapsed within a median time of 19.5 (range 5.5 -1) months and resumed insulin. “C-peptide levels increased significantly at 3 months in both groups and later decreased, with the insulin group, showing more rapid deterioration.” In the AHSCT group most of the adverse events were identified as transplant-related complications. In summary, the authors concluded that “because of high relapse rate, more information on longer-term outcomes is needed before AHSCT can be routinely considered for T1D patients”.

Madani and colleagues (2022) conducted a systematic review and meta-analysis of HSCT for treatment of T1D, alone or in combination with mesenchymal stem cell transplantation. A total of 21 studies using HSCT alone were included, involving 491 individuals with T1D. Most of these clinical trials were single arm. There was some evidence that HSCT was associated with improved beta cell function: an insulin-free period (from 1 to 80 months) was experienced by 168 subjects (34.2%), and 332 (67.6%) had some reduction in total daily dose of insulin. However, heterogeneity in the HSCT studies was high, as judged by I² statistics of 79-98%, suggesting that there were significant inconsistencies in the studies that may affect the results. Heterogeneity may be due to different follow-up periods in these studies (ranging from 3 months to 5 years), individual nutrition, exercise, weight and stem cell dose. In addition, HCST with conditioning using granulocyte colony stimulating factor and cyclophosphamide was suggested to not be safe due to potential severe adverse events and mortality. Overall, the authors concluded that well-designed randomized clinical trials are needed to clarify the efficacy of HSCT in treating T1D.

There is insufficient evidence in the published peer-reviewed literature to support the use of hematopoietic stem cell transplantation to treat diabetes mellitus.

According to the Centers for Disease Control and Prevention, there was an estimated 34.2 million (10.5%) of the U.S. population affected by diabetes mellitus in 2018. 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 (CDC, 2020). 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, formerly known as Juvenile Diabetes, is a condition where the body does not produce insulin, requiring the injection of insulin from other sources in order to maintain normal blood glucose levels. Approximately 5% to 10% of all diagnosed cases of diabetes are type 1. Although the onset can occur at any time, it usually affects children and young adults (Centers for Disease Control and Prevention [CDC]).
• Type 2 diabetes is a condition where the body's cells do not effectively use the insulin that is present in the blood and/or there is a progressive inability to produce adequate levels of insulin. Approximately 90-95% of individuals with diabetes are type 2, making this the most common form of diabetes.
• Gestational diabetes is a condition where blood glucose levels become elevated during pregnancy in women who normally do not have blood sugar problems. This type of diabetes affects about 4% of all pregnant women and the cause remains unknown.  In the majority of cases, there is a return to normal blood glucose levels after delivery.

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.

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.

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:

Peer Reviewed Publications:

1. Bhansali A, Asokumar P, Walia R, et al. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant. 2013; 23(9):1075-1085.
2. 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.
3. 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.
4. 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.
5. 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.
6. D'Addio F, Valderrama Vasquez A, Ben Nasr M, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: a multicenter analysis. Diabetes. 2014; 63(9):3041-3046.
7. 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.
8. El-Badawy A, El-Badri N. Clinical efficacy of stem cell therapy for diabetes mellitus: a meta-analysis. PLoS One. 2016; 11(4):e0151938.
9. Gu B, Miao H, Zhang J, et al. Clinical benefits of autologous haematopoietic stem cell transplantation in type 1 diabetic patients. Diabetes Metab. 2018; 44(4):341-345.
10. Madani S, Amanzadi M, Aghayan HR, et al. Investigating the safety and efficacy of hematopoietic and mesenchymal stem cell transplantation for treatment of T1DM: a systematic review and meta-analysis. Syst Rev. 2022; 11(1):82.
11. 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.
12. 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.
13. Zhang X, Ye L, Hu J, Tang W, Liu R, Yang M, et al. Acute response of peripheral blood cell to autologous hematopoietic stem cell transplantation in type 1 diabetic patient. PLoS One. 2012; 7(2):e31887.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Diabetes Association. Diagnosis and classification of diabetes. Diabetes Care. 2021; 44 (Suppl 1): S15-S33.
2. Centers for Disease Control and Prevention. National diabetes statistics report, 2020. Available at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed on September 25, 2023.
3. National Cancer Institute. Blood-Forming Stem Cell Transplants. Reviewed August 12, 2013. Available at: http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant. Accessed on September 25, 2023.
4. National Library of Medicine. Clinical Trials. Available at: http://clinicaltrials.gov/. Accessed on September 25, 2023.

1. American Diabetes Association available at: http://www.diabetes.org/. Accessed on September 25, 2023.
2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Reviewed September 6, 2022. Available at: https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm. Accessed on September 25, 2023.
3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). Diabetes in America, 3^rd Edition. August 2018. Available at: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/diabetes-in-america-3rd-edition. Accessed on September 25, 2023.
4. World Health Organization. Diabetes fact sheet. Revised April 5, 2023. Available at: http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed on September 25, 2023.

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)

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