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MP 8.01.25 Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/9:2012
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Autoimmune Diseases
Autoimmune diseases represent a heterogeneous group of immune-mediated disorders, with some of the most common types being multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis/scleroderma. The National Institutes of Health estimates that 5–8% of Americans have an autoimmune disorder.

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)

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem cell transplantation (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 “naïve” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in policy No. 7.01.50.

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).

Autologous Stem-Cell Transplantation for Autoimmune Diseases

The goal of autologous HSCT in patients with autoimmune diseases is to eliminate self-reactive lymphocytes (lymphoablative) and generate new self-tolerant lymphocytes. (2) This approach is in contrast to destroying the entire hematopoietic bone marrow (myeloablative), as is often performed in autologous HSCT for hematologic malignancies. (2) 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)

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 post-transplant immunosuppression after an allogeneic transplant. (1)

Allogeneic Stem-Cell Transplantation for Autoimmune Diseases

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)



Autologous or allogeneic hematopoietic stem-cell transplant is considered investigational as a treatment of autoimmune diseases, including, but not limited to multiple sclerosis, juvenile idiopathic and rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis/scleroderma, and type 1 diabetes mellitus.

Policy Guidelines


In 2003, CPT centralized codes describing allogeneic and autologous hematopoietic stem-cell support services to the hematology section (CPT 38204-38242). Not all codes are applicable for each HDC/stem- cell support procedure. For example, Plans should determine if cryopreservation is performed. A range of codes describe services associated with cryopreservation, storage, and thawing of cells. (38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215).

CPT 38208 and 38209 describe thawing and washing of cryopreserved cells

CPT 38210, 38211, 38212, 38213 & 38214 describe certain cell types being depleted

CPT 38215 describes plasma cell concentration

Benefit Application
BlueCard/National Account Issues

No applicable information

Two TEC Assessments have addressed the issue of high-dose lymphoablative therapy and stem-cell rescue in autoimmune diseases and support the policy. (3,4)

Recent reviews summarize the experience to date with HSCT and autoimmune diseases. (5,6)

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 (n =379), systemic sclerosis (n =207), systemic lupus erythematosus (n =92), rheumatoid arthritis (n =88), juvenile idiopathic arthritis (n =70), idiopathic thrombocytopenic purpura (n =23), and Crohn’s disease (n =23). (6)

Multiple Sclerosis

Currently, MS is the most common autoimmune disease for which autologous HSCT is being studied. (7) Following initial promising clinical experience, more than 350 consecutive cases have been reported by the EBMT over the last decade. (7) Most patients who underwent autologous HSCT 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. (7) 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. (7) 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 autologous HSCT in patients with progressive MS refractory to conventional medical treatment. (8) Eight case series were included which 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. (9) A small number of patients have undergone autologous HSCT 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. (10-12) These patients had persistent disease activity despite numerous different treatments. All patients but one were relapse-free without the need for ongoing immunosuppression after autologous HSCT 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 autologous HSCT 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. (9) Studies are mainly case series that report the outcomes of autologous HSCT 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 autologous HSCT 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 autologous HSCT, 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. (13) 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 improvement in their EDSS score.

The EBMT Autoimmune Diseases Working Party database reported new data from a retrospective survey of 178 patients with MS who underwent autologous HSCT following one of several different preparative regimens. (14) Overall, at median follow-up of about 42 months, the disease remained stable or improved in 63% of cases and worsened in 37%. Autologous HSCT was associated with significantly better PFS in a subset of younger patients (i.e., younger than 40 years of age) affected by severe, progressive MS who received autologous HSCT within 5 years from diagnosis compared to those older than 40 years. The authors suggest that autologous HSCT could be considered after failure of conventional treatments in patients with rapidly progressing MS.

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. (15) 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) Expanded Disability Status Scale (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. (16) The patients underwent early, conventional, and salvage/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 autologous HSCT with an intermediate intensity conditioning regimen in the period from 1996 to 2008. (17) 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 Expanded Disability Status Scale 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 autologous HSCT in advanced MS. (18) Neurologic examinations, brain MRI and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. There were 26 patients with a mean Expanded Disability Status Scale (EDSS) of 7.0; 17 with secondary progressive MS, 8 with primary progressive, and 1 with relapsing/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 Trials

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 autologous HSCT in severe cases of MS was terminated due to difficulty in accruing patients and lack of funds. (19)

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 autologous HSCT 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 autologous HSCT on early-stage MS. Estimated enrollment is 24. Enrollment completed July 2009.

Systemic Sclerosis/Scleroderma

A 2011 review article summarizes the clinical studies that have been performed using conventional therapy, as well as those using autologous HSCT in the treatment of systemic sclerosis. (20) 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. (21) 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. (22) 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, (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%. (23)

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 autologous HSCT. (24) 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 overall survival (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. (25) 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 autologous HSCT resulted in significant improvement in most patients with systemic sclerosis.

Clinical Trials

ASTIS 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. (22) 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 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).

Systemic Lupus Erythematosus

Burt and colleagues published the results of the largest single-center series of this treatment in systemic lupus erythematosus (SLE) available in the U.S. (26) Between April 1997 through January 2005, they enrolled 50 patients (mean age: 30 years [SD +/- 10.9 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 American College of Rheumatology criteria for SLE and required more than 20 mg per day of prednisone or its equivalent in spite of use of cyclophosphamide. Patients underwent autologous SCT 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, 6 months to 7.5 years), overall 5-year survival was 84%, and the probability of disease-free survival was 50%. Several parameters of SLE activity (described in the 2001 TEC Assessment (4)) improved, including renal function, SLE disease activity index (DAI) score, antinuclear antibody, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity. The investigators suggest these results justify a randomized trial comparing immunosuppression plus autologous SCT versus continued standard of care.

Song and colleagues reported on the efficacy and toxicity of autologous stem-cell transplantation for 17 patients with SLE after 7 years follow-up. 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 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 autologous HSCT seems beneficial for SLE patients.

Clinical Trials

Three nonrandomized, open-label Phase II trials are recruiting patients, ongoing or completed studying the effectiveness of autologous HSCT 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).

Juvenile Arthritis

A review article by Saccardi et al. summarizes the experience thus far with juvenile idiopathic and rheumatoid arthritis (RA) as follows (27): More than 50 patients with juvenile idiopathic arthritis 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 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.

Clinical Trials

No Phase II or III clinical trials were identified at online site: using HSCT in juvenile idiopathic or RA.

Type 1 Diabetes Mellitus

Couri and colleagues reported the results of a prospective Phase I/II study of autologous HSCT in 23 patients with type 1 diabetes mellitus (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. (28) 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 Trials

Three Phase I/II and two Phase II trials are recruiting patients with type 1 diabetes mellitus for autologous HSCT (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 autologous HSCT is unknown. (NCT00644241, NCT01065298).

Other Autoimmune Diseases

Phase II/III protocols are being developed for Crohn’s disease and chronic inflammatory demyelinating polyneuropathy. 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. (29)


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, use of HSCT for these autoimmune diseases is considered investigational.




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  20. Milanetti F, Bucha J, Testori A et al. Autologous hematopoietic stem cell transplantation for systemic sclerosis. Curr Stem Cell Res Ther 2011; 6(1):16-28.
  21. Burt RK, Shah SJ, Dill K et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomized phase 2 trial. Lancet 2011; 378(9790):498-506.
  22. Vonk MC, Marjanovic Z, van den Hoogen FH et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis 2008; 67(1):98-104.
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  26. Burt RK, Traynor A, Statkute L et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 2006; 295(5):527-35.
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  28. Couri CE, Oliveira MC, Stracieri AB et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009; 301(15):1573-9.
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CPT  38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogenic
  38206  Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous 
  38208  Thawing of previously frozen harvest 
  38209  Washing of harvest 
  38210  Specific cell depletion with harvest, T-cell depletion 
  38211 Tumor cell depletion
  38212  Red blood cell removal 
  38213  Platelet depletion 
  38214  Plasma (volume) depletion 
  38215  Cell concentration in plasma, mononuclear, or buffy coat layer 
  38220  Bone marrow, aspiration only 
  38221  Biopsy, needle or trocar 
  38240  Bone marrow or blood-derived peripheral stem-ell transplantation; allogeneic 
  38241  Bone marrow or blood-derived peripheral stem-cell transplantation; autologous 
ICD-9 Procedure  41.01  Autologous bone marrow transplant 
  41.02 Allogeneic bone marrow transplant with purging
  41.03 Allogeneic bone marrow transplant without purging
  41.04  Autologous hematopoietic stem-cell transplant 
  41.05 Allogeneic hematopoietic stem cell transplant without purging
  41.06 Cord blood stem cell transplant
  41.07 Autologous hematopoietic stem cell transplant with purging
  41.08 Allogeneic hematopoietic stem cell transplant with purging
  41.09 Autologous bone marrow transplant with purging
  41.91  Aspiration of bone marrow from donor for transplant 
  99.79  Other therapeutic apheresis (includes harvest of stem cells) 
ICD-9 Diagnosis    Investigational for all relevant diagnoses
  250.00 -250.93 Diabetes mellitus code range
  340  Multiple sclerosis 
  710.0  Systemic lupus erythematosus 
  710.1  Systemic sclerosis 
  714.0–714.9  Rheumatoid arthritis code range 
HCPCS  Q0083, Q0084, Q0085  Chemotherapy, administer code range 
  J9000, J9001, J9010, J9015, J9017, J9020, J9025, J9027, J9031, J9035, J9040, J9041, J9045, J9050, J9055, J9060, J9062, J9065, J9070, J9080, J9090, J9091, J9092, J9093, J9094, J9095, J9096, J9097, J9098, J9100, J9110, J9120, J9130, J9140, J9150, J9151, J9160, J9165, J9170, J9175, J9178, J9181, J9182, J9185, J9190, J9200, J9201, J9202, J9206, J9208, J9209, J9211, J9212, J9213, J9214, J9215, J9216, J9217, J9218, J9219, J9225, J9226, J9230, J9245, J9250, J9260, J9261, J9263, J9264, J9265, J9266, J9268, J9270, J9280, J9290, J9291, J9293, J9300, J9303, J9305, J9310, J9320, J9340, J9350, J9355, J9357, J9360, J9370, J9375, J9380, J9395, J9600, J9999 Chemotherapy drug code range 
  S2150  Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic, and emergency services) 
ICD-10-CM (effective 10/1/13)   Investigational for all relevant diagnoses
   E10.10-E10.9 Type 1 diabetes mellitus codes range
   G35 Multiple sclerosis
   M05.10 M06.9 Rheumatoid arthritis code range
   M08.00 -M08.99 Juvenile arthritis code range
   M32.0 -M32.9 Systemic lupus erythematosus code range
   M34.0-M34.9 Systemic sclerosis (scleroderma) code range
ICD-10-PCS (effective 10/1/13)   ICD-10-PCS codes are only used for inpatient services.
   30243G0, 30243X0, 30243Y0  Percutaneous transfusion, central vein, bone marrow or stem cells, autologous, code list 
   30243G1, 30243X1, 30243Y1  Percutaneous transfusion, central vein, bone marrow or stem cells, nonautologous, code list 
   07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ  Surgical, lymphatic and hemic systems, extraction, bone marrow, code list 
Type of Service  Therapy 
Place of Service  Inpatient/Outpatient 


Autoimmune Diseases, High-Dose Chemotherapy/Stem-Cell Rescue
High-Dose Chemotherapy, Autoimmune Diseases
Lupus (SLE), Autologous Stem Cell Transplant
Multiple Sclerosis, Autologous Stem Cell Transplant
Rheumatoid Arthritis, Autologous Stem Cell Transplant
SLE, Autologous Stem Cell Transplant
Systemic Sclerosis, Autologous Stem Cell Transplant

Policy History

Date Action Reason
12/01/99 Add to Therapy section New policy
08/18/00 Replace policy Policy statement revised to state that allogeneic transplant after a prior failed autotransplant is considered investigational, based on 2000 TEC Assessment
02/15/02 Replace policy Policy updated based on 2002 TEC Assessment; policy statement unchanged
12/18/02 Replace policy Update CPT codes only
07/15/04 Replace policy Updated with MEDLINE literature review for the period of 2002 through May 2004; policy statement unchanged
06/27/05 Replace policy Literature review update for the period of May 2004 through May 2005; no clinical trial information found. Policy statement unchanged
04/25/06 Replace policy Literature review update; references added; no changes to policy statement
09/18/07 Replace policy Literature review update; references 10–14 added; no changes to policy statement.
09/11/08 Replace policy Policy reviewed with literature search; Description revised extensively; “high-dose chemotherapy” removed from policy title and policy statements. “Stem-cell transplantation” (SCT) now used instead of “stem-cell support” (SCS) in policy and policy statements. Intent of current policy statements unchanged. References 1-3 added
09/10/09 Replace policy Policy updated with literature search; references 12 and 13 added. Minor wording changes to policy statement; however, intent remains unchanged.
9/16/10 Replace policy Policy updated and extensively revised with literature search; reference numbers 5–12, 14–18, and 20 and 21 added. Added indications of juvenile idiopathic arthritis and diabetes mellitus to policy statement as investigational
09/01/11 Replace policy Policy updated with literature search; reference numbers 8, 16 and 17 added; references renumbered. Policy statements unchanged
9/13/12 Replace policy Policy updated with literature search; reference numbers 15-18 and 25 added; references renumbered. Policy statements unchanged