Latest Review Date: January 2024

Category: Surgery                                                                                                                                                                   

POLICY:

Autologous hematopoietic cell transplantation is considered medically necessary as a treatment of systemic sclerosis/scleroderma if all of the following conditions are met:

• Adult individuals <60 years of age; AND
• Maximum duration of condition of 5 years; and
• Modified Rodnan Scale Scores >15; and
• Internal organ involvement as noted below:
  • Individuals with internal organ involvement indicated by the following measurements may be considered for autologous HCT:
    • Cardiac: abnormal electrocardiogram; OR
    • Pulmonary: diffusing capacity of carbon monoxide (DLCo) <80% of predicted value; decline of forced vital capacity (FVC) of >10% in last 12 months; pulmonary fibrosis; ground glass appearance on high resolution chest CT; or
    • Renal: scleroderma-related renal disease AND
  • Individuals with internal organ involvement indicated by the following measurements should not be considered for autologous HCT:
    • Cardiac: left ventricular ejection fraction <50%; tricuspid annular plane systolic excursion <1.8 cm; pulmonary artery systolic pressure >40 mm Hg; mean pulmonary artery pressure >25 mm Hg
    • Pulmonary: DLCo <40% of predicted value; FVC <45% of predicted value
    • Renal: creatinine clearance <40 ml/minute

Autologous hematopoietic cell transplantation as a treatment of systemic sclerosis/scleroderma not meeting the above criteria is considered investigational.

Allogeneic hematopoietic cell transplantation as a treatment of systemic sclerosis/scleroderma is considered investigational.

Autologous or allogeneic hematopoietic cell transplantation is considered investigational as a treatment for all other autoimmune diseases, including, but not limited to:

• Multiple sclerosis
• Systemic lupus erythematosus
• Juvenile idiopathic or rheumatoid arthritis
• Chronic inflammatory demyelinating polyneuropathy
• Type 1 diabetes

POLICY GUIDELINES:

Autologous HCT should be considered for individuals with systemic sclerosis only if the condition is rapidly progressing and the prognosis for survival is poor. An important factor influencing the occurrence of treatment-related adverse effects and response to treatment is the level of internal organ involvement. If organ involvement is severe and irreversible, HCT is not recommended. 

DESCRIPTION OF PROCEDURE OR SERVICE:

Most individuals with autoimmune disorders respond to conventional drug therapies; however, conventional drug therapies are not curative and a proportion of individuals suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive. It is in this group of individuals with a severe autoimmune disease that alternative therapies have been sought, including hematopoietic cell transplantation (HCT).

Autoimmune Disease Treatment

Immune suppression is a common treatment strategy for many of these diseases, particularly rheumatic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma). Most individuals with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressant’s, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of individuals suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive. It is for this group of individuals with severe autoimmune disease that alternative therapies have been sought, including hematopoietic cell transplantation (HCT). The primary concept underlying the use of HCT for these diseases is this: ablating and “resetting” the immune system can alter the disease process by inducing a sustained remission that possibly leads to a cure.

Hematopoietic Cell Transplantation

Hematopoietic stem-cell transplantation (HCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in individuals who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. The use of cord blood is discussed in Medical Policy #439: Placental/Umbilical Cord Blood as a Source of Stem Cells.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and individual is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. The term HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the individual at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents ( eg, cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versusmalignancy (GVM) effect mediated by non-self-immunologic effector cells. While the slower GVM effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to individuals who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the individual before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the individual’s disease is in complete remission. Individuals who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial GVM effect of allogeneic transplantation develops. Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and individual condition. Individuals who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

KEY POINTS:

The most recent literature review was performed through November 14, 2023.

Summary of Evidence

For individuals with systemic sclerosis/scleroderma who receive autologous HCT, the evidence includes systemic reviews, three RCTs and observational studies. Relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. All three RCTs compared cyclophosphamide conditioning plus autologous HCT with cyclophosphamide alone. Individuals in the RCTs were adults <60 years of age, maximum duration of disease of 5 years, with modified Rodnan skin scores >15, and internal organ involvement. Individuals with severe and irreversible organ involvement were excluded from the trials. Short-term results of the RCTs show higher rates of adverse events and TRM among individuals receiving autologous HCT compared with individuals receiving chemotherapy alone. However, long-term improvements (four years) in clinical outcomes such as modified Rodnan skin scores and forced vital capacity, as well as overall mortality in individuals receiving HCT compared with individuals receiving cyclophosphamide alone, were consistently reported in all RCTs. Due to sample size limitations in two of the RCTs, statistical significance was found only in the larger RCT. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes.

For individuals with multiple sclerosis who receive HCT, the evidence includes two RCTs, systematic reviews, and several nonrandomized studies. Relevant outcomes are overall survival (OS), health status measures, quality of life (QOL), and treatment-related mortality (TRM) and morbidity. Systematic reviews are primarily comprised of observational data. One RCT compared HCT with mitoxantrone, and the trial reported intermediate outcomes (number of new T2 magnetic resonance imaging lesions); the group randomized to HCT developed significantly fewer lesions than the group receiving conventional therapy. The other RCT compared nonmyeloablative HCT results in individuals with continued disease-modifying therapy and found a benefit to HCT in prolonged time to disease progression. The findings of the nonrandomized studies revealed improvements in clinical parameters following HCT compared with baseline. Adverse event rates were high, and most studies reported treatment-related deaths. Controlled trials (with appropriate comparator therapies) reporting on clinical outcomes are needed to demonstrate efficacy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals with systemic lupus erythematosus who receive HCT, the evidence includes a systematic review and case series. The relevant outcomes are OS, symptoms, QOL, and TRM and morbidity. Studies were heterogeneous in conditioning regimens and source of cells. The largest series (n=50) reported an overall 5-year survival rate of 84% and the probability of disease-free survival was 50%. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals with juvenile idiopathic or rheumatoid arthritis who receive HCT, the evidence includes registry data and a case series. Relevant outcomes are OS, symptoms, QOL, and TRM and morbidity. The registry included 50 individuals with juvenile idiopathic or rheumatoid arthritis. The overall drug-free remission rate was approximately 50% in the registry individuals and 69% in the smaller case series. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals with chronic inflammatory demyelinating polyneuropathy who receive HCT, the evidence includes a recent observational study and case reports. Relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. Additional data is needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals with type 1 diabetes who receive HCT, the evidence includes case series and two meta-analyses. Relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. While a substantial proportion of individuals tended to become insulin-free after HCT, remission rates were high. A meta-analyses further revealed that HCT is more effective in individuals with type 1 diabetes compared with type 2 diabetes and when the treatment is administered soon after the diagnosis. Certain factors limit the conclusions that can be drawn about the overall effectiveness of HCT in treating diabetes; those factors are heterogeneity in the stem cell types, cell number infused, and infusion methods. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals with other autoimmune diseases (e.g., Crohn disease, immune cytopenias, relapsing polychondritis) who receive HCT, the evidence includes 1 RCT and small retrospective studies. Relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. The RCT was conducted on patients with Crohn disease. At one-year follow-up, one individual in the control group and two individuals in the HCT group achieved remission. Data are needed from additional controlled studies to demonstrate efficacy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Practice Guidelines and Position Statements

American Society for Blood and Marrow Transplantation

In 2020, the American Society for Blood and Marrow Transplantation published consensus guidelines on the use of HCT to treat specific conditions in and out of the clinical trial setting. Table 1 summarizes recommendations for specific indications addressed in this guideline.

Table 1. Recommendations for the Use of HCT to Treat Autoimmune Diseases

a “Standard of care (S): This category includes indications that are well defined and are generally supported by evidence in the form of high quality clinical trials and/or observational studies (eg, through CIBMTR or EBMT).” “Standard of care, clinical evidence available (C): This category includes indications for which large clinical trials and observational studies are not available. However, HCT/immune effector cell therapy (IECT) has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multi-center cohort studies. HCT/IECT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care’.” "Standard of care, rare indication (R): Indications included in this category are rare diseases for which clinical trials and observational studieswith sufficient number of patients are not currently feasible because of their very low incidence. However, single-center or multicenter or registry studies in relatively small cohorts of patients have shownHCT/IECT to be effective treatment with acceptable risks of morbidity and mortality. For patients with diseases in this category, HCT/IECT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits." “Developmental; (D): Developmental indications include diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option. HCT/IECT is best pursued for these indications as part of a clinical trial. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care, Clinical Evidence Available’ or ‘Standard of Care’.” “Not generally recommended (N): HCT/IECT is not currently recommended for these indications where evidence and clinical practice do not support the routine use of HCT/IECT. However, this recommendation does not preclude investigation of HCT/IECT as a potential treatment and may be pursued for these indications within the context of a clinical trial.

U.S. Preventive Services Task Force Recommendations

Not Applicable.

KEY WORDS:

Autoimmune Diseases, High-Dose Chemotherapy/Stem-Cell Rescue, High-Dose Chemotherapy, Autologous Stem Cell Transplant, Multiple Sclerosis, Rheumatoid Arthritis, Systemic Sclerosis/Scleroderma, Systemic Lupus Erythematosus (SLE), Juvenile Idiopathic Arthritis, Type I Diabetes Mellitus, JIA

APPROVED BY GOVERNING BODIES:

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. Hematopoietic stem cells are included in these regulations.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan. 

CURRENT CODING:

CPT Codes:

HCPCS:

REFERENCES:

1. Atkins HL, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. Aug 06 2016; 388(10044):576-585.
2. Boffa G, Massacesi L, Inglese M, et al. Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. Jan 20 2021.
3. Brierley CK, Castilla-Llorente C, Labopin M, et al. Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation. J Crohns Colitis. Aug 29 2018; 12(9): 1097-1103.
4. Bruera S, Sidanmat H, Molony DA, et al. Stem cell transplantation for systemic sclerosis. Cochrane Database Syst Rev. Jul 29 2022; 7(7): CD011819. 
5. Bryant A, Atkins H, Pringle CE, et al. Myasthenia gravis treated with autologous hematopoietic stem cell transplantation. JAMA Neurol. Jun 01 2016; 73(6):652-658.
6. Burman J, Iacobaeus E, Svenningsson A, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. Oct 2014; 85(10):1116-1121.
7. Burt RK, Balabanov R, Burman J, et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. Jan 15 2019; 321(2): 165-174. 
8. Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. Jan 20 2015; 313(3):275-284.
9. Burt RK, Balabanov R, Tavee J, et al. Hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol. Nov 2020; 267(11): 3378-3391.
10. Burt RK, Han X, Gozdziak P, et al. Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome. Bone Marrow Transplant. Jun 2018; 53(6):692-700.
11. Burt RK, Han X, Quigley K, et al. Real-world application of autologous hematopoietic stem cell transplantation in 507 patients with multiple sclerosis. J Neurol. Oct 11, 2021.
12. Burt RK, Han X, Quigley K, et al. Real-world application of autologous hematopoietic stem cell transplantation in 507 patients with multiple sclerosis. J Neurol. May 2022; 269(5): 2513-2526. 
13. Burt RK, Shah SJ, Dill K et al Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomized phase 2 trial. Lancet 2011; 378(9790):498-506.
14. Burt RK, Traynor A, Statkute L et al Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 2006; 295(5):527-535.
15. Cantu-Rodriguez OG, Lavalle-Gonzalez F, Herrera-Rojas MA, et al. Long-term insulin independence in type 1 diabetes mellitus using a simplified autologous stem cell transplant. J Clin Endocrinol Metab. May 2016; 101(5):2141-2148.
16. Cao C, Wang M, Sun J, et al. Autologous peripheral blood haematopoietic stem cell transplantation for systemic lupus erythematosus: the observation of long-term outcomes in a Chinese centre. Clin Exp Rheumatol. May-Jun 2017; 35(3):500-507.
17. El-Badawy A, El-Badri N. Clinical efficacy of stem cell therapy for diabetes mellitus: a meta-analysis. PLoS One. 2016; 11(4):e0151938.
18. Fassas A, Kimiskidis VK, Sakellari I et al. Long-term results of stem cell transplantation for MS: a single-center experience. Neurology 2011; 76(12): 1066-1070.
19. Ge F, Lin H, Li Z, et al. Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis. Neurol Sci. Mar 2019; 40(3): 479-487.
20. Hawkey CJ, Allez M, Clark MM, et al. Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial. JAMA. Dec 15 2015;314(23):2524-2534.
21. Henes J, Oliveira MC, Labopin M, et al. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective noninterventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Haematologica. Jan 16 2020.
22. Henes JC, Schmalzing M, Voget W et al. Optimization of autologous stem cell transplantation for systemic sclerosis – a single-center longterm experience in 26 patients with severe organ manifestations. J Rheumatol 2012; 39(2):269-75.
23. Higashitani K, Takase-Minegishi K, Yoshimi R, et al. Benefits and risks of Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis. Mod Rheumatol. Mar 12 2022.
24. Host L, Nikpour M, Calderone A, Cannell P, Roddy J. Autologous stem cell transplantation in systemic sclerosis: a systematic review. Clin Exp Rheumatol. Sep-Oct 2017; 35 Suppl 106(4):198-207.
25. Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB et al Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med 2005; 118(1):2–10.
26. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
27. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247-1256. 
28. Kazmi MA, Mahdi-Rogers M, Sanvito L. Chronic inflammatory demyelinating polyradiculoneuropathy: a role for haematopoietic stem cell transplantation?  Autoimmunity 2008; 41(8):611-615.
29. Kvistad SAS, Lehmann AK, Trovik LH, et al. Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway. Mult Scler. Dec 13 2019: 1352458519893926.
30. Lehmann HC, Hughes RA, Hartung HP. Treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Handb Clin Neurol. 2013; 115: 415-27. 
31. Leng XM, Jiang Y, Zhou DB, et al. Good outcome of severe lupus patients with high-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation: a 10-year follow-up study. Clin Exp Rheumatol. May-Jun 2017; 35(3):494-499.
32. Leone A, Radin M, Almarzooqi AM, et al. Autologous hematopoietic stem cell transplantation in Systemic Lupus Erythematosus and antiphospholipid syndrome: A systematic review. Autoimmune Rev. May 2017; 16(5):469-477.
33. Lindsay JO, Allez M, Clark M, et al. Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol Hepatol. Jun 2017; 2(6):399-406.
34. Mancardi GL, Sormani MP, Gualandi F, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. Mar 10 2015; 84(10):981-988.
35. Mancardi GL, Sormani MP, Di Gioia M et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity-conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult Scler 2012; 18(6):835-842.
36. M F Silva J, Ladomenou F, Carpenter B, et al. Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis. Blood Adv. Apr 10 2018; 2(7): 777-786. 
37. Milanetti F, Abinun M, Voltarelli JC et al Autologous hematopoietic stem cell transplantation for childhood autoimmune disease. Pediatr Clin North Am 2010; 57(1):239-271.
38. Milanetti F, Bucha J, Testori A et al Autologous hematopoietic stem cell transplantation for systemic sclerosis. Curr Stem Cell Res Ther 2011; 6(1):16-28.
39. Muraro PA, Pasquini M, Atkins HL, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. Apr 1 2017; 74(4):459-469.
40. Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. Feb 28 2017; 88(9):842-852.
41. Nash RA, McSweeney PA, Crofford LJ et al High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 2007; 110(4):1388-1396.
42. Nabizadeh F, Pirahesh K, Rafiei N, et al. Autologous Hematopoietic Stem-Cell Transplantation in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Neurol Ther. Dec 2022; 11(4): 1553-1569. 
43. Nikolov NP, Pavletic SZ. Technology insight: hematopoietic stem cell transplantation for systemic rheumatic disease. Nat Clin Pract Rheumatol 2008; 4(4):184-191.
44. Peltier AC, Donofrio PD. Chronic inflammatory demyelinating polyradiculoneuropathy: from bench to bedside. Semin Neurol 2012; 32(3):187-195.
45. Reston JT, Uhl S, Treadwell JR et al Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler 2011; 17(2):204-213.
46. Saccardi R, Di Gioia M, Bosi A. Haematopoietic stem cell transplantation for autoimmune disorders. Curr Opin Hematol 2008; 15(6):594-600.
47. Shevchenko JL, Kuznetsov AN, Ionova TI et al. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. Nov 2012; 40(11):892-898.
48. Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician's and patient's perspectives. Ann Hematol. Jul 2015; 94(7):1149-1157.
49. Shouval R, Furie N, Raanani P, Nagler A, Gafter-Gvili A. Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant. May 2018; 24(5):937-944.
50. Snarski E, Milczarczyk A, Halaburda K, et al. Immunoablation and autologous hematopoietic stem cell transplantation in the treatment of new-onset type 1 diabetes mellitus: long-term observations. Bone Marrow Transplant. Mar 2016; 51(3):398-402.
51. Song XN, Lv HY, Sun LX, et al. Autologous stem cell transplantation for systemic lupus erythematosus: Report of efficacy and safety at 7 years of follow-up in 17 patients. Transplant Proc. 2011; 43(5):1924-1927.
52. Sormani MP, Muraro PA, Schiavetti I, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. May 30 2017; 88(22):2115-2122.
53. Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018 Jan 4; 378(1):35-47.
54. Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United States. Biol Blood Marrow Transplant 2010; 16(1 suppl):S48-56.
55. Sun SY, Gao Y, Liu GJ, et al. Efficacy and Safety of Stem Cell Therapy for T1DM: An Updated Systematic Review and Meta-Analysis. J Diabetes Res. 2020; 2020: 5740923.
56. van Bijnen S, de Vries-Bouwstra J, van den Ende CH, et al. Predictive factors for treatment-related mortality and major adverse events after autologous haematopoietic stem cell transplantation for systemic sclerosis: results of a long-term follow-up multicentre study. Ann Rheum Dis. Aug 2020; 79(8): 1084-1089.
57. van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. Jun 25 2014; 311(24):2490-2498.
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59. Vonk MC, Marjanovic Z, van den Hoogen FH et al Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis 2008; 67(1):98-104.
60. Walicka M, Milczarczyk A, Snarski E, et al. Lack of persistent remission following initial recovery in patients with type 1 diabetes treated with autologous peripheral blood stem cell transplantation. Diabetes Res Clin Pract. Sep 2018;143:357-363.
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POLICY HISTORY:

Medical Policy Group, September 2011

Medical Policy Administration Committee, October, 2011

Available for comment October 5 through November 21, 2011

Medical Policy Group, December 2011 (3): Updated CPT Codes 38208 & 38209 and added code 38230 & 38232 for 2012 code updates

Medical Policy Group, October 2012 (3): 2012 Updates to Key Points, Key Words and References

Medical Policy Panel, October 2013

Medical Policy Group, October 2013 (3): 2013 Updates to Description, Key Points and References; policy statement added chronic inflammatory demyelinating polyneuropathy to included but not limited to list of  autoimmune diseases for which this treatment is considered investigational

Available for comment October 16 through November 30, 2013

Medical Policy Panel, October 2014

Medical Policy Group, October 2014 (3): 2014 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, January 2016

Medical Policy Group, February 2016 (2): Updates to Description, Key Points and References. No change to policy statement.

Medical Policy Panel, July 2017

Medical Policy Group, August 2017 (7): Title updated- removed “stem”. Updates to Key Points and References; no change to policy statement.

Medical Policy Group, December 2017: Annual Coding Update 2018. Added new CPT codes 38222, 0489T and 0490T effective 1/1/18 to Current Coding section. Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Panel, January 2018

Medical Policy Group, February 2018(7): Updates to Description, Key Points, Approved by Governing Bodies, and References. No change to policy statement.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): Updates to Key Points, Practice Guidelines and Position Statements, References and Key Words: added Juvenile Idiopathic Arthritis and JIA. Policy statement for systemic sclerosis/scleroderma was changed from “investigational” to “medically necessary” and added “allogeneic stem cell transplant is considered not medically necessary and investigational for systemic sclerosis/scleroderma”. Placed on DRAFT 2/6/19. Available for comment from February 6, 2019 through March 22, 2019.

Medical Policy Panel, January 2020

Medical Policy Group, March 2020 (3): 2020 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

Medical Policy Panel, January 2021

Medical Policy Group, January 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. Policy statement updated to remove “not medically necessary,” no change to policy statement or intent.

Medical Policy panel, January 2022

Medical Policy Group, January 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements and References. No changes to policy statement or intent.

Medical Policy Panel, January 2023

Medical Policy Group, February 2023 (3): 2023 Updates Key Points, Practice Guidelines and Position Statements and References. No changes to policy statement or intent.  

Medical Policy Panel, January 2024  

Medical Policy Group, January 2024 (3): Updates to Key Points, Benefit Application and References. Current Coding CPT codes 0489T and 0490T removed; these codes will remain on the investigational listing. Updates to the Policy statement and Policy Guidelines -clarification of internal organ involvement information. No change to the policy intent.                                                                                                                                         

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.