MEDICAL POLICY

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APPENDIX
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Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases

Number 8.01.25

Effective Date December 17, 2014

Revision Date(s) 12/08/14; 12/09/13; 11/13/12; 10/11/11; 12/14/10; 11/10/09; 11/11/08; 12/11/07; 07/11/06; 08/09/05; 10/12/04; 08/12/03; 06/17/03; 05/14/2002; 12/21/00; 02/01/00

Replaces N/A

Policy

Autologous or allogeneic hematopoietic stem-cell transplantation is considered investigational as a treatment of autoimmune diseases, including, but not limited to , the following: multiple sclerosisjuvenile idiopathic and rheumatoid arthritissystemic lupus erythematosussystemic sclerosis/sclerodermatype 1 diabetes mellituschronic inflammatory demyelinating polyneuropathy.

Related Policies

7.01.50

Placental and Umbilical Cord Blood as a Source of Stem Cells

8.01.21

Allogeneic Hematopoietic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

8.01.22

Allogeneic Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias

8.01.23

Hematopoietic Stem-Cell Transplantation for Epithelial Ovarian Cancer

8.01.24

Hematopoietic Stem-Cell Transplantation for Miscellaneous Solid Tumors in Adults

8.01.26

Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia

8.01.27

Hematopoietic Stem-Cell Transplantation for Breast Cancer

8.01.28

Hematopoietic Stem-Cell Transplantation for CNS Embryonal Tumors and Ependymoma

8.01.29

Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma

8.01.30

Hematopoietic Stem-Cell Transplantation for Treatment of Chronic Myelogenous Leukemia

8.01.511

Hematopoietic Stem-Cell Transplantation for Solid Tumors of Childhood

8.01.520

Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia

8.01.529

Hematopoietic Stem-Cell Transplantation for Non-Hodgkin Lymphomas

8.01.530

Hematopoietic Stem-Cell Transplantation for Primary Amyloidosis

8.01.532

Hematopoietic Stem-Cell Transplantation in the Treatment of Germ Cell Tumors

8.02.02

Plasma Exchange

Policy Guidelines

Coding

CPT

38208

Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing, per donor

38209

Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, with washing, per donor

38210

Transplant preparation of hematopoietic progenitor cells; specific cell depletion within harvest, T-cell depletion

38211

Transplant preparation of hematopoietic progenitor cells; tumor cell depletion

38212

Transplant preparation of hematopoietic progenitor cells; red blood cell removal

38213

Transplant preparation of hematopoietic progenitor cells; platelet depletion

38214

Transplant preparation of hematopoietic progenitor cells; plasma (volume) depletion

38215

Transplant preparation of hematopoietic progenitor cells; cell concentration in plasma, mononuclear, or buffy coat layer

Description

Most patients with autoimmune disorders respond to conventional therapies. 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).

Autoimmune Diseases

Autoimmune diseases represent a heterogeneous group of immune-mediated disorders, including MS, rheumatoid arthritis (RA), SLE, systemic sclerosis/scleroderma, and chronic immune demyelinating polyneuropathy (CIDP). The National Institutes of Health (NIH) estimates that 5% to 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, scleroderma). Most patients with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immune-modulating 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 HSCT. The primary concept underlying use of HSCT for these diseases is that ablating and “resetting” the immune system can alter the disease process, first inducing a sustained remission that possibly leads to cure.1

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 wholebody 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). Cord blood is discussed in greater detail in a separate medical policy. (See Related Policies)

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 (lymphoablation) and generate new self-tolerant lymphocytes. (2) This approach is in contrast to destroying the entire hematopoietic bone marrow (myeloablation), 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 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

Regulatory Status

Hematopoietic Stem-Cell Transplantation is not a U.S. Food and Drug Administration (FDA)-regulated procedure.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

N/A

Rationale

This policy was created in December 1999, and has been updated regularly with reviews of the MEDLINE database. The most recent literature review was performed for the period August 31, 2013 through September 15, 2014.

Recent reviews summarize the experience to date with hematopoietic stem-cell transplantation (HSCT) and a number of autoimmune diseases. (3,4)

As of March 2009, patients with an autoimmune disease registered in the European Group for Blood and Marrow Transplantation/European League Against Rheumatism (EBMT/EULAR) database who have undergone HSCT include a total of 1,031 with the clinical indications of multiple sclerosis (MS) (n=379), systemic sclerosis (n=207), systemic lupus erythematosus (SLE) (n=92), rheumatoid arthritis (RA) (n=88), juvenile idiopathic arthritis (n=70), idiopathic thrombocytopenic purpura (n=23), and Crohn disease (n=23). (4)

MS

MS is the most common autoimmune disease for which autologous HSCT is being studied. (5) Following initial promising clinical experience, more than 350 consecutive cases have been reported by the EBMT over the last decade. (5) 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 to 9.5 at the time of HSCT. (5) 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 to 2007. (5) 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 systematic review published in 2011 evaluated the safety and efficacy of autologous HSCT in patients with progressive MS refractory to conventional medical treatment. (6) Eight case series were included that met the inclusion criteria for the primary outcome of progression-free survival (PFS) with a median follow-up of at least 2 years. An additional 6 studies were included for a summary of mortality and morbidity. For the 8 case series, there was substantial heterogeneity across studies. Most 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% 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 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 review published in 2010 summarizes the experience with HSCT and MS. (7) 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. (8-10) 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.

Most 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. (7) 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% to 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 et al. have transplanted 21 patients with relapsing-remitting MS with ongoing relapses during treatment with interferon. (11) 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 scores.

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. (12) 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., <40 years old) affected by severe, progressive MS who received autologous HSCT within 5 years from diagnosis compared with 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 et al. 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. (13) 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 to 22) and 2 years (0-6). 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. 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 et al. 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. (14) 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 most quality-of-life parameters (p<0.05).

Mancardi et al. 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. (15) 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 of 25 subjects with a relapsing-remitting course (31%) had a 6 to 12 months confirmed Expanded Disability Status Scale improvement greater than 1 point after HSCT, compared with 1 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 et al. 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 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 to 0.75). Five patients had an EDSS at baseline of 6.0 or less; 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.

Systemic Sclerosis/Scleroderma

A recent review summarized the clinical studies that have been performed using conventional therapy, as well as those using autologous HSCT in the treatment of systemic sclerosis. (17) Ongoing randomized trials are also discussed.

The results of the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial (ISRCTN54371254) were published in June 2014. (18) ASTIS was a Phase III randomized controlled trial (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. Individual patients were eligible if they were between 18 and 65 years of age; had diffuse cutaneous systemic sclerosis according to American Rheumatism Association criteria, with maximum duration of 4 years; minimum modified Rodnan skin score (mRSS) of 15 (range, 0-51 with higher scores indicating more sever skin thickening); and, involvement of heart, lungs, or kidneys. Patients were randomly allocated to receive high-dose chemotherapy (intravenous cyclophosphamide 200 mk/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, 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 mRSS, organ function, body weight, and quality-of-life scores. The internal validity (risk of bias) of ASTIS was assessed according to the United States Preventive Services Task Force (USPSTF) criteria for randomized trials. The study was rated as “poor” quality according to this framework because it has 2 fatal flaws: outcome assessment was not masked to patients or assessors, and 18 of 75 (24%) of the control group discontinued intervention because of death, major organ failure, adverse events, or nonadherence. Furthermore, the article states that crossover was allowed after the second year, but whether any patients did so and were analyzed as such is not mentioned. Finally, the authors report 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.

A total of 53 primary end point events were recorded: 22 in the HSCT group (19 deaths and 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 in the control group (23 deaths and 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 show patients treated with HSCT experienced more events in the first year but appeared to have better long-term event-free survival than the controls, as the Kaplan-Meier curves for overall survival (OS) cross at about 2 years after treatment with OS at that time estimated at 85%. According to data from the Kaplan-Meier curves, at 5 years, OS was an estimated 66% in the control group and about 80% the HSCT group (p value unknown). Time-varying hazard ratios (modeled with treatment x time interaction) for event-free survival were 0.35 (95% CI: 0.15-0.74) at 2 years and 0.34 (95% CI: 0.16-0.74) at 4 years, supporting a benefit of HSCT versus pulsed cyclophosphamide. Severe or life-threatening grade 3 or 4 adverse events were reported in 51 (63%) of the HSCT group compared with 30 (37% by intention-to-treat, p=0.002).

An open-label, randomized, controlled Phase II trial (ASSIST) assessed the safety and efficacy of autologous nonmyeloablative HSCT compared with the standard of care cyclophosphamide. (19) Nineteen consecutively enrolled patients who were younger than 60 years of age with diffuse systemic sclerosis, 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 of follow-up, compared with none of the 9 allocated to cyclophosphamide (p<0.001). Treatment failure (ie, disease progression without interval improvement), occurred in 8 of 9 controls, compared with none of the 10 patients treated by HSCT (p<0.001). 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 (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<0.001) and forced vital capacity (p<0.03) persisted.

Vonk et al. reported the long-term results of 28 patients with severe diffuse cutaneous systemic sclerosis who underwent autologous HSCT from 1998 to 2004.20 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., >25%) decrease (i.e., improvement) was achieved in 19 of 26 patients after 1 year and in 15 of 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 year 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 with 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 event-free survival, (survival without mortality, relapse, or progression of systemic sclerosis 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 systemic sclerosis at 40%.21

Nash et al. 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.22 Of the 34 patients, 79% survived 1 year and were evaluable for response (there were 8 transplant-related deaths and 4 systemic sclerosis-related deaths). Seventeen of the 27 (63%) evaluable patients had sustained responses at a median follow-up of 4 years (range, 1-8 years). Skin biopsies showed a statistically significant decrease in dermal fibrosis compared with baseline (p<0.001) and, in general, lung, heart, and kidney function remained stable. Overall function as assessed in 25 patients by the modified Health Assessment Questionnaire Disability Index showed improvement in 19, and disease response was observed in the skin of 23 of 25 and lungs of 8 of 27 patients. Estimated OS and progression-free survival (PFS) were both 64% at 5 years.

Henes et al. reported on their experience with autologous HSCT for systemic sclerosis in 26 consecutive patients scheduled for HSCT between 1997 and 2009.23 The major outcome variable was the response to treatment (reduction of mRSS by 25%) at 6 months. Secondary end points were TRM 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.

SLE

Burt et al published the results of the largest single-center series of this treatment in SLE available in the United States. (24) Between April 1997 through January 2005, they enrolled 50 patients (mean age, 30 years, SD=10.9; 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) 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 et al. 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 progression-free survival (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 82.49.2% and 64.711.6%, 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.

Juvenile Arthritis

A review article by Saccardi et al. summarizes the experience thus far with juvenile idiopathic and RA as follows25: 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.

Chronic Inflammatory Demyelinating Polyneuropathy

Several review articles have summarized experience with HSCT in treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). (26-28) In general, evidence comprises a few case reports describing outcomes of autologous HSCT in patients who failed standard treatments such as corticosteroids, intravenous immunoglobulins, and plasma exchange.

Type 1 Diabetes Mellitus

Couri et al. 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. (29) Enrollment was November 2003 to 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 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, HbA1c levels were less than 7.0% and mean area under the curve (AUC) C-peptide levels increased significantly from 225.0 (SE=75.2) ng/mL per 2 hours pretransplantation to 785.4 (SE=90.3) ng/mL per 2 hours at 24 months posttransplantation (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.

Other Autoimmune Diseases

Phase II/III protocols are being developed for Crohn disease. 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. (30)

Ongoing and Unpublished Clinical Trials

A review of online site ClinicalTrials.gov in September 2014 (and prior years) identified the following clinical studies in progress.

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 end point is disease progression. Patients will be followed for 5 years after randomization. Estimated enrollment is 110, and estimated study completion date is December 2017 (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.

The High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) Study is a Phase 2 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.

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 postrandomization (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). As of September 2014, SCOT has not been published in full-length form.

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 October 2013 (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).

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

One nonrandomized, Phase II clinical trial is recruiting patients to study nonmyeloablative autologous HSCT in patients with CIDP (NCT00278629). It is estimated the study will be complete in December 2014.

Three Phase I/II and 2 Phase II trials are recruiting patients with type 1 diabetes mellitus for autologous HSCT (NCT00315133, NCT01121029, NCT00807651, NCT01341899, NCT01285934). The status of 1 Phase II and 1 Phase II/III trial for patients with type 2 diabetes mellitus for autologous HSCT is unknown. (NCT00644241, NCT01065298).

Clinical Input Received from Physician Specialty Societies and Academic Medical Centers

None.

Summary of Evidence

Initial studies focused on using hematopoietic stem-cell transplantation (HSCT) as salvage therapy for 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, systemic lupus erythematosus [SLE], and multiple sclerosis [MS]) the impact of HSCT in selected autoimmune diseases.

The results of the ASTIS trial suggest high-dose chemotherapy with autologous HSCT may improve survival among patients with diffuse cutaneous systemic sclerosis compared with pulsed intravenous cyclophosphamide. However, analysis of the internal validity of the trial using USPSTF 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 compared with controls. The investigators acknowledge this limitation in addition to stating that the unblinded outcome assessments may have influenced results, and wide confidence intervals for some secondary outcomes indicated less certainty about those results. An accompanying editorial concurs that autologous HSCT to treat systemic sclerosis requires further study before it should be offered to patients in routine clinical practice.31

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 with 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.

Practice Guidelines and Position Statements

A review of the guidelines from the American Academy of Neurology and the American College of Rheumatology did not find the mention of stem-cell transplantation in guidelines for MS, lupus, RA, or juvenile arthritis. No pertinent guidelines for autologous stem-cell transplantation for autoimmune diseases were identified.

U.S. Preventive Services Task Force Recommendations

Stem cell transplantation is not a preventive service.

Medicare National Coverage

There are numerous autoimmune diseases and the Centers for Medicare and Medicaid Services have not issued a national coverage determination (NCD) for stem cell transplantation for each individual disease. A general NCD for stem cell transplantation (110.8.1) states the following:

“Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

Item/Service Description

A. General

Stem-cell transplantation is a process in which stem cells are harvested from either a patient’s (autologous) or donor’s (allogeneic) bone marrow or peripheral blood for intravenous infusion. Autologous stem cell transplants (AuSCT) must be used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies. Allogeneic stem-cell transplants may be used to restore function in recipients having an inherited or acquired deficiency or defect. Hematopoietic stem cells are multi-potent stem cells that give rise to all the blood cell types; these stem cells form blood and immune cells. A hematopoietic stem cell is a cell isolated from blood or bone marrow that can renew itself, differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosis - a process by which cells that are unneeded or detrimental self-destruct.

The Centers for Medicare & Medicaid Services (CMS) is clarifying that bone marrow and peripheral blood stem-cell transplantation is a process which includes mobilization, harvesting, and transplant of bone marrow or peripheral blood stem cells and the administration of high-dose chemotherapy or radiotherapy prior to the actual transplant. When bone marrow or peripheral blood stem-cell transplantation is covered, all necessary steps are included in coverage. When bone marrow or peripheral blood stem-cell transplantation is noncovered, none of the steps are covered.

Indications and Limitations of Coverage

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure in which a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion.

  1. Nationally Covered Indications

The following uses of allogeneic HSCT are covered under Medicare:

  1. Effective for services performed on or after August 1, 1978, for the treatment of leukemia, leukemia in remission, or aplastic anemia when it is reasonable and necessary,
  2. Effective for services performed on or after June 3, 1985, for the treatment of severe combined immunodeficiency disease (SCID) and for the treatment of Wiskott-Aldrich syndrome.
  3. Effective for services performed on or after August 4, 2010, for the treatment of Myelodysplastic Syndromes (MDS) pursuant to Coverage with Evidence Development (CED) in the context of a Medicare-approved, prospective clinical study.

The MDS refers to a group of diverse blood disorders in which the bone marrow does not produce enough healthy, functioning blood cells. These disorders are varied with regard to clinical characteristics, cytologic and pathologic features, and cytogenetics. The abnormal production of blood cells in the bone marrow leads to low blood cell counts, referred to as cytopenias, which are a hallmark feature of MDS along with a dysplastic and hypercellular-appearing bone marrow.

Medicare payment for these beneficiaries will be restricted to patients enrolled in an approved clinical study. In accordance with the Stem Cell Therapeutic and Research Act of 2005 (US Public Law 109-129) a standard dataset is collected for all allogeneic transplant patients in the United States by the Center for International Blood and Marrow Transplant Research. The elements in this dataset, comprised of two mandatory forms plus one additional form, encompass the information we require for a study under CED.

A prospective clinical study seeking Medicare payment for treating a beneficiary with allogeneic HSCT for MDS pursuant to CED must meet one or more aspects of the following questions:

  • Prospectively, compared to Medicare beneficiaries with MDS who do not receive HSCT, do Medicare beneficiaries with MDS who receive HSCT have improved outcomes as indicated by:
  • Relapse-free mortality,
  • Progression-free survival,
  • Relapse, and
  • Overall survival?
  • Prospectively, in Medicare beneficiaries with MDS who receive HSCT, how do International Prognostic Scoring System (IPSS) score, patient age, cytopenias and comorbidities predict the following outcomes:
  • Relapse-free mortality,
  • Progression-free survival,
  • Relapse, and
  • Overall survival?
  • Prospectively, in Medicare beneficiaries with MDS who receive HSCT, what treatment facility characteristics predict meaningful clinical improvement in the following outcomes:
  • Relapse-free mortality,
  • Progression-free survival,
  • Relapse, and
  • Overall survival?

In addition, the clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:

  1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.
  2. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
  3. The research study does not unjustifiably duplicate existing studies.
  4. The research study design is appropriate to answer the research question being asked in the study.
  5. The research study is sponsored by an organization or individual capable of executing the proposed study successfully.
  6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46.
  7. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org).
  8. The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage.
  9. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
  10. The clinical research study is registered on the ClinicalTrials.gov Web site by the principal sponsor/investigator prior to the enrollment of the first study subject.
  11. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than 3 years after the end of data collection.
  12. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
  13. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

Consistent with section 1142 of the Social Security Act, the Agency for Health Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

The clinical research study should also have the following features:

  • It should be a prospective, longitudinal study with clinical information from the period before HSCT and short- and long-term follow-up information.
  • Outcomes should be measured and compared among pre-specified subgroups within the cohort.
  • The study should be powered to make inferences in subgroup analyses.
  • Risk stratification methods should be used to control for selection bias. Data elements to be used in risk stratification models should include:
  • Patient selection:
  • Patient age at diagnosis of MDS and at transplantation
  • Date of onset of MDS
  • Disease classification (specific MDS subtype at diagnosis prior to preparative/conditioning regimen using World Health Organization (WHO) classifications). Include presence/absence of refractory cytopenias
  • Comorbid conditions
  • IPSS score (and WHO-adapted Prognostic Scoring System (WPSS) score, if applicable) at diagnosis and prior to transplantation
  • Score immediately prior to transplantation and one year post-transplantation
  • Disease assessment at diagnosis at start of preparative regimen and last assessment prior to preparative regimen Subtype of MDS (refractory anemia with or without blasts, degree of blasts, etc.)
  • Type of preparative/conditioning regimen administered (myeloabalative, non-myeloablative, reduced–intensity conditioning)
  • Donor type
  • Cell source
  • IPSS Score at diagnosis

Facilities must submit the required transplant essential data to the Stem-Cell Therapeutics Outcomes Database.

Nationally Non-Covered Indications

Effective for services performed on or after May 24, 1996, allogeneic HSCT is not covered as treatment for multiple myeloma.

Autologous Stem-Cell Transplantation (AuSCT)

Autologous stem cell transplantation (AuSCT) is a technique for restoring stem cells using the patient's own previously stored cells.

Nationally Covered Indications

  1. Effective for services performed on or after April 28, 1989, AuSCT is considered reasonable and necessary under §l862(a)(1)(A) of the Social Security Act (the Act) for the following conditions and is covered under Medicare for patients with:
  • Acute leukemia in remission who have a high probability of relapse and who have no human leucocyte antigens (HLA)-matched;
  • Resistant non-Hodgkin's lymphomas or those presenting with poor prognostic features following an initial response;
  • Recurrent or refractory neuroblastoma; or
  • Advanced Hodgkin's disease who have failed conventional therapy and have no HLA-matched donor.
  1. Effective October 1, 2000, single AuSCT is only covered for Durie-Salmon Stage II or III patients that fit the following requirements:
  • Newly diagnosed or responsive multiple myeloma. This includes those patients with previously untreated disease, those with at least a partial response to prior chemotherapy (defined as a 50% decrease either in measurable paraprotein [serum and/or urine] or in bone marrow infiltration, sustained for at least 1 month), and those in responsive relapse; and,
  • Adequate cardiac, renal, pulmonary, and hepatic function.
  1. Effective for services performed on or after March 15, 2005, when recognized clinical risk factors are employed to select patients for transplantation, high-dose melphalan (HDM) together with AuSCT is reasonable and necessary for Medicare beneficiaries of any age group with primary amyloid light chain (AL) amyloidosis who meet the following criteria:
  • Amyloid deposition in 2 or fewer organs; and,
  • Cardiac left ventricular ejection fraction (EF) greater than 45%.

Nationally Non-Covered Indications

Insufficient data exist to establish definite conclusions regarding the efficacy of AuSCT for the following conditions:

  • Acute leukemia not in remission;
  • Chronic granulocytic leukemia;
  • Solid tumors (other than neuroblastoma);
  • Up to October 1, 2000, multiple myeloma;
  • Tandem transplantation (multiple rounds of AuSCT) for patients with multiple myeloma;
  • Effective October 1, 2000, non primary AL amyloidosis; and,
  • Effective October 1, 2000, thru March 14, 2005, primary AL amyloidosis for Medicare beneficiaries age 64 or older.

In these cases, AuSCT is not considered reasonable and necessary within the meaning of §l862(a)(1)(A) of the Act and is not covered under Medicare.

Other

All other indications for stem cell transplantation not otherwise noted above as covered or non-covered nationally remain at Medicare Administrative Contractor discretion.

(This NCD last reviewed August 2010.).

References

  1. Nikolov NP, Pavletic SZ. Technology insight: hematopoietic stem cell transplantation for systemic rheumatic disease. Nat Clin Pract Rheumatol. 2008; 4(4):184-191. PMID
  2. 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):3750-3760. PMID
  3. Milanetti F, Abinun M, Voltarelli JC, et al. Autologous hematopoietic stem cell transplantation for childhood autoimmune disease. Pediatr Clin North Am. 2010; 57(1):239-271. PMID
  4. Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United States. Biol Blood Marrow Transplant. 2010; 16(1 suppl):S48-56. PMID
  5. Pasquini MC, Griffith LM, Arnold DL, et al. Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies. Biol Blood Marrow Transplant. 2010; 16(8):1076-1083. PMID
  6. Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler. 2011; 17(2):204-213. PMID
  7. Atkins H. Hematopoietic SCT for the treatment of multiple sclerosis. Bone Marrow Transplant. 2010; 45(12):1671-1681. PMID
  8. Fagius J, Lundgren J, Oberg G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler. 2009; 15(2):229–237. PMID
  9. Kimiskidis V, Sakellari I, Tsimourtou V, et al. Autologous stem-cell transplantation in malignant multiple sclerosis: a case with a favorable long-term outcome. Mult Scler. 2008; 14(2):278–283. PMID
  10. Mancardi GL, Murialdo A, Rossi P, et al. Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis. Mult Scler. 2005; 11(3):367–371. PMID
  11. Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative haematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009; 8(3): 244–253. PMID
  12. 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):814-823. PMID
  13. Fassas A, Kimiskidis VK, Sakellari I, et al. Long-term results of stem cell transplantation for MS: a single-center experience. Neurology. Mar 22 2011; 76(12):1066-1070. PMID 21422458
  14. Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. Jul 4 2012. PMID 22771495
  15. Mancardi GL, Sormani MP, Di Gioia M, et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult Scler. Jun 2012; 18(6):835-842. PMID 22127896
  16. Bowen JD, Kraft GH, Wundes A, et al. Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results. Bone Marrow Transplant. Jul 2012; 47(7):946-951. PMID 22056644
  17. 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. PMID
  18. van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. Jun 25 2014;311(24):2490-2498. PMID 25058083
  19. 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. PMID
  20. 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. PMID
  21. Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, et al. Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med. 2005; 118(1):2–10. PMID
  22. Nash RA, McSweeney PA, Crofford LJ, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007; 110(4):1388-1396. PMID
  23. Henes JC, Schmalzing M, Vogel W, et al. Optimization of autologous stem cell transplantation for systemic sclerosis -- a single-center longterm experience in 26 patients with severe organ manifestations. J Rheumatol. Feb 2012; 39(2):269-275. PMID 22247352
  24. Burt RK, Traynor A, Statkute L, et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. 2006; 295(5):527-535. PMID
  25. Saccardi R, Di GM, Bosi A. Haematopoietic stem cell transplantation for autoimmune disorders. Curr Opin Hematol. 2008; 15(6):594-600. PMID
  26. Kazmi MA, Mahdi-Rogers M, Sanvito L. Chronic inflammatory demyelinating polyradiculoneuropathy: a role for haematopoietic stem cell transplantation? Autoimmunity. Dec 2008; 41(8):611-615. PMID 18958756
  27. Lehmann HC, Hughes RA, Hartung HP. Treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Handb Clin Neurol. 2013; 115:415-427. PMID 23931793
  28. Peltier AC, Donofrio PD. Chronic inflammatory demyelinating polyradiculoneuropathy: from bench to bedside. Semin Neurol. Jul 2012; 32(3):187-195. PMID 23117943
  29. 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):1573-1579. PMID
  30. Tyndall A, Gratwohl A. Adult stem cell transplantation in autoimmune disease. Curr Opin Hematol. 2009; 16(4):285-291. PMID
  31. Khanna D, Georges GE, Couriel DR. Autologous hematopoietic stem cell therapy in severe systemic sclerosis: ready for clinical practice? JAMA. Jun 25 2014;311(24):2485-2487. PMID 25058081

Coding

Codes

Number

Description

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

 

38207

Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage

 

38208

thawing of previously frozen harvest, without washing

 

38209

Thawing of previously frozen harvest, with washing

 

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

 

38230

Bone marrow harvesting for transplantation; allogeneic

 

38232

Bone marrow harvesting for transplantation; autologous

 

38240

Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic

 

38241

Bone marrow or blood-derived peripheral stem cell transplantation; autologous

 

38242

Allogeneic donor lymphocyte infusions

 

86825

Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); first serum sample or dilution

 

86826

Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); each additional serum sample or sample dilution (List separately in addition to primary procedure)

HCPCS

S2150

Bone marrow or blood-derived peripheral stem cell (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

Type of Service

Therapy

 

Place of Service

Inpatient / Outpatient

 

Appendix

N/A

History

Date

Reason

02/01/00

Add to Therapy Section - New Policy

12/21/00

Replace policy - Policy statement revised to state that allogeneic transplant after a prior failed autotransplant is considered investigational, based on 2000 TEC Assessment.

05/14/02

Replace policy - Policy updated based on 2002 TEC Assessment; policy statement unchanged.

06/17/03

Replace policy - Update CPT codes only.

8/12/03

Replace policy - Reviewed and recommended for adoption without any changes by Company Oncology Advisory Panel July 22, 2003.

10/12/04

Replace policy - Policy reviewed with literature search; no change to policy statement. Approved by OAP 10/29/04, no need to go back to MPC.

08/09/05

Replace policy - Policy reviewed with literature search; no clinical trial information found; policy statement unchanged.

07/11/06

Replace policy - Policy updated with literature review; references added; no changes to policy statement.

12/11/07

Replace policy - Policy updated with literature review; references added; no change in policy statement.

05/13/08

Cross Reference Update - No other changes

11/11/08

Replace policy - Policy updated with literature search. Minor change to the policy statement to align with new title. Hematopoietic and Transplantation added to the title and incorporated throughout the policy. References added.

11/10/09

Replace policy - Policy updated with literature search; “hematopoietic” added to the policy statement, intent unchanged. References added.

02/09/10

Code Update - New 2010 codes added.

12/14/10

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.

10/11/11

Replace policy – Policy updated with literature search; reference numbers 8, 16 and 17 added; references renumbered. Policy statements unchanged. ICD-10 codes added; codes 38220 and 38221 removed from policy.

01/24/12

Code 38232 added.

06/20/12

Minor update: Related Policies updated; 8.01.17 replaced 8.01.507 effective June 12, 2012.

07/30/12

Related policy updates to titles of 8.01.17,8.01.21, 8.01.26, 8.01.27, 8.01.29, 8.01.30, 8.01.31, 8.01.514, 8.01.520

11/27/12

Replace policy - Policy updated with literature search; reference numbers 15-18 and 25 added; references renumbered. Policy statements unchanged.

02/01/13

Update Related Policies, change title of policy 8.01.21.

03/20/13

The following codes were removed from the policy, as they were not suspending and just informational: HCPCS J9000-J999 and Q0083 – Q0085.

09/30/13

Update Related Policies. Change title to 8.01.31.

10/18/13

Update Related Policies. Change title to 8.01.17.

12/09/13

Replace policy. Policy updated with literature search through August 31, 2013; reference numbers 28-30 added. Chronic inflammatory demyelinating polyneuropathy added as an investigational indication.

03/11/14

Coding Update. Codes 41.06 and 41.08 were removed per ICD-10 mapping project; these codes are not utilized for adjudication of policy.

03/21/14

Update Related Policies. Delete 8.01.514.

04/18/14

Update Related Policies. Remove 8.01.20 and add 8.01.529.

06/24/14

Update Related Policies. Remove 8.01.35, 8.01.42, then add 8.01.530 and 8.01.532.

12/17/14

Annual Review. Policy updated with literature review through September 15, 2014; references 3-4 deleted and 18, 31 added. Policy statements unchanged. ICD-9 and ICD-10 diagnosis and procedure codes removed; these do not relate to policy adjudication.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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