Medical Policies - Surgery
Hematopoietic Stem-Cell Transplantation for Autoimmune Disorders
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Autologous or allogeneic hematopoietic stem-cell transplantation is considered experimental, investigational and/or unproven as a treatment of autoimmune diseases, including, but not limited to, the following:
• Chronic inflammatory demyelinating polyneuropathy (CIDP),
• Juvenile idiopathic and rheumatoid arthritis (RA),
• Multiple sclerosis (MS),
• Systemic lupus erythematosus (SLE),
• Systemic sclerosis/scleroderma (SSc), and
• Type 1 diabetes mellitus (IDDM).
NOTE 1: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.
Hematopoietic Stem-Cell Transplantation (HSCT)
HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients 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 HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).
Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. 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).
Most patients with autoimmune disorders respond to conventional drug therapies; however, conventional drug therapies are not curative and a proportion of patients suffer from autoimmune diseases that range from the severe to the recalcitrant to the rapidly progressive. It is in this group of patients with severe autoimmune disease that alternative therapies have been sought, including hematopoietic stem-cell transplantation (HSCT).
Autoimmune diseases represent a heterogeneous group of immune-mediated disorders, including multiple sclerosis (MS), systemic sclerosis/scleroderma (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and chronic immune demyelinating polyneuropathy (CIDP). The National Institutes of Health estimates that 5% to 8% of Americans have an autoimmune disorder.
The pathogenesis of autoimmune diseases is not well understood, but it 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, SSc). Most patients with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive. It is for this group of patients with severe autoimmune disease that alternative therapies have been sought, including HSCT. The primary concept underlying use of HSCT for these diseases is that ablating and “resetting” the immune system can alter the disease process, by inducing a sustained remission that possibly leads to cure. (1)
Autologous HSCT for Autoimmune Diseases
The goal of autologous HSCT in patients with autoimmune diseases is to eliminate self-reactive lymphocytes (lymphoablation) and generate new self-tolerant lymphocytes. (2) This approach is in contrast to destroying the entire hematopoietic bone marrow (myeloablation [MA]), as is often performed in autologous HSCT for hematologic malignancies. (2) However, no standard conditioning regimen exists 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)
Currently, for autoimmune diseases, autologous transplant is preferred over allogeneic, in part because of the lower toxicity of autotransplant relative to allogeneic, the GVHD associated with allogeneic transplant, and the need to administer posttransplant immunosuppression after an allogeneic transplant. (1)
Allogeneic HSCT for Autoimmune Diseases
The experience of using allogeneic HSCT for autoimmune diseases is currently limited but has 2 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)
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under the Code of Federal Regulation title 21, parts 1270 and 1271. (39) Hematopoietic stem-cells are included in these regulations.
This policy was originally created in 1990, moved to this policy in 2010, which has been updated with reviews of the MedLine database. The most recent literature review was performed through October 25, 2017. While the coverage of this policy does not address myeloablative (MA) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes may be influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date.
Recent reviews summarize the research to date using HSCT to treat a number of autoimmune diseases. (3, 4)
In March 2009, patients with an autoimmune disease who had undergone HSCT were registered in the European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism database. The database included 1031 with the clinical indications of multiple sclerosis (MS; n=379), systemic sclerosis (SSc; n=207), systemic lupus erythematosus (SLE; n=92), rheumatoid arthritis (RA; n=88), juvenile idiopathic arthritis (n=70), idiopathic thrombocytopenic purpura (ITP; n=23), and Crohn disease (CD; n=23). (4)
Multiple Sclerosis (MS)
Randomized Controlled Trials (RCTs)
A RCT, Autologous Stem-Cell Transplantation in MS, comparing HSCT with mitoxantrone for treatment of MS, was published in 2015 by Mancardi et al. (5) Due to low patient enrollment, this trial’s protocol, initially designed as a phase 3 study evaluating disability progression, was amended to a phase 2 study with a new primary outcome of disease activity, as measured by the number of new T2 magnetic resonance imaging (MRI) lesions in 4 years post-treatment. Eligibility for the trial was secondary progressive or relapsing-remitting MS (RRMS), a documented worsening during the last year, and lack of response to conventional therapy. Twenty-one patients were randomized to autologous HSCT (n=9) or medical therapy (mitoxantrone) (n=12). Follow-up data were collected every 6 months for 48 months. Data were not available for 4 patients; missing data were imputed in the intention-to-treat analysis of the primary outcome. The median number of new T2 MRI lesions was 2.5 in the HSCT group and 8 in the conventional therapy group (rate ratio, 0.21; 95% confidence interval [CI], 0.10 to 0.48, p<0.001). Among secondary outcomes, the annualized relapse rate was significantly lower in the HSCT group (19%) compared with the conventional therapy group (60%) (p<0.03). There was no statistically significant difference between groups in the rate of disease progression (defined as increase of >1 point in Expanded Disability Status Scale [EDSS] score if baseline was 3.5 to 5.5 or increase of >0.5 if baseline 5.5 to 6.5) or change in disability status.
A 2011 systematic review evaluated the safety and efficacy of autologous HSCT in patients with progressive MS refractory to conventional medical treatment. (6) Fourteen studies met inclusion criteria, of which 8 case series met inclusion criteria for the primary outcome of progression-free survival (PFS), with a median follow-up of at least 2 years. The other 6 studies were included for a summary of mortality and morbidity rates. Across the 8 case series, there was substantial heterogeneity. Most patients (77%) had secondary progressive MS, although studies also included patients with primary progressive, progressive-relapsing, and RRMS. Sample sizes across studies ranged between 14 and 26 patients. The studies differed in the types and intensities of conditioning regimens used before HSCT, with 5 studies using an intermediate-intensity regimen and 3 using high-intensity regimens. All studies were rated moderate quality. The estimated rate of long-term PFS for patients receiving an intermediate-intensity conditioning regimen was 79.4% (95% CI, 69.9% to 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% to 64.5%) at a median follow-up of 24 months. Of the 14 studies that reported adverse events, 13 were case series; from these, 7 treatment-related deaths were recorded; 6 non-treatment-related deaths occurred, with 5 associated with disease progression.
A 2012 study by Shevchenko et al. reported on the results of a prospective, open-label, single-center study that analyzed the safety and efficacy of autologous HSCT with a RIC regimen in 95 patients with different types of MS. (7) Patients underwent early, conventional, and salvage/late transplantation. Efficacy was evaluated based on clinical and quality of life (QOL) outcomes. No transplantation-related deaths were observed. All patients, except 1, responded to treatment. At long-term follow-up (mean, 46 months), the overall clinical response regarding disease improvement or stabilization was 80%. The estimated PFS rate at 5 years was 92% in the group after early transplant and 73% in the group after conventional/salvage transplant (p=0.01). No active, new, or enlarging lesions on MRI were found without disease progression. All patients who did not have disease progression did not receive therapy during the post-transplantation period. HSCT was accompanied by a significant improvement in QOL, with statistically significant changes in most QOL parameters (p<0.05). A subsequent 2015 publication reported on 64 patients participating in this trial who had at least 36 months of follow-up (median, 62 months). (8) (Another 35 patients had shorter follow-up, and the remainder were lost to follow-up.) Thirty (47%) of the 64 patients improved by at least 0.5 points on the EDSS score compared with baseline. Among the other patients, 29 (45%) were stable, and 5 (7%) experienced worsening disease.
In 2012, Mancardi et al. reported on 74 consecutive patients with MS treated with autologous HSCT following an intermediate-intensity conditioning regimen during the period from 1996 to 2008. (9) Thirty-six patients had secondary progressive disease and 25 had RRMS. Clinical and MRI outcomes were reported. The median follow-up was 48.3 months (range, 0.8-126 months). Two (2.7%) patients died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with follow-up more than 1 year, 8 (31%) of 25 subjects with RRMS had a 6- to 12-month confirmed EDSS score improvement more than 1 point after HSCT compared with 1 (3%) of 36 patients with a secondary progressive disease course (p=0.009). Among the 18 cases with a follow-up more than 7 years, 8 (44%) remained stable or had sustained improvement, while 10 (56%), after an initial period of stabilization or improvement (median duration, 3.5 years), showed a slow disability progression.
A 2015 single-center case series by Burt et al. reported on 151 patients, 123 with RRMS and 28 with secondary progressive MS. (10) Patients were treated with nonmyeloablative HSCT between 2003 and 2014. Six patients were not included in the outcomes analysis (lost to follow-up and nonreproducible neurologic findings). The remaining 145 patients were followed for a median of 2 years (range, 6 months to 5 years). There were no treatment-related deaths. Change in EDSS score was the primary outcome. A decrease of at least 1.0 point was considered a significant improvement and an increase of at least 1.0 point was considered a significant progression. There was a statistically significant improvement in EDSS score for the group as a whole compared with the pre-transplant mean score of 4.0, decreasing to a mean EDSS score of 2.5 at 3, 4, and 5 years. In post hoc analysis, patients most likely to have statistically significant improvements in EDSS scores were those with RRMS, with duration of disease of 10 years or less, and those without sustained fever during HSCT.
Several studies have focused on patients with aggressive MS. In 2011, Fassas et al. reported the long-term results of a single-center study that investigated the effect of HSCT on the treatment of MS. (11) After a median follow-up of 11 years (range, 2-15 years), the authors reported on the clinical and MRI outcomes of 35 patients with aggressive MS treated with HSCT. Disease PFS at 15 years was 44% for patients with active central nervous system (CNS) disease and 10% for those without (p=0.01); the median time to progression was 11 years (range, 0-22 years) for patients with active CNS disease and 2 years for patients without (range, 0-6 years). Improvements by 0.5 to 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.
A 2014 multicenter case series by Burman et al. reported on 48 patients with aggressive RRMS (defined as a disease with high relapse frequency, and who failed conventional therapy). (12) Patients underwent autologous HSCT. At the 5-year follow-up, relapse-free survival (RFS) was 87%, and the EDSS score PFS (defined as a deterioration in EDSS score of <0.5 points) was 77%. The rate of disease-free survival (DFS; no relapses, no new MRI lesions, no EDSS score progression) was 68%.
In 2016, Atkins et al. published a phase 2 trial investigating the use of immune-ablation and autologous HSCT for the treatment of aggressive MS. (13) Inclusion criteria were: poor prognosis, ongoing disease activity, and EDSS score between 3.0 and 6.0. Twenty-four patients enrolled, and had a median follow-up of 6.7 years (range, 4-13 years). One patient died of transplant-related complications (hepatic necrosis following sepsis). The primary outcome (activity-free survival at 3 years after transplantation) was 70% (95% CI, 47% to 84%). During the extended follow-up period, without the use of disease-modifying drugs, no signs of CNS inflammation were detected clinically or radiologically. Clinical relapses did not occur among the 23 surviving patients in 179 patient-years of follow-up. Thirty-three percent of the patients experienced grade 2 toxic effects and 58% experienced grade 1 transplantation-related toxic effects.
Results from the High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) trial were published in 2017 by Nash et al. (14) The trial evaluated 24 patients with MS who were treated with high-dose immunosuppression and autologous HSCT. The median follow-up was 62 months (range, 12-72 months). Outcomes were PFS (91%; 90% CI, 75% to 97%), clinical RFS (87%; 90% CI, 69% to 95%), and MRI activity-free survival (86%; 90% CI, 68% to 95%). Patients experienced high rates of adverse events: 92% had grade 3 and 100% had grade 4 adverse events. The majority of adverse events occurred between the start of conditioning to day 29 in the trial.
Section Summary: MS
Evidence for the use of HSCT in patients with MS consists of an RCT and many single-arm studies. The RCT compared HSCT (n=9) with mitoxantrone (n=12). The primary outcome was the number of new T2 lesions detected by MRI. The HSCT group developed statistically fewer lesions than the mitoxantrone group. Outcomes in the single-arm studies included PFS, RFS, disease activity-free survival, disease stabilization, number of new lesions, and improvements in EDSS scores. While improvements were seen in all outcomes compared with baseline, there were no comparative treatments. Adverse event rates were high, and most studies reported treatment-related deaths.
Systemic Sclerosis/Scleroderma (SSc)
In 2015, van Laar et al. conducted a systematic review of evidence on the use of HSCT for treating poor-prognosis SSc. (15) They identified 3 RCTs comparing HSCT with the standard of care (cyclophosphamide): a phase 2 trial and a completed phase 3 trial, both of which are described in the RCT section, plus a phase 3 trial (Scleroderma: Cyclophosphamide Or Transplantation [SCOT]). SCOT has been completed and results presented at a 2016 American College of Rheumatology conference. Results have not been published at the time of this update. Reviewers concluded that there is evidence HSCT can result in significant improvements in skin thickness and functional outcomes. However, HSCT is associated with serious toxicities that can be fatal. Additional trials are needed to assess how to reduce toxicity and to determine which patients with scleroderma would benefit most from HSCT.
A review in 2011 by Milanetti et al. summarized 8 phase 1 and 2 clinical studies using autologous HSCT to treat SSc. (16) The number of patients in each study ranged from 6 to 57. The proportion of patients across the studies achieving a 25% decrease in the Rodnan Skin Score (RSS) ranged from 60% to 100%. Pooled analyses were not conducted.
Results of the Autologous Stem-Cell Transplantation International Scleroderma (ASTIS) trial (ISRCTN54371254) were published in 2014. (17) ASTIS was a phase 3 RCT conducted in 10 countries at 29 centers with access to an EBMT-registered transplant facility. A total of 156 patients were recruited between March 2001 and October 2009. Patients were eligible if they were between 18 and 65 years of age; had diffuse cutaneous SSc according to American Rheumatism Association criteria, with maximum duration of 4 years; minimum modified Rodnan Skin Score (RSS) of 15 (range, 0-51; higher scores indicate more severe skin thickening); and involvement of heart, lungs, or kidneys. Patients were randomly allocated to receive high-dose chemotherapy (HDC; intravenous cyclophosphamide 200 mL/kg over 4 consecutive days and intravenous rabbit antithymocyte globulin 7.5 mg/kg total dose over 3 consecutive days) followed by CD34+ selected autologous HSCT support (n=79) or 12 monthly treatments with intravenous pulsed cyclophosphamide (750 mg/m2). Median follow-up was 5.8 years (interquartile range, 4.1-7.8 years). The primary end-point was event-free survival (EFS) defined as the time in days from randomization until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney). Main secondary end-points included treatment-related mortality, toxicity, and disease-related changes in modified RSS, organ function, body weight, and QOL scores. The internal validity (risk of bias) of ASTIS was assessed according to the U.S. Preventive Services Task Force criteria for randomized trials. The study was rated as “poor” quality according to this framework because of 2 fatal flaws: outcome assessment was not masked to patients or assessors, and 18 (24%) of 75 of the control group discontinued intervention because of death, major organ failure, adverse events, or non-adherence. Furthermore, the trial design permitted crossover after the second year, but whether any patients did so and were analyzed as such is not mentioned. Finally, the authors reported that the use of unspecified concomitant medications or other supportive care measures were allowed at the discretion of the investigators, adding further uncertainty to the results.
Of the 53 primary end-point events recorded, 22 were in the HSCT group (19 deaths, 3 irreversible organ failures; 8 patients died of treatment-related causes in the first year, 9 of disease progression, 1 of cerebrovascular disease, 1 of malignancy) and 31 were in the control group (23 deaths, 8 irreversible organ failures [7 of whom died later]; 19 patients died of disease progression, 4 of cardiovascular disease, 5 of malignancy, 2 of other causes). The data showed patients treated with HSCT experienced more events in the first year but appeared to have better long-term EFS than the controls, with Kaplan-Meier curves for overall survival (OS) crossing at about 2 years after treatment with OS at that time estimated at 85%. According to the Kaplan-Meier curves, at 5 years, OS was an estimated 66% in the control group and an estimated 80% in the HSCT group (p value unknown). Time-varying hazard ratios (modeled with a treatment by time interaction) for EFS were 0.35 (95% CI, 0.15 to 0.74) at 2 years and 0.34 (95% CI, 0.16 to 0.74) at 4 years, supporting a benefit of HSCT compared with pulsed cyclophosphamide. Severe or life-threatening grade 3 or 4 adverse events were reported in 51 (63%) of the HSCT group and 30 (37% by intention-to-treat, p=0.002) of the control group.
An open-label, randomized, controlled phase 2 trial (ASSIST; Autologous Stem-cell Systemic Sclerosis Immune Suppression Trial [DIScl201]; 2011) evaluated the safety and efficacy of autologous nonmyeloablative HSCT compared with the standard of care (cyclophosphamide). (18) Nineteen consecutively enrolled patients less than 60 years of age with diffuse SSc, modified RSS greater than 14, and organ involvement or restricted skin involvement (modified RSS, <14) but coexistent pulmonary involvement were randomized 1:1 to HSCT, intravenous cyclophosphamide 200 mg/kg, plus rabbit antithymocyte globulin or to intravenous cyclophosphamide 1.0 g/m2 once per month for 6 months. The primary outcome was an improvement at 12 months, which was defined as a decrease in modified RSS (<25% for those with initial modified RSS >14) or an increase in forced vital capacity of more than 10%. Patients in the control group with disease progression (>25% increase in modified RSS 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 the 12-month follow-up compared with none of the 9 patients allocated to cyclophosphamide (p<0.001). Treatment failure (i.e., disease progression without interval improvement), occurred in 8 of 9 controls but did not occur in any of the 10 patients treated by HSCT (p<0.001). After long-term follow-up (mean, 2.6 years) of patients allocated to HSCT, all but 2 patients had sustained improvement in modified RSS 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; all improved after HSCT. Four of these patients, followed for at least 1 year, had a mean (standard deviation [SD]) decrease in modified RSS from 27 (SD=15.5) to 15 (SD=7.4), an increase in forced vital capacity from 65% (20.6%) to 76% (26.5%), and an increase in total lung capacity from 81% (14.0%) to 88% (13.9%). Data for 11 patients with follow-up to 2 years after HSCT suggested that the improvements in modified RSS (p<0.001) and forced vital capacity (p<0.03) persisted.
Vonk et al. (2008) reported the long-term results of 28 patients with severe diffuse cutaneous SSc who underwent autologous HSCT from 1998 to 2004. (19) 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 RSS, and a significant (i.e., >25%) decrease (i.e., improvement) was achieved in 19 of 26 patients after 1 year and in 15 of 16 after 5 years. At study baseline, 65% of patients had significant lung involvement; all pulmonary function parameters remained stable after transplant at 5- and 7-year follow-ups. Based on the World Health Organization 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 Status score of 0 increased to 56% from 4% at baseline. Estimated survival at 5 years was 96.2% (95% CI, 89% to 100%) and at 7 years was 84.8% (95% CI, 70.2% to 100%); and EFS (survival without mortality, relapse, or progression of SSc resulting in major organ dysfunction) was 64.3% (95% CI, 47.9% to 86%) at 5 years and 57.1% (95% CI, 39.3% to 83%) at 7 years. For comparison, an international meta-analysis published in 2005 estimated the 5-year mortality rate in patients with severe SSc at 40%. (20)
Nash et al. (2007) reported on the long-term follow-up of 34 patients with diffuse cutaneous SSc with significant visceral organ involvement who were enrolled in a multi-institutional pilot study SSc-deaths. (21) Of the 27 evaluable patients, 17 (63%) 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 using the Disability Index of the modified Health Assessment Questionnaire 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 rates were both 64% at 5 years.
Henes et al. (2012) reported on 26 consecutive patients with SSc scheduled for autologous HSCT between 1997 and 2009. (22) The main outcome variable was response to treatment (reduction of modified RSS by 25%) at 6 months. Secondary end-points were transplant-related mortality and PFS. At 6 months, significant skin and lung function improvement assessed on the modified RSS was achieved in 78.3% of patients. Overall response rate was 91%, and some patients even improved after month 6. Three patients died between mobilization and conditioning treatment -- 2 due to severe disease progression and 1 treatment-related. Seven patients relapsed during the 4.4 years of follow-up. PFS was 74%. Four patients died during follow-up, with the most frequent causes of death being pulmonary and cardiac complications of SSc.
Section Summary: SSc
Evidence for the use of HSCT in patients with SSc consists of 3 RCTs and nonrandomized studies. Two (1 with 19 patients, the other with 156 patients) have published results, and reported statistical significant improvements in clinical outcomes (skin thickness, forced vital capacity). The larger trial (ASTIS) also reported improved OS. However, HSCT can result in serious adverse events due to toxicity. The third RCT, completed and expected to be published soon, employed a different transplant regimen. Additional information on the best treatment regimen to reduce toxicity and long-term follow-up is still needed.
Systemic Lupus Erythematosus (SLE)
Burt et al. (2006) published results on the largest single-center series using HSCT for SLE in the U.S. (23) Between 1997 through 2005, investigators enrolled 50 patients (mean age, 30 years, 43 women, 7 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 4 of 11 ACR criteria for SLE and required more than 20 mg/d of prednisone or its equivalent, despite the use of cyclophosphamide. Patients underwent autologous HSCT following a lymphoablative conditioning regimen. Two patients died after mobilization, yielding a treatment-related mortality rate of 4% (2/50). After a mean follow-up of 29 months (range, 6 months to 7.5 years), the 5-year OS rate was 84%, and the probability of DFS rate was 50%. Several parameters of SLE activity improved, including renal function, SLE Disease Activity Index score, antinuclear antibody, anti-double stranded DNA, complement C3 and C4 levels, and carbon monoxide diffusion lung capacity. The investigators suggested these results justified a randomized trial comparing immunosuppression plus autologous HSCT with continued standard of care.
Song et al. (2011) reported on the efficacy and toxicity of autologous HSCT for 17 patients with SLE after 7 years follow-up. (24) OS and PFS rates were used to assess the efficacy and toxicity levels of the treatment. The median follow-up was 89 months (range, 33-110 months). The probabilities of 7-year OS and PFS were 82.4% (SD=9.2%) and 64.7% (SD=11.6%), respectively. The principal adverse events included allergy, infection, elevated liver enzymes, bone pain, and heart failure. Two patients died, 1 due to severe pneumonia and the other due to heart failure at 33 and 64 months after transplantation, respectively. The authors concluded that their 7-year follow-up results suggested that autologous HSCT was beneficial for SLE patients.
Leng et al. (2017) reported on 24 patients with severe SLE who received high-dose immunosuppressive therapy and HSCT. (25) Patients were followed for 10 years. One patient died following treatment. At the 6-month follow-up, 2 patients had achieved partial remission, and 21 patients had achieved remission. At the 10-year follow-up, the OS rate was 86%; 16 patients remained in remission, 4 were lost to follow-up, 2 patients had died, and 1 patient had active disease.
Section Summary: SLE
Evidence for the use of autologous HSCT to treat patients with SLE consists of several case series (total n=91 patients). A 4% treatment-related mortality rate was reported in 2 studies. High rates of remission were reported at 6 months, and at 2- to 10-year follow-ups. While HSCT has shown beneficial effects on patients with SLE, further investigation of more patients is needed.
Juvenile Idiopathic or Rheumatoid Arthritis (RA)
A 2008 review article by Saccardi et al. on HSCT for autoimmune diseases has summarized the experience with juvenile idiopathic arthritis and RA as follows. (26) More than 50 patients with juvenile idiopathic arthritis have been reported to the EBMT Registry. The largest cohort study initially used a single 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 RA 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.
Section Summary: Juvenile Idiopathic or RA
Evidence for the use of HSCT on patients with juvenile idiopathic arthritis consists of data from an EBMT Registry (n>50). Different conditioning regimens were used among the patients, with remission rates averaging 50%. However, relapse has been reported within 6 months in many cases, and new biologic therapies are available for these patients.
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Several review articles have summarized experience with HSCT in the treatment of CIDP. (27-29) In general, the evidence includes a few case reports describing outcomes for autologous HSCT in patients who failed standard treatments such as corticosteroids, intravenous immunoglobulins, and plasma exchange. While improvements were reported, some with long-term follow-up, the numbers of patients undergoing the procedure are small, and the potential for serious adverse events is a concern.
Section Summary: CIDP
Evidence for the use of HSCT to treat patients with CIDP consists of case reports. Additional investigations are needed due to the toxicity associated with this procedure.
Type 1 Diabetes Mellitus (IDDM)
In 2016, El-Badawy and El-Badri published a meta-analysis on the use of HSCT to treat diabetes. (30) The literature search, conducted through August 2015, identified 22 studies for inclusion. Fifteen of the studies (n=300 patients) involved patients with IDDM; 7 studies (n=224 patients) involved patients with type 2 diabetes (NIDDM). The quality of the selected studies was assessed using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. The following items were evaluated to determine the risk of bias: attrition, confounding measurement, intervention, performance, selection, and conflict of interest. The mean follow-up in the studies ranged from 6 to 48 months (median, 12 months). Comparisons of C-peptide levels and hemoglobin A1c levels after 12-month follow-up were calculated by type of diabetes (1 or 2) and source of stem-cells (see Table 1). Adverse events were reported in 22% of the patients, with no reported mortality. Reviewers concluded that remission of diabetes is possible and safe with stem-cell therapy, patients with previously diagnosed ketoacidosis are not good candidates for HSCT, and that early-stage patients may benefit more from HSCT. Large-scale well-designed randomized studies considering stem-cell type, cell number, and infusion method is needed.
Table 1. Standard Mean Differences from Baseline in C-Peptide and HbA1c Levels in Patients with Diabetes Treated with HSCT After 12 Months of Follow-Up
SMD (95% CI)
1.07 (0.67 to 1.48)
0.05 (-0.30 to 0.41)
-0.91 (-1.67 to -0.16)
1.19 (0.41 to 1.98)
-1.37 (-1.69 to -1.05)
3.87 (3.29 to 4.44)
-1.18 (-2.15 to -0.22)
IS-ADSc + BM-HSC
-1.01 (-1.73 to -0.30)
0.93 (0.27 to 1.59)
-0.57 (-1.73 to -0.35)
1.09 (0.83 to 1.35)
-0.55 (-4.23 to 3.13)
0.73 (-3.83 to 5.29)
-0.61 (-1.21 to 0.00)
0.93 (0.30 to 1.55)
-0.38 (-1.27 to 0.50)
1.50 (0.49 to 2.53)
-1.29 (-1.77 to -0.81)
1.16 (0.85 to 1.46)
-0.93 (-1.27 to -0.58)
1.14 (0.88 to 1.40)
CI: confidence interval;
HbA1c: hemoglobin A1c;
BM-HSC: bone marrow hematopoietic stem-cells;
BM-MNC: bone marrow mononuclear stem-cells;
BM-MSC: bone marrow mesenchymal stem-cells;
HSCT: hematopoietic stem-cell transplantation;
IS-ADSc: insulin secreting-adipose derived stem-cells;
N/A: not applicable;
PD-MSC: placenta-derived mesenchymal stem-cells;
SMD: standard mean difference; UCB: umbilical cord blood;
UC-MSC: umbilical cord mesenchymal stem-cells.
Several case series evaluated autologous HSCT in patients with new-onset IDDM; there were no published comparative studies. Although a substantial proportion of patients tended to become insulin-free after HSCT, remission rates were high.
In 2016, Cantu-Rodriguez et al. published a study of 16 patients with IDDM who received a less toxic conditioning regimen and transplantation. (31) The outpatient procedures were completed without severe complications. At the 6-month follow-up, 3 (19%) were non-responders, 6 (37%) partially independent from insulin, and 7 (44%) were completely independent of insulin. Hemoglobin A1c levels decreased by a mean of -2.3% in the insulin-independent group.
In 2015, Xiang et al. published data on 128 patients ages 12 to 35 years who had been diagnosed with IDDM no more than 6 weeks before study enrollment. (32) After a mean follow-up of 28.5 months (range, 15-38 months), 71 (55%) patients were considered to be insulin-free. These patients had a mean remission period of 14.2 months. The other 57 (45%) patients were insulin-dependent. The latter group included 27 patients with no response to treatment and another 30 patients who relapsed after a transient remission period. Adverse events included ketoacidosis and renal dysfunction (1 patient each); there was no transplant-related mortality. In multiple logistic regression analysis, factors independently associated with becoming insulin-free after autologous HSCT were younger age at onset of diabetes, lower tumor necrosis factor α levels, and higher fasting C-peptide levels.
A 2016 case series by Snarski et al. reported on 24 patients with a diagnosis of IDDM who underwent autologous HSCT. (33) Mean age was 26.5 years (range, 18-34 years). After treatment, 20 (87%) of 23 patients went into diabetes remission, defined as being insulin-free with normoglycemia for at least 9.5 months. The median time of remission was 31 months (range, 9.5-80 months). Mean insulin doses remained significantly lower than baseline doses at 2 and 3 years, but the insulin doses returned to pre-HSCT levels at years 4 and 5. Among 20 patients remaining in follow-up at the time of data analysis for publication, 4 (20%) remained insulin-free. Adverse events include neutropenic fever in 12 (50%) patients. There were 4 cases of sepsis, including a fatal case of Pseudomonas aeruginosa sepsis. There was also 1 case of pulmonary emphysema after insertion of a central venous catheter.
In 2009, Couri et al. reported on the results of a prospective case series evaluating autologous HSCT in 23 patients with IDDM (age range, 13-31 years) diagnosed in the 6 weeks before transplant based on clinical findings including hyperglycemia and confirmed by measurement of serum levels of anti-glutamic acid decarboxylase antibodies. (34) At a mean follow-up of 29.8 months (range, 7-58 months) after autologous nonmyeloablative HSCT, C-peptide levels increased significantly (C-peptide measures islet cell mass, and an increase after HSCT indicates preservation of islet cells), and most 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, hemoglobin A1c levels were less than 7.0%. There was no transplant-related mortality.
Section Summary: IDDM
Evidence for the use of HSCT to treat diabetes consists of several case series and a meta-analysis of 22 studies. The meta-analysis revealed that HSCT is more effective in patients with IDDM and when the treatment is administered soon after the diagnosis. Certain factors limit the conclusions that can be drawn about the overall effectiveness of HSCT to treat diabetes; those factors are: heterogeneity in the stem-cell types, cell number infused, and infusion methods.
Other Autoimmune Diseases
Phase 2/3 protocols are being developed for CD. For the remaining autoimmune diseases (e.g., immune cytopenias, relapsing polychondritis), sample sizes are too small to draw conclusions.
A case series of 7 patients with myasthenia gravis was reported by Bryant et al. (2016). (35) Using the Myasthenia Gravis Foundation of America clinical classification, all patients achieved complete stable remission, with follow-up from 29 to 149 months. The authors concluded that these positive long-term results warranted further investigation of HSCT for patients with myasthenia gravis.
Section Summary: Other Autoimmune Diseases
Evidence for the use of HSCT for other autoimmune diseases consists of small retrospective studies. Information from larger prospective studies is needed.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 2.
Table 2. Summary of Key Trials
Autologous Stem-Cell Transplantation for Progressive Systemic Sclerosis: a Prospective Non-interventional Approach Across Europe (NISSC) for the Autoimmune Diseases Working Party of the EBMT
Randomized Study of Different Non-myeloablative Conditioning Regimens with Hematopoietic Stem-cell Support in Patients with Scleroderma (ASSIST-IIb)
Hematopoietic Stem-Cell Therapy for Patients with Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study.
Non-myeloablative Autologous Hematopoietic Stem-Cell Transplantation in Patients with Chronic Inflammatory Demyelinating Polyneuropathy: A Phase II Trial.
A Pilot Study of Autologous Stem-Cell Transplantation with Post-transplant Cyclophosphamide for Children and Young Adults with Refractory Crohn’s Disease
Outpatient Hematopoietic Grafting in Patients with Multiple Sclerosis Employing Autologous Non-Cryopreserved Peripheral Blood Stem-Cells: a Feasibility Study
Evaluation of the Safety and Efficacy of Reduced-Intensity Immunoablation and Autologous Hematopoietic Stem-Cell Transplantation (AHSCT) in Multiple Sclerosis
An Open-Label, Phase II Multicenter Cohort Study of Immunoablation with Cyclophosphamide and Antithymocyte-Globulin and Transplantation of Autologous CD34-Enriched Hematopoietic Stem-Cells versus Currently Available Immunosuppressive/Immunomodulatory Therapy for Treatment of Refractory Systemic Lupus Erythematosus
A Randomized, Open-Label, Phase II Multicenter Study of High-Dose Immunosuppressive Therapy Using Total Body Irradiation, Cyclophosphamide, ATGAM, and Autologous Transplantation with Auto-CD34+HPC Versus Intravenous Pulse Cyclophosphamide for the Treatment of Severe Systemic Sclerosis (SCSSc-01).
NCT: National Clinical Trial.
Practice Guidelines and Position Statements
American Academy of Neurology (AAN) et al.
A review of guidelines from the AAN and the ACR found no mention of stem-cell transplantation for MS, SLE, RA, or juvenile idiopathic arthritis. In 2016, the Academy affirmed the statements in the Myasthenia Gravis Foundation of America’s consensus guidelines for the management of myasthenia gravis. (36) The consensus guidelines did not discuss HSCT as a therapeutic option.
European Group for Blood and Marrow Transplantation (EBMT)
In 2012, the EBMT updated its guidelines on HSCT for severe autoimmune diseases (37) EBMT recommended as follows: “HSCT [hematopoietic stem-cell transplantation] should be considered as a therapeutic option at second line or beyond for patients with severe ADs [autoimmune diseases] progressing despite standard established and/or approved therapy” (level of evidence II). The following conditions should be met if HSCT is chosen for treatment: referral to a center with JACIE (Joint Accreditation Committee of International Society for Cellular Therapy and EBMT) accreditation; when possible, HSCT should be conducted within a phase 2 or 3 trial; if such a trial is not available, then a multidisciplinary team should meet with patients to discuss HSCT and non-HSCT treatment options.
In 2015, EBMT issued additional guidelines on HSCT for severe autoimmune diseases, focusing on immune monitoring and biobanking. (38) To standardize clinical HSCT protocols, EBMT developed guidelines for “good laboratory practice” in relation to procuring, processing, storing, and analyzing biologic specimens of patients with autoimmune diseases undergoing HSCT. The guidance provides a table that specifies the type of biologic sample (e.g., serum, biopsy, cerebrospinal fluid), sample tests, testing methods (e.g., enzyme linked immunosorbent assay, fluorescent activated cell sorter), and timing of testing for the following autoimmune diseases: MS, SSc, SLE, CD, IDDM, and RA.
Summary of Evidence
For individuals with multiple sclerosis (MS) who receive hematopoietic stem-cell transplantation (HSCT), the evidence includes a randomized controlled trial (RCT) and several case series. Relevant outcomes are overall survival (OS), health status measures, quality of life (QOL), and treatment-related mortality and morbidity. The phase 2 RCT compared HSCT with mitoxantrone, and the trial reported intermediate outcomes (number of new T2 magnetic resonance imaging [MRI] lesions); the group randomized to HSCT developed significantly fewer lesions than the group receiving conventional therapy. The findings of the case series revealed improvements in clinical parameters following HSCT compared with baseline. Adverse event rates were high, and most studies reported treatment-related deaths. Controlled trials (with appropriate comparator therapies) that report on clinical outcomes are needed to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with systemic sclerosis/scleroderma (SSc) who receive HSCT, the evidence includes RCTs and observational studies. Relevant outcomes are OS, symptoms, health status measures, QOL, and treatment-related mortality and morbidity. The results of the ASTIS trial (n=156) have suggested high-dose chemotherapy (HDC) plus autologous HSCT might improve survival among patients with diffuse cutaneous SSc compared with pulsed intravenous cyclophosphamide. However, analysis of the internal validity of the trial using U.S. Preventive Services Task Force criteria showed fatal flaws and a poor study rating due to attrition in the control group that could have skewed the survival curve to show better survival for HSCT recipients than for controls. A smaller RCT (n=19) found that the rate of improvement at 12 months was significantly higher in the HSCT group than in the conventional therapy group. Data from these trials, however, are inconclusive, and additional studies are needed to confirm safety and efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with systemic lupus erythematosus (SLE) who receive HSCT, the evidence includes case series. Relevant outcomes are OS, symptoms, QOL, and treatment-related mortality and morbidity. Several case series (total n=91 patients) have been published. The largest series (n=50) reported an overall 5-year survival rate of 84% and the probability of disease-free survival (DFS) was 50%. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with juvenile idiopathic or rheumatoid arthritis (RA) who receive HSCT, the evidence includes registry data. Relevant outcomes are symptoms, QOL, medication use, and treatment-related mortality and morbidity. The registry included 50 patients with juvenile idiopathic or RA. The overall drug-free remission rate was approximately 50%. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive HSCT, the evidence includes case reports. Relevant outcomes are OS, symptoms, health status measures, QOL, and treatment-related mortality and morbidity. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with type 1 diabetes (IDDM) who receive HSCT, the evidence includes case series and a meta-analysis of 22 studies. Relevant outcomes are OS, symptoms, health status measures, QOL, and treatment-related mortality and morbidity. While a substantial proportion of patients tended to become insulin-free after HSCT, remission rates were still high. The meta-analysis further revealed that HSCT is more effective in patients with IDDM and when HSCT is administered soon after the diagnosis. Certain factors limit the conclusions that can be drawn about the overall effectiveness of HSCT in treating diabetes; those factors are: heterogeneity in the stem-cell types, cell number infused, and infusion methods. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with other autoimmune diseases (e.g., Crohn disease [CD], immune cytopenias, relapsing polychondritis) who receive HSCT, the evidence includes small retrospective studies. Relevant outcomes are OS, symptoms, health status measures, QOL, and treatment-related mortality and morbidity. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
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36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38230, 38232, 38240, 38241, 38242, 38243, 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, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241
S2140, S2142, S2150
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18. 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. Aug 6 2011; 378(9790):498-506. PMID 21777972
19. 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. Jan 2008; 67(1):98-104. PMID 17526554
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40. High-Dose Lymphoablative Therapy (HDLT) with or without Stem-cell Rescue for Treatment of Severe Autoimmune Diseases. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2000 June) Volume 15; Tab 1.
41. High-Dose Lymphoablative Therapy (HDLT) with or without Stem-Cell Rescue for Treatment of Severe Autoimmune Diseases. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2002 February) Volume 16; Tab 14.
42. Hematopoietic Cell Transplantation for Autoimmune Disease. Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 July) Therapy 8.01.25.
|8/15/2018||Reviewed. No changes.|
|12/15/2017||Document updated with literature review. Coverage unchanged.|
|6/1/2016||Document updated with literature review. Coverage unchanged.|
|5/1/2015||Document updated with literature review. Chronic inflammatory demyelinating polyneuropathy was added to the listing of experimental, investigational and/or unproven indications. The policy title changed from Stem-Cell Transplant for Autoimmune Disorders.|
|10/15/2013||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 related services for the treatment of any autoimmune disease, including but not limited to MS, JRA, RA, SLE, systemic sclerosis/scleroderma, and TIDM, such as short tandem repeat (STR) markers, are considered experimental, investigational and unproven. Otherwise, coverage unchanged. Description and Rationale significantly revised.|
|4/1/2010||New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies. Stem-cell transplant remains experimental, investigational and unproved when used to treat autoimmune disorders. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): • Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; • Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; • Cord Blood as a Source of Stem-cells; • Donor Leukocyte Infusion (DLI); and • Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies.|
|Title:||Effective Date:||End Date:|
|Hematopoietic Stem-Cell Transplantation for Autoimmune Disorders||12-15-2017||08-14-2018|
|Hematopoietic Stem-Cell Transplantation for Autoimmune Disorders||06-01-2016||12-14-2017|
|Hematopoietic Stem-Cell Transplantation for Autoimmune Disorders||05-01-2015||05-31-2016|
|Stem-Cell Transplant for Autoimmune Disorders||10-15-2013||04-30-2015|
|Stem-Cell Transplant for Autoimmune Disorders||04-01-2010||10-14-2013|