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

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. (4,5)

2006 Update

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 U.S. (6) Between April 1997 through January 2005, they enrolled 50 patients (mean age 30 +/- 10.9 years [SD], 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/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 [5]) improved, including renal function, SLE disease activity index (DAI) score, antinuclear antibody, anti-ds DNA, complement, and CO diffusion lung capacity. The investigators suggest these results justify a randomized trial comparing immunosuppression plus autologous SCT versus continued standard of care.

An editorial by Petri and Brodsky (7) 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.

At the time of this update, one Phase III randomized, open-label, active controlled clinical trial, “Scleroderma: Cyclophosphamide or Transplantation” (SCOT, NCT00114530, NIAID No. SCSSc-01) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) was recruiting patients in the U.S. Two other NIAID-sponsored Phase II trials were planned but not yet open for patient recruitment. The first was a randomized, active control, open-label trial, Lupus Immunosuppressive/Immunomodulatory Therapy or Stem Cell Transplant (LIST, NCT00230035, NIAID No. SCSLE-01). The second was 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 were 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 had been completed, longer-term follow-up is needed before conclusions can be reached from study findings. Therefore, the policy statement was unchanged.

2007 Update
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. (8) 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 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. (9-11)

A review article on randomized trials of autologous SCT for autoimmune diseases discusses the relative merits of lymphoablative versus myeloablative stem cell transplantation regimens, concurring that randomized, controlled trials are needed to confirm benefits observed with this therapy in case reports and uncontrolled series. (3) The randomized trials outlined in the 2006 update to this policy remain in progress. The policy statement is unchanged.

2008 Update

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 at the time of this update was 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 was unchanged.

2009 Update

An updated literature search performed in August 2009 revealed no completed randomized clinical trials that would alter the policy statement.

Recent review articles (12-13) summarize the experience to date with autologous and allogeneic HSCT in autoimmune diseases. Although recent case reports and small series have shown that HSCT is able to induce high rates of sustained remissions in many severe autoimmune diseases that are unresponsive to conventional therapies, these review articles stress the importance of carefully conducted prospective trials and state that evidence-based indications for these procedures can only be issued after the completion of ongoing prospective, comparative trials.

The review article from Tyndall (12) summarizes the experience with HSCT and autoimmune diseases since this technique was first applied for this indication in 1996. Since that time, over 1,500 patients with severe autoimmune disorders have undergone HSCT (mostly autologous and in the context of Phase I/II controlled trials). Of these patients, approximately one-third have experienced sustained, drug-free remissions, and the others did not respond, worsened, or died of treatment-related mortality. From the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR) database, up to March 2008, nearly 1,000 patients received an HSCT for an autoimmune disease as follows: multiple sclerosis (n =353), systemic sclerosis (n =176), systemic lupus erythematosus (n =85), rheumatoid arthritis (n =86) and other diseases in fewer patients. The authors state that the most meaningful data have been obtained for multiple sclerosis, systemic sclerosis, and systemic lupus erythematosus, as discussed in the following text.

In a review of 400 cases of multiple sclerosis, 60 –70% of patients who underwent HSCT had a 3-year progression-free survival, and that transplant-related mortality had been reduced from 5% to 1–2% in the past 5 years. Two prospective trials are in progress, one in the U.S. and one in Europe. For systemic sclerosis, transplant-related mortality has dropped in recent years from 12.5% to 8.5%. In a recent series of 26 patients who underwent HSCT, 81% demonstrated a clinically beneficial response, with event-free survival (defined as survival without mortality, relapse or progression resulting in major organ dysfunction) of 64.3% (95% confidence interval [CI] 47.9 –86%) at 5 years and 57.1% (95% CI: 39.3 –83%) at 7 years. Reversal of fibrosis and improved microvascularization has been observed with HSCT. The results of 2 Phase III trials for HSCT and scleroderma (ASTIS and SCOT) are awaited.

For systemic lupus erythematosus, outcomes from Phase I/II studies have been reported, one of which has been discussed previously in this policy. (6)

The review article by Saccardi summarizes the experience thus far with juvenile idiopathic and rheumatoid arthritis as follows. (13) 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. A new retrospective analysis is ongoing on behalf of the Autoimmune Diseases, Pediatric and Inborn Error EBMT Working Parties. 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.

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. (12)

Summary

No Phase III trials have been published, and the policy statement remains unchanged. At this time the effect on net health outcome is uncertain.

References:

1. Nikolov NP, Pavletic SZ. Technology insight: hematopoietic stem cell transplantation for systemic rheumatic disease. Nat Clin Pract Rheumatol 2008; 4(4):184-91.
2. Passweg J, Tyndall A. Autologous stem cell-transplantation in autoimmune diseases. Semin Hematol 2007; 44(4):278-85.
3. Burt RK, Marmont A, Oyama Y et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum 2006; 54(12):3750-60.
4. 2000 TEC Assessments; Tab 1.
5. 2001 TEC Assessments; Tab 14.
6. Burt RK, Traynor A, Statkute L et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 2006; 295(5):527-35.
7. Petri M, Brodsky R. High-dose cyclophosphamide and stem cell transplantation for refractory systemic lupus erythematosus. JAMA 2006; 295(5):559-60.
8. Saccardi R, Kozak T, Bocelli-Tyndall C et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler 2006; 12(6):814-23.
9. Illei GG. Hematopoietic stem cell transplantation in autoimmune diseases: is the glass half full of half empty? Arthritis Rheum 2006; 54(12):3730-4.
10. Martin R. Is haematopoietic stem cell transplantation a treatment option for severe MS or not? Brain 2007; 130(pt 5):1181-2.
11. Scolding N. Stem cell therapy in patients with multiple sclerosis. Mult Scler 2006; 12(6):677-8.
12. Tyndall A, Gratwohl A. Adult stem cell transplantation in autoimmune disease. Curr Opin Hematol 2009; 16(4):285-91.
13. Saccardi R, Di Gioia M, Bosi A. Haematopoietic stem cell transplantation for autoimmune disorders. Curr Opin Hematol 2008; 15(6):594-600.