BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Autoimmune Disorders
Chapter: Transplant
Current Effective Date: December 27, 2013
Original Effective Date: April 18, 2013
Publish Date: September 27, 2013
Revised Dates: September 16, 2013
Description

The use of hematopoietic stem-cell transplantation (HSCT) has been investigated for treatment of patients with autoimmune disorders. Hematopoietic stem cells are infused to restore bone marrow function following cytotoxic doses of chemotherapeutic agents with or without whole body radiation therapy.

Autoimmune diseases represent a heterogeneous group of immune-mediated disorders, with the most common types being multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis/scleroderma. These include over 40 disorders that are recognized as having an autoimmune pathogenesis, ranging from insulin dependent diabetes mellitus, rheumatoid arthritis and other connective tissue disorders to multiple sclerosis. Immune suppression is a common treatment strategy for many of these diseases, particularly the rheumatic diseases (such as RA, and scleroderma). The National Institutes of Health (NIH) estimates 5–8% of Americans have an autoimmune disorder. Some of the more common types of autoimmune disorders include but are not limited to:

  • Multiple sclerosis (MS) is an autoimmune condition in which the immune system attacks the central nervous system, leading to demyelination (the destructive removal of myelin, an insulating and protective fatty protein which sheaths nerve cells).
  • Juvenile idiopathic rheumatoid arthritis (JRA) may also be known as juvenile idiopathic arthritis (JIA), is a chronic, persistent, systemic autoimmune disorder of children, as it commonly occurs from the ages of 7 to 12, and before 16. JRA is a subset of arthritis seen in children and the most common form. Since there is no defined cause of the arthritis or inflammation of the synovium of the joint(s), it is referred to as idiopathic. Researchers sometimes refer JIA as juvenile chronic arthritis (JCA), which is a term that is not precise as JIA refers to all types of childhood arthritis. So, terminology for this condition is evolving.
  • Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder that causes the immune system to attack the joints, where it causes inflammation (arthritis) and destruction. It can also damage some organs, such as the lungs and skin.
  • Systemic lupus erythematosus (SLE) may also be known as lupus, and is an acquired chronic autoimmune connective tissue disorder manifested by multi-organ involvement and potentially fatal. Women and minorities are disproportionately affected. SLE is most common in women of child-bearing age although it has been reported in both extremes of life (e.g., diagnosed in infants and in the tenth decade of life).
  • Systemic sclerosis (scleroderma) is a chronic autoimmune disease characterized by a hardening or sclerosis in the skin or other organs.  
  • Type I diabetes mellitus (Type I DM, TIDM) is formerly known as insulin dependent or juvenile diabetes (IDDM) that results from autoimmune destruction of insulin-producing beta cells of the pancreas becoming a metabolic disease. TIDM can be further classified as immune-mediated or idiopathic. The majority of TIDM is of the immune-mediated nature, in which beta cell loss is a T-cell-mediated autoimmune attack.

The pathogenesis of autoimmune diseases is not well-understood but appears to involve underlying genetic susceptibility and environmental factors that lead to loss of self-tolerance, culminating in tissue damage by the patient’s own immune system (T cells).

Immune suppression is a common treatment strategy for many of these diseases, particularly the rheumatic diseases (e.g., RA, SLE, and scleroderma). Most patients with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs. However, these drugs are not curative, and a proportion of patients will have severe, recalcitrant, or rapidly progressive disease. It is in this group of patients with severe autoimmune disease that alternative therapies have been sought, including hematopoietic stem-cell transplantation (HSCT). HSCT in autoimmune disorders raises the question of whether ablating and “resetting” the immune system can alter the disease process and sustain remission and possibly lead to cure. (1)

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Investigational

Coverage of, evaluation for, and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of autoimmune disorders is identified in the grid below.

NOTE: SCT may be known by different terminology and used interchangeably. Hereinafter, SCT will be known as stem-cell support (SCS) throughout the balance of this medical policy.

Allogeneic

Is considered experimental, investigational and unproven for treatment of any autoimmune disease, including but not limited to multiple sclerosis (MS), juvenile idiopathic rheumatoid arthritis (JRA), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis/scleroderma, and type 1 diabetes mellitus (TIDM).

Autologous

 

Is considered experimental, investigational and unproven for treatment of any autoimmune disease, including but not limited to MS, JRA, RA, SLE, systemic sclerosis/scleroderma, and TIDM.

Tandem or Triple

Stem-Cell Support

Is considered experimental, investigational and unproven for treatment of any autoimmune disease, including but not limited to MS, JRA, RA, SLE, systemic sclerosis/scleroderma, and TIDM.

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven for treatment of any autoimmune disease, including but not limited to MS, JRA, RA, SLE, systemic sclerosis/scleroderma, and TIDM.

Hematopoietic Progenitor Cell Boost (Stem-Cell Boost)

Is considered experimental, investigational and unproven for treatment of any autoimmune disease, including but not limited to MS, JRA, RA, SLE, systemic sclerosis/scleroderma, and TIDM.

Any use of short tandem repeat (STR) markers for the treatment of any autoimmune disease, including but not limited to MS, JRA, RA, SLE, systemic sclerosis/scleroderma, and TIDM is considered experimental, investigational and unproven.

Rationale

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) transplant is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, umbilical cord blood, or bone marrow stem-cells. 

Initially, this policy was based on two Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments in 2000 and 2002, which addressed the issue of high-dose lymphoablative therapy (HDLT) and stem-cell rescue, also known as SCS, in autoimmune diseases. (2, 3)

The 2000 TEC Assessment concluded that there was inadequate scientific evidence to permit conclusions. Specifically, the published evidence consists of case reports of single-case studies describing a variety of outcomes in a total of 71 patients with at least 12 different autoimmune diseases. The determined that due to the general complexity of the autoimmune disease and the wide variations in disease activity among patients with the same disease and in any one patient at various points in time, scientific evidence must be designed that examines an adequate number of patients in each disease category and that applies sufficiently standardized patient selection criteria, disease severity stratification, and clinical outcomes measurement. The case reports currently available for analysis do not adequately address these issues. (2) The TEC Assessment was updated in 2002, focusing on HDLT both with and without autologous stem-cell rescue (AuSCS). The TEC Assessment noted that registry data suggest that the outcomes of high-dose therapy, also known as HDC, with stem-cell rescue as a treatment of autoimmune disease does not have predictable and always favorable results. Overall, approximately 10% of the patients died from the procedure. There are relatively little data regarding high-dose lymphoablative therapy without stem-cell rescue. One trial was terminated prematurely due to apparent excess morbidity in the treatment arm. (3)

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in AuSCS. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT (AlloSCS). Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood). (1)

The quality of life after HDC followed by HSCT (i.e., blood or marrow) transplant is of utmost importance. In aplastic anemia and malignancies, there is the expectation of improved status after HDC and HSCT. Conversely, quality of life outcomes (measured by growth, skeletal development dysfunction, and neuropsychological) for patients with storage diseases is gradually being defined. Because of these long-term problems, non-malignant or maldevelopment indications for HDC and HSCTs should not be reviewed with criteria similar to that for malignancies.

Autologous Stem-Cell Transplantation for Autoimmune Diseases

The medical community is most familiar with the use of HDC with AuSCS as a treatment of non-marrow-based malignancies. In this situation, the scientific rationale for the HDC was clear— the targeted tumor showed a steep dose-response curve such that higher doses of chemotherapy would result in increased tumor cell kill with ultimate cure. In this setting, marrow ablation was considered a lethal side effect unless treated with reinfusion with autologous stem cells. For marrow-based malignancies, such as multiple myeloma or chronic lymphocytic leukemia, reinfusion of autologous stem cells always carried the risk of reinfusion of the malignant stem cells. In all these situations, targeted tumor cells represented a single clone of malignant cells.

The scientific rationale for the use of AuSCS in autoimmune diseases is not as clear-cut as in oncologic applications. For example, the pathogenesis of autoimmune diseases is not precisely known. While the immunologic component is undisputed, there is no readily identifiable pathogenic clone of cells. It is not clear whether the disorder is related to an abnormal stem cell, to a pathogenic clone of more mature lymphocytes, or to immune dysregulation. (4) However, interest in high-dose therapy was initially stimulated by the observation that patients with autoimmune diseases treated with high-dose therapy and allogeneic stem-cell transplant for other reasons (frequently therapy-related secondary aplastic anemia) often enjoyed prolonged remission of their autoimmune disease. Nevertheless, the use of allogeneic stem cells is not practical in many patients due to the lack of an available donor and the older age of most patients with autoimmune diseases.

The initial experience with AuSCS in patients with autoimmune disease involved several individual case reports of patients with autoimmune diseases who were principally being treated for a co-existing malignancy. As reviewed by Snowden, the early data suggest that AuSCS may result in initial remissions, but relapses are common. (5) In this country, the largest experience has been reported by Burt and colleagues at Northwestern University in Chicago.

(6) In 1998, the authors reported on a case series of 10 patients, including six with MS, two with SLE, and two with rheumatoid arthritis. (7) All patients had progressive disease refractory to standard treatment. Stem cells were collected from either the marrow or peripheral blood. Stem cells were enriched ex vivo by CD34+ selection (CD34+ cells permit positive selection of the critical stem cell and exclusion of potentially pathogenic T-cells). All patients received HDC. In addition, the patients with multiple sclerosis (MS) received total body irradiation to ablate lymphocytes sequestered in the central nervous system (CNS). All six patients with MS enjoyed stabilization of their disease; both patients with systemic lupus erythematosus (SLE) had no evidence of active disease after transplant; and the patients with rheumatoid arthritis (RA) improved. Median follow-up period was 11 months. The authors state that the reason for post-transplant disease stabilization is unclear. One hypothesis posits that post-transplant there is a prolonged period of relative immunosuppression, which may function to reset the balance between tolerance and autoimmunity. The authors also state that longer term follow-up is necessary to determine the duration of response, and that randomized controlled trials are needed.

Burt and colleagues recently published the results of the largest single-center series available in the United States. (8) Between April 1997 and January 2005, they enrolled 50 patients (mean age 30 ± 10.9 years [SD], 43 women, seven men) with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement in a single-arm trial. All subjects had at least four of 11 American College of Rheumatology criteria for SLE and required more than 20 mg/d of prednisone or its equivalent despite use of cyclophosphamide. Patients underwent AuSCS following a lymphoablative conditioning regimen. Two patients died after mobilization, yielding a treatment-related mortality of 4% (2/50). After a mean follow-up of 29 months (range, six months to 7.5 years) overall five year survival was 84%, and the probability of disease-free survival was 50%. Several parameters of SLE activity (described in the 2002 TEC Assessment) improved, including renal function, SLE disease activity index (DAI) score, antinuclear antibody, anti-ds DNA, complement, and CO diffusion lung capacity. The investigators suggest these results justify a randomized trial comparing immunosuppression plus AuSCS versus continued standard of care.

An editorial by Petri and Brodsky (9) that accompanied the article by Burt and colleagues concurred that randomized clinical trials are needed to determine whether this treatment approach improves outcomes when compared with conventional therapies.

One phase III randomized, open-label, active control clinical trial, “Scleroderma: Cyclophosphamide or Transplantation” (SCOT, NCT00114530, National Institute of Allergy and Infectious Diseases (NIAID) No. SCSSc-01) sponsored by the NIAID is currently recruiting patients in the United States. Two other NIAID-sponsored phase II trials are planned but not yet open for patient recruitment. The first is a randomized, active control, open-label trial, Lupus Immunosuppressive/Immunomodulatory Therapy or Stem Cell Transplant (LIST, NCT00230035, NIAID No. SCSLE-01). The second is a nonrandomized, open-label uncontrolled trial, High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis Study (HALT MS, NCT00288626, NIAID No. SCMS2). Other phase III randomized clinical trials are being conducted in Europe for scleroderma in the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, for multiple sclerosis (ASTIMS), and for rheumatoid arthritis (ASTIRA). While several phase I/II studies have been completed, longer-term follow-up is needed before conclusions can be reached from study findings.

The European Group for Blood and Marrow Transplantation (EBMT) autoimmune diseases working party database reported new data from a retrospective survey of 178 patients with MS who underwent AuSCS following one of several different preparative regimens. (10) Overall, at median follow-up of about 42 months, the disease remained stable or improved in 63% of cases and worsened in 37%. AuSCS was associated with significantly better progression-free survival in a subset of younger patients (i.e., younger than 40 years of age) affected by severe, progressive MS who received AuSCS within five years from diagnosis compared to those older than 40 years. The authors suggest that AuSCS could be considered after failure of conventional treatments in patients with rapidly progressing MS. However, they caution that the role of AuSCS in the treatment of refractory MS needs to be established through prospective randomized, controlled trials. Several editorials concur with the view that the role of AuSCS is not established in MS or other autoimmune diseases. (11, 12, 13)

A review article on randomized trials of AuSCS for autoimmune diseases discusses the relative merits of lymphoablative versus myeloablative stem cell transplantation regimens, concurring that randomized, controlled trials are needed to confirm benefits observed with this therapy in case reports and uncontrolled series. (14)

The goal of AuSCS in patients with autoimmune diseases is to eliminate self-reactive lymphocytes (lymphoablative) and generate new self-tolerant lymphocytes. (14) This approach is in contrast to destroying the entire hematopoietic bone marrow (myeloablative), as is often performed in AuSCS for hematologic malignancies. (14) However, there is currently no standard conditioning regimen for autoimmune diseases and both lymphoablative and myeloablative regimens are used. (1) The efficacy of the different conditioning regimens has not been compared in clinical trials. (1)

Clearly, the experience with AuSCS for autoimmune diseases is preliminary in nature. (5, 15) Additional research will need to address the following challenges:

  • Until there is a solid scientific rationale for the treatment effect of AuSCS, evidence will have to rely solely on empiric trials. Given the unpredictable waxing and waning course of many autoimmune diseases, randomized trials will be important.
  • Numerous technical issues remain, notably the role of T-cell depletion among the harvested stem cell. However, the role of T-cells in different stages of disease is not precisely known.
  • Patient selection criteria are difficult. Ideally, the best use of AuSCS may be in those patients with prognostic factors reliably predictive for progressive refractory disease, before the onset of irreversible organ damage. For example, many patients with SLE or scleroderma might not be candidates for AuSCS due to co-existing renal failure that increases the morbidity of high-dose regimens.
  • Final health outcome data may be difficult to define. For example, outcomes of MS are often evaluated with the Kurtz extended disability status scale (EDSS). This scale is weighted toward ambulatory status and thus may not reflect improvements in other outcomes such as incontinence or upper extremity function. Some studies of MS have used serial MRI scans to detect new brain lesions as an alternative.
  • The definition of a successful final health outcome is unclear. Will AuSCS be used for curative intent? Absent complete cure, would the risk-benefit ratio suggest that partial remission with reduction in steroid dosage is a successful outcome?
  • At the same time that the use of AuSCS is evolving, new therapies are emerging for autoimmune diseases, particularly rheumatoid arthritis. Therefore, the outcomes with non-marrow ablative therapies may be improving.

Therefore, AuSCS following lymphoablative and myeloablative regimens is considered experimental, investigation and unproven when used to treat autoimmune disorders.

Allogeneic Stem-Cell Transplantation for Autoimmune Diseases

Currently, for autoimmune diseases, autologous transplant is preferred over allogeneic, in part because of the lower toxicity of autotransplant relative to allogeneic, the graft-versus-host disease (GVHD) associated with allogeneic transplant, and the need to administer post-transplant immunosuppression after an allogeneic transplant. (1)

The experience of using allogeneic HSCT for autoimmune diseases is currently limited (1) but has two potential advantages over autologous transplant. First, the use of donor cells from a genetically different individual could possibly eliminate genetic susceptibility to the autoimmune disease and potentially result in a cure. Second, there exists a possible graft-versus-autoimmune effect, in which the donor T cells attack the transplant recipient’s autoreactive immune cells. (1)

Therefore, search of published literature did not locate any random, controlled studies that indicate improved patient outcomes for AlloSCS when used for autoimmune disorders.

Additional Infusion Treatments for Autoimmune Disorders

Tandem or triple SCS or donor leukocyte infusion (DLI) for autoimmune disorders is considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

2013 Update

A search of peer reviewed literature through October 2012 was conducted. The following is a summary of the key literature recently reviewed HCST and autoimmune diseases to date. (16, 17)

As of March 2009, patients with an autoimmune disease registered in the European Group for Blood and Marrow Transplantation/European League Against Rheumatism (EBMT/EULAR) database who have undergone HSCT include a total of 1,031 with the clinical indications of multiple sclerosis (MS) (n=379), rheumatoid arthritis (RA) (n=88), juvenile idiopathic arthritis (JRA, JIA) (n=70), systemic lupus erythematosus (SLE) (n=92), systemic sclerosis/scleroderma (n=207), idiopathic thrombocytopenic purpura (ITP) (n=23), and Crohn’s disease (CD) (n=23). (17)

Multiple Sclerosis (MS)

Currently, MS is the most common autoimmune disease for which AuSCS is being studied. (18) Following initial promising clinical experience, more than 350 consecutive cases have been reported by the EBMT over the last decade. (18) Most patients who underwent AuSCS for MS in the early studies had secondary progressive MS, and relatively fewer had relapsing remitting disease, with a Kurtzke Expanded Disability Status Scale (EDSS) of 3.0–9.5 at the time of HSCT. (18) Improvements in supportive care and patient selection have contributed to improved outcomes, with a significant reduction in treatment-related mortality to 1.3% seen during 2001–2007. (18) It is now generally accepted that administering HSCT relatively early in the course of the disease to reduce inflammation before irreversible neuronal damage occurs is important. Current studies target MS patients with active disease and worsening disability, as evidenced clinically by relapse, change in EDSS, and/or inflammatory activity seen on magnetic resonance imaging (MRI) and who have failed at least one approved first-line immunomodulatory MS therapy for enrollment. Follow-up of several years will be needed to evaluate outcomes of these clinical trials.

A 2011 systematic review evaluated the safety and efficacy of AuSCS in patients with progressive MS refractory to conventional medical treatment. (19) Eight case series were included that met the inclusion criteria for the primary outcome of progression-free survival (PFS) with a median follow-up of at least 2 years. An additional 6 studies were included for a summary of mortality and morbidity. For the 8 case series, there was substantial heterogeneity across studies. The majority of patients (77%) had secondary progressive MS, although studies also included those with primary progressive, progressive-relapsing, and relapse-remitting disease. Numbers of patients across studies ranged between 14 and 26. The studies differed in the types and intensities of conditioning regimens used prior to HSCT, with 5 studies using an intermediate-intensity regimen, while the other 3 used high-intensity regimens. All of the studies were rated of moderate quality. The estimated rate of long-term PFS of patients receiving intermediate-intensity conditioning regimen was 79.4% (95% confidence interval [CI]: 69.9-86.5%) with a median follow-up of 39 months, while the estimate for patients who received a high-dose regimen was 44.6% (95% CI: 26.5-64.5%) at a median follow-up of 24 months. Of the 14 studies that reported on adverse events, 13 were case series; from these, a total of 7 treatment-related deaths were recorded; 6 non-treatment-related deaths occurred, 5 associated with disease progression.

A 2010 review summarizes the experience with HSCT and MS. (20) A small number of patients have undergone AuSCS for the rare malignant form of MS, which is characterized by very active inflammatory disease with high relapse rates leading to a rapid progression of disabilities from the onset. (21, 22, 23) These patients had persistent disease activity despite numerous different treatments. All patients, but one, were relapse-free without the need for ongoing immunosuppression after AuSCS with up to 66 months of follow-up. One patient experienced a mild relapse that improved with conventional treatment. All of the patients had remarkable improvement in their functional abilities.

The majority of patients who have undergone AuSCS have had poor prognosis MS, which manifests as frequent relapses or the early onset of the secondary progressive (SPMS) phase of the illness within 3 to 5 years of diagnosis. (20) Studies are mainly case series that report the outcomes of AuSCS in MS patients with ongoing disease activity that is refractory to conventional disease-modifying agents. There has not been a “standard” transplant regimen, and different mobilization and conditioning regimens have been used throughout the published series. Clinical relapses were reported following AuSCS in one series, but overall, there has been an absence of ongoing acute episodic inflammatory disease activity in most reports. Evidence of ongoing chronic disease activity was seen in 14–76% of cases in the different series, with median follow-up between 1.5 to 3 years. Although the frequency of progression seems to be similar to what might be expected from historical controls, in many of the transplant studies, between 5% and 60% of patients actually had significant and sustained improvement in their disability score, and MS PFS seems to level off with increasing length of follow-up after AuSCS, a change from the expected natural history of progressive disabilities increasing with time.

Burt and colleagues have transplanted 21 patients with relapsing-remitting MS with ongoing relapses during treatment with interferon. (24) The conditioning regimen was nonmyeloablative. With a median follow-up of 37 months, 16 patients remained free of relapse, whereas 17 of the 21 patients had a 1-point or greater improvements in their EDSS score.

Fassas and colleagues reported the long-term results of a Phase I/II study conducted in a single center that investigated the effect of HSCT in the treatment of MS. (25) The authors reported on the clinical and MRI outcomes of 35 patients with aggressive MS treated with HSCT after a median follow-up period of 11 (range 2-15) years. Disease PFS at 15 years was 44% for patients with active central nervous system (CNS) disease and 10% for those without (p=0.01); median time to progression was 11 years (95% CI: 0-22) and 2 years (0-6). Improvements by 0.5-5.5 (median 1) EDSS points were observed in 16 cases lasting for a median of 2 years. In 9 of these patients, EDSS scores did not progress above baseline scores. Two patients died, at 2 months and 2.5 years, from transplant-related complications. Gadolinium-enhancing lesions were significantly reduced after mobilization but were maximally and persistently diminished post-HSCT. The authors concluded that HSCT should be reserved for aggressive cases of MS, still in the inflammatory phase of the disease, and for the malignant form, in which it can be life-saving, and that HSCT can result in PFS rates of 25% and can have an impressive and sustained effect in suppressing disease activity on MRI.

Shevchenko and colleagues reported the results of a prospective Phase II open-label single-center study which analyzed the safety and efficacy of autologous HSCT with reduced-intensity conditioning regimen in 95 patients with different types of MS. (26) The patients underwent early, conventional, and salvage or late transplantation. The efficacy was evaluated based on clinical and quality-of-life outcomes. No transplantation-related deaths were observed. All of the patients, except one, responded to the treatment. At long-term follow-up (mean 46 months), the overall clinical response in terms of disease improvement or stabilization was 80%. The estimated PFS at 5 years was 92% in the group after early transplant versus 73% in the group after conventional/salvage transplant (p=0.01). No active, new, or enlarging lesions in MRI were registered in patients without disease progression. All patients who did not have disease progression were off therapy throughout the post-transplantation period. HSCT was accompanied by a significant improvement in quality of life with statistically significant changes in the majority of quality-of-life parameters (p<0.05).

Mancardi and colleagues reported their experience with 74 consecutive patients with MS treated with AuSCS with an intermediate intensity conditioning regimen in the period from 1996 to 2008. (27) Clinical and MRI outcomes were reported. The median follow-up period was 48.3 months (range=0.8-126). Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, 8 out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed EDSS improvement >1 point after HSCT, as compared with 1 out of 36 (3%) patients with a secondary progressive disease course (p=0.009). Among the 18 cases with a follow-up longer than 7 years, 8 (44%) remained stable or had a sustained improvement, while 10 (56%), after an initial period of stabilization or improvement with a median duration of 3.5 years, showed a slow disability progression.

Bowen and colleagues reported the long-term safety and effectiveness of high-dose immunosuppressive therapy followed by AuSCS in advanced MS. (28) Neurologic examinations, brain MRI and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. There were 26 patients with a mean EDSS of 7.0; 17 with secondary progressive MS, 8 with primary progressive, and 1 with relapsing or remitting. Median follow up was 48 months after HSCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% CI: 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; 4 of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurologic worsening after treatment. HSCT may be more effective in patients with less advanced relapsing/remitting MS.

Clinical Guidelines or Trials for MS

A Phase III randomized trial (Stem Cell Therapy for Patients With Multiple Sclerosis Failing Interferon A Randomized Study) is recruiting participants to study the effect of autologous peripheral blood HSCT in patients with relapsing MS versus U.S. Food and Drug Administration (FDA)-approved standard of care. Primary endpoint is disease progression. Patients will be followed for 5 years after randomization. Estimated enrollment is 110, and estimated study completion date is January 2013 (NCT00273364).

The Phase II randomized ASTIMS trial evaluating AuSCS in severe cases of MS was terminated due to difficulty in accruing patients and lack of funds. (29)

The High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) Study is a Phase II nonrandomized, uncontrolled trial to determine the effectiveness of AuSCS for the treatment of poor prognosis (relapsing-remitting or secondary progressive) MS. The primary outcome measure is time to treatment failure. Estimated enrollment is 25, and estimated study completion date is September 2015 (NCT00288626).

The Canadian MS-BMT Phase II study is to determine the effect of AuSCS on early-stage MS. Estimated enrollment is 24. Enrollment completed July 2009.

Juvenile Idiopathic Rheumatoid Arthritis (JRA) or Juvenile Idiopathic Arthritis (JIA)

A review article by Saccardi et al. summarizes the experience thus far with JRA/JIA as follows (30). More than 50 patients with JIA have been reported to the EBMT Registry. The largest cohort study initially used one conditioning regimen, and thereafter, a modified protocol. Overall drug-free remission rate was approximately 50%. Some late relapses have been reported, and only partial correction of growth impairment has been seen. The frequency of HSCT for JRA has decreased significantly since 2000, due to the introduction of new biologic therapies. Most patients who have undergone HSCT have had persistence or relapse of disease activity within 6 months of transplant.

Clinical Guidelines or Trials for JRA/JIA

No Phase II or III clinical trials were identified at online site, ClinicalTrials.gov using HSCT for treatment of JRA or JIA.

Systemic Lupus Erythematosus (SLE)

Song and colleagues reported on the efficacy and toxicity of autologous stem-cell transplantation for 17 patients with SLE after 7 years follow-up. (31) The probabilities of OS and PFS were used to assess the efficacy and toxicities of the treatment. The median follow-up time was 89 months (range 33-110 months). The probabilities of 7 year overall survival (OS) and PFS were 82.4% ± 9.2% and 64.7% ± 11.6%, respectively. The principal adverse events included allergy, infection, elevation of liver enzymes, bone pain, and heart failure. Two patients died due to severe pneumonia and heart failure at 33 and 64 months after transplantation, respectively. The authors concluded that their 7 year follow-up results suggest that AuSCS seems beneficial for SLE patients.

Clinical Guidelines or Trials for SLE

Three nonrandomized, open-label Phase II trials are recruiting patients, ongoing or completed studying the effectiveness of AuSCS in patients with SLE: one with an estimated enrollment of 9 and study completion date of April 2018 (NCT00076752), another with an estimated enrollment of 30 and study completion date of April 2014 (NCT00750971), and a third with an estimated enrollment of 52 and study completion date of April 2012 (NCT00271934).

Systemic Sclerosis/Scleroderma

A 2011 review article summarizes the clinical studies that have been performed using conventional therapy, as well as those using AuSCS in the treatment of systemic sclerosis. (32) Ongoing randomized trials are also discussed.

An open-label, randomized, controlled Phase 2 trial (ASSIST) assessed the safety and efficacy of autologous non-myeloablative HSCT compared with the standard of care cyclophosphamide. (33) Nineteen consecutively enrolled patients who were younger than 60 years of age with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement were randomly allocated 1:1 by use of a computer-generated sequence to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and rabbit antithymocyte globulin or to 1.0 g/m2 intravenous cyclophosphamide once per month for 6 months. The primary outcome was improvement at 12 months’ follow-up, defined as a decrease in mRSS (<25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrollment. No deaths occurred in either group during follow-up. Patients allocated to HSCT (n=10) improved at or before 12 months’ follow-up, compared with none of the 9 allocated to cyclophosphamide (p=0.00001). Treatment failure (i.e., disease progression without interval improvement), occurred in 8 of 9 controls, compared with none of the 10 patients treated by HSCT (p=0.0001). After long-term follow-up (mean 2.6 years) of patients who were allocated to HSCT, all but 2 patients had sustained improvement in mRSS and forced vital capacity, with a longest follow-up of 60 months. Seven patients allocated to receive cyclophosphamide switched treatment groups at a mean of 14 months after enrollment and underwent HSCT without complication, and all improved after HSCT. Four of these patients followed for at least 1 year had a mean decrease in mRSS points from 27 (standard deviation [SD]: 15.5) to 15 (SD: 7.4), an increase in forced vital capacity from 65% (SD: 20.6) to 76% (SD: 26.5) and an increase in total lung capacity from 81% (SD: 14.0) to 88% (SD: 13.9%). Data for 11 patients with follow-up to 2 years after HSCT suggested that the improvements in mRSS (p<0.0001) and forced vital capacity (p<0.03) persisted.

Vonk and colleagues reported the long-term results of 28 patients with severe diffuse cutaneous systemic sclerosis who underwent autologous HSCT from 1998 to 2004. (34) There was 1 transplant-related death and 1 death due to progressive disease, leaving 26 patients for evaluation. After a median follow-up of 5.3 years (range, 1–7.5 years), 81% (n=21/26) of the patients demonstrated a clinically beneficial response. Skin sclerosis was measured with a modified Rodnan skin score, and a significant (i.e., greater than 25%) decrease (i.e., improvement) was achieved in 19 of 26 patients after 1 year and in 15/16 after 5 years. At inclusion into the study, 65% of patients had significant lung involvement; all pulmonary function parameters remained stable after transplant at 5 and 7 years’ follow-up. Analyzing World Health Organization (WHO) performance status, which reflects the effect of HSCT on the combination of functional status, skin, lung, heart, and kidney involvement, the percentage of patients with a performance score of 0 increased to 56% compared to 4% at baseline. Estimated survival at 5 years was 96.2% (95% CI: 89–100%) and at 7 years was 84.8% (95% CI: 70.2–100%), and event-free survival (EFS), (survival without mortality, relapse, or progression of systemic sclerosis resulting in major organ dysfunction) was 64.3% (95% CI: 47.9–86%) at 5 years and 57.1% (95% CI: 39.3–83%) at 7 years. For comparison, an international meta-analysis published in 2005 estimated the 5 year mortality rate in patients with severe systemic sclerosis at 40%. (35)

Nash and colleagues reported the long-term follow-up of 34 patients with diffuse cutaneous systemic sclerosis with significant visceral organ involvement who were enrolled in a multi-institutional pilot study between 1997 and 2005 and underwent AuSCS. (36) Of the 34 patients, 79% survived 1 year and were evaluable for response (there were 8 transplant-related deaths and 4 systemic sclerosis-related deaths). Seventeen of the 27 (63%) evaluable patients had sustained responses at a median follow-up of 4 years (range, 1-8 years). Skin biopsies showed a statistically significant decrease in dermal fibrosis compared with baseline (p<0.001) and, in general, lung, heart, and kidney function remained stable. Overall function as assessed in 25 patients by the modified Health Assessment Questionnaire Disability Index showed improvement in 19, and disease response was observed in the skin of 23 of 25 and lungs of 8 of 27 patients. Estimated OS and PFS were both 64% at 5 years.

Henes and colleagues reported on their experience with autologous HSCT for systemic sclerosis in 26 consecutive patients scheduled for HSCT between 1997 and 2009. (37) The major outcome variable was the response to treatment (reduction of modified Rodnan skin score [mRSS] by 25%) at 6 months. Secondary endpoints were transplant-related mortality and PFS. At 6 months, significant skin and lung function improvement of the mRSS was achieved in 78.3% of patients. The overall response rate was 91%, as some patients improved even after month 6. Three patients died between mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was considered treatment-related. Seven patients experienced a relapse during the 4.4 years of follow up. PFS was 74%. Four patients died during follow-up, and the most frequent causes of death were pulmonary and cardiac complications of systemic sclerosis. The authors concluded that AuSCS resulted in significant improvement in most patients with systemic sclerosis.

Clinical Guidelines or Trials for Systemic Sclerosis/Scleroderma

Adult Stem Cell Treatment of Scleroderma (ASTIS) in Europe is a Phase III randomized, international, multicenter trial. Patients with diffuse systemic sclerosis were randomized to high-dose immunoablation and autologous HSCT or pulsed cyclophosphamide. Crossover to the HSCT arm was not allowed. Outcome measures included survival and prevention of major organ failure, safety, and quality of life. As of 2009, enrollment was completed with 156 patients. (34) Initial results were presented at EULAR 2012, the Annual Congress of the European League Against Rheumatism: as of May 1, 2012, data indicated that HSCT resulted in better long-term survival than conventional treatment for patients with poor prognosis early diffuse cutaneous systemic sclerosis.

The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial is a randomized Phase II study comparing HSCT and pulsed cyclophosphamide. Primary outcome measure is the global rank composite score at 54 months post-randomization (which includes measures of event-free survival, death, lung function, and skin score). Crossover to the HSCT arm is not allowed. The trial is still recruiting, with an estimated enrollment of 114 patients with an estimated study completion date of June 2016 (NCT00114530).

Type 1 Diabetes Mellitus (TIDM)

Couri and colleagues reported the results of a prospective Phase I/II study of autologous HSCT in 23 patients with TIDM (age range, 13-31 years) diagnosed in the previous 6 weeks by clinical findings with hyperglycemia and confirmed by measurement of serum levels of antiglutamic acid decarboxylase antibodies. (38) Enrollment was November 2003-April 2008, with follow-up until December 2008. After a mean follow-up of 29.8 months (range, 7-58 months) following autologous nonmyeloablative HSCT, C-peptide levels increased significantly (C-peptide is a measure of islet cell mass, and an increase after HSCT indicates preservation of islet cells), and the majority of patients achieved insulin independence with good glycemic control. Twenty patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin-free. Twelve patients maintained insulin independence for a mean of 31 months (range, 14-52 months), and 8 patients relapsed and resumed low-dose insulin. In the continuously insulin-independent group, HbA1c levels were less than 7.0% and mean area under the curve (AUC) C-peptide levels increased significantly from 225.0 (standard error [SE]: 75.2) ng/mL per 2 hours pretransplantation to 785.4 (SE: 90.3) ng/mL per 2 hours at 24 months post-transplantation (p<0.001) and to 728.1 (SE: 144.4) ng/mL per 2 hours at 36 months (p=0.001). In the transiently insulin-independent group, mean AUC of C-peptide levels also increased from 148.9 (SE: 75.2) ng/mL per 2 hours pretransplantation to 546.8 (SE: 96.9) ng/mL per 2 hours at 36 months (p=0.001), which was sustained at 48 months. In this latter group, 2 patients regained insulin independence after treatment with sitagliptin (Januvia®), which was associated with an increase in C-peptide levels. There was no transplant-related mortality.

Clinical Guidelines or Trials for TIDM

Three Phase I/II and two Phase II trials are recruiting patients with TIDM for AuSCS (NCT00315133, NCT01121029, NCT00807651, NCT01341899, NCT1285934). The status of one Phase II and one Phase II/III trial for patients with type 2 diabetes mellitus for AuSCS is unknown. (NCT00644241, NCT01065298).

Other Autoimmune Diseases

Phase II/III protocols are being developed for Crohn’s disease (CD) and chronic inflammatory demyelinating polyneuropathy (CIDP). For the remaining autoimmune diseases (including immune cytopenias, relapsing polychondritis, and others), the numbers are too small to draw conclusions, with further Phase I/II pilot studies proceeding. (39)

Additional Infusion Treatments for Autoimmune Disorders Using Hematopoietic Progenitor Cell (HPC) Boost or Stem-Cell Boost (SCB)

As with DLI, HPC Boost has a positive response rate for relapse following AlloSCS. (25) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (25, 26, 27, 28)

Short Tandem Repeat (STR) Markers

Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (29, 30) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of autoimmune disorders, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (29, 30, 31, 32, 33, 34)

Summary

Initial studies focused on using HSCT as salvage therapy for end-stage treatment of refractory autoimmune diseases. More recent experience has better helped to define which patients are most likely to benefit from HSCT, and the field has shifted to the use of HSCT earlier in the disease course before irreversible organ damage and to the use of safer and less intense nonmyeloablative conditioning regimens.

The experience with HSCT and autoimmune disorders has been predominantly with autologous transplants, and a number of published clinical reports with follow-up have demonstrated the safety and in some patients (particularly those with systemic sclerosis, SLE, and MS) the impact of HSCT in selected autoimmune diseases.

Although some of the initial results have been promising, this field continues to evolve. Many trials (randomized and nonrandomized) are currently recruiting or ongoing comparing the use of HSCT to conventional therapy for most of the diseases addressed in this policy; the results of these trials will further define the role of HSCT in the management of these diseases.

Thus, as of October 2012, no clinical trials have been published that would alter the current policy statement; thus the use of HSCS, as a single treatment or infusion, tandem or triple stem-cell transplant and DLI in autoimmune disorders, listed in the coverage statement, remains experimental, investigational and unproven.

Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of autoimmune disorders are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79

ICD-10 Codes

30230G0, 30230G1, 30233G0, 30233G1, 30240G0, 30240G1, 30243G0, 30243G1, 30250G0, 30250G0, 30250G1, 30253G0, 30253G1, 30260G0, 30260G1, 30263G0, 30263G1, 3E03005, 3E03305, 3E04005, 3E04305, 3E05005, 3E05305, 3E06005, 3E06305, 6A550Z2, 6A551Z2, 6A550ZT, 6A550ZV, 6A551ZT, 6A551ZV

Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38230, 38232, 38240, 38241, 38242, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
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History
January 2013 New 2013 BCBSMT medical policy.  Considered investigational.
September 2013 Policy formatting and language revised.  Document updated with literature review. The following was added: 1) Donor leukocyte infusion and hematopoietic progenitor cell boost are considered experimental, investigational and unproven; and 2) Any use of short tandem repeat (STR) markers for the treatment of autoimmune disorders is considered experimental, investigational and unproven. Otherwise, coverage unchanged. Description and Rationale significantly revised.  
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Stem-Cell Transplant for Autoimmune Disorders