High dose chemotherapy with allogeneic or autologous stem cell support for the treatment of autoimmune diseases, including but not limited to arthritis, SLE and systemic sclerosis (scleroderma) does not meet primary coverage criteria for effectiveness.

 

For contracts without primary coverage criteria language, high dose chemotherapy with allogeneic or autologous stem cell support for the treatment of autoimmune diseases, including but not limited to arthritis, SLE and systemic sclerosis (scleroderma) is considered investigational and is not covered.  Investigational services are an exclusion in the member certificate of coverage.

 

Tandem transplants are not covered based on a specific exclusion in the member benefit contract.

 

Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is not covered.

An updated literature search performed in February 2006 revealed no evidence from randomized clinical trials that would alter the policy statement. However, Burt and colleagues recently published the results of the largest single-center series available in the United States.  Between April 1997 through January 2005, they enrolled 50 patients (mean age 30 +/- 10.9 years [SD], 43 women, 7 men) with systemic lupus erythematosus (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/d of prednisone or its equivalent despite 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 Assessment ) 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.

 

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

 

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

 

An updated literature search performed in July 2007 revealed no evidence from randomized, clinical trials that would alter the policy statement.

 

The European Group for Blood and Marrow Transplantation (EBMT) autoimmune diseases working party database reported new data from a retrospective survey of 178 patients with MS who underwent autologous SCT following one of several different preparative regimens.  Overall, at median follow-up of about 42 months, the disease remained stable or improved in 63% of cases and worsened in 37%. Autologous SCT was associated with significantly better progression-free survival in a subset of younger patients (i.e., younger than 40 years of age) affected by severe, progressive multiple sclerosis (MS) who received autologous SCT within 5 years from diagnosis compared to those older than 40 years. The authors suggest that autologous SCT could be considered after failure of conventional treatments in patients with rapidly progressing MS. However, they caution that the role of autologous SCT in the treatment of refractory MS needs to be established through prospective randomized, controlled trials. Several editorials concur with the view that the role of autologous SCT is not established in MS or other autoimmune diseases.  

 

A review article on randomized trials of autologous SCT for autoimmune diseases discusses the relative merits of lymphoablative versus myeloablative SCT regimens, concurring that randomized, controlled trials are needed to confirm benefits observed with this therapy in case reports and uncontrolled series.  The randomized trials outlined in the 2006 update to this policy remain in progress. The policy statement is unchanged.

 

The trials outlined in the 2006 update in this policy remain in progress, with the exception of the LIST study (NCT00230035, NIAID No. SCSLE-01), which was terminated due to lack of accrual.

 

An additional study recruiting patients is a phase II/III randomized, open-label multicenter study of high-dose immunosuppressive therapy followed by autologous SCT versus high-dose pulse cyclophosphamide in patients with severe systemic sclerosis (NCT00545038).

 

Therefore, the policy statement is unchanged.

 

Currently, multiple sclerosis is the most common autoimmune disease for which autologous HSCT is being studied (Pasquini, 2010).  Following initial promising clinical experience, more than 350 consecutive cases have been reported by the EBMT over the last decade (Pasquini, 2010).  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 (Pasquini, 2010). 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(Pasquini, 2010).  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 recent review summarizes the experience with HSCT and MS (Atkins, 2010).  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 (Fagius, 2009) (Kimiskidis, 2008) (Mancardi. 2005).  These patients had persistent disease activity despite numerous different treatments. All but one patient 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 (Atkins, 2010).  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 progression-free survival 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 (Burt, 2009).  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 (Saccardi, 2006).  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 progression-free survival 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.

 

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 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 2012 (NCT00273364).

 

The Phase II randomized ASTIMS trial mentioned in an earlier update was terminated due to difficulty in accruing patients and lack of funds.

 

The HALT-MS Study (mentioned in an earlier update) is ongoing. Estimated enrollment is 25, and estimated study completion date is January 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.

 

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 (Vonk, 2008).  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), 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 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% confidence interval [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% (Ioannidis, 2005).

 

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 (Nash, 2007).  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 less than 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 and progression-free survival were both 64% at 5 years.

 

Clinical Trials

 

ASTIS is a Phase III randomized, international, multicenter trial. A total of 155 patients with diffuse systemic sclerosis will be randomized to high-dose immunoablation and autologous HSCT or pulsed cyclophosphamide. Outcome measures include survival and prevention of major organ failure, safety, and quality of life. As of September 2009, 151 patients had been accrued .

 

A Phase II randomized, open-label study is recruiting patients with systemic scleroderma to undergo either autologous peripheral blood HSCT or receive pulsed cyclophosphamide. Primary outcome measures are time to treatment failure and improvement in skin score of at least 25% or a 10% improvement in lung function or in cardiac tests. Estimated enrollment is 60, with an estimated study completion date of September 2012 (NCT00278525).

 

The SCOT trial (mentioned in an earlier update) is ongoing.  Estimated enrollment is 114 patients with an estimated study completion date of June 2016 (NCT00114530).

 

 

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. (Burt, 2006)  Between April 1997 through January 2005, they enrolled 50 patients (mean age: 30 [standard deviation: +/- 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.

 

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 50 and study completion date of May 2008 (NCT00271934).

 

A review article by Saccardi et al. summarizes the experience thus far with juvenile idiopathic and rheumatoid arthritis as follows (Saccardi, 2008): More than 50 patients with juvenile idiopathic arthritis have been reported to the EBMT Registry. The largest cohort study initially used 1 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 rheumatoid arthritis 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 on ClinicalTrials.gov using HSCT in juvenile idiopathic or rheumatoid arthritis.

 

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 (Couri, 2009).  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 (Couri, 2009).  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 less than 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

 

Two Phase I/II and one Phase II trials are recruiting patients with type 1 diabetes mellitus for autologous HSCT (NCT00315133, NCT01121029, NCT00807651). One Phase II and one Phase II/III trial are ongoing or recruiting patients with type 2 diabetes mellitus for autologous HSCT (NCT00644241, NCT01065298).

 

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 (Tyndall, 2009).

 

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.