Hematopoietic Stem Cell Transplantation for Autoimmune Diseases - CAM 80125HB

Description
Most patients with autoimmune disorders respond to conventional drug therapies; however, conventional drug therapies are not curative-and a proportion of patients suffer from autoimmune diseases that range from the severe to the recalcitrant to the rapidly progressive. It is in this group of patients with severe autoimmune disease that alternative therapies have been sought, including hematopoietic cell transplantation (HCT).

For individuals with multiple sclerosis who receive HCT, the evidence includes a randomized controlled trial (RCT) and several case series. The relevant outcomes are overall survival (OS), health status measures, quality of life (QOL), and treatment-related mortality (TRM) and morbidity. The phase 2 RCT compared HCT with mitoxantrone, and the trial reported intermediate outcomes (number of new T2 magnetic resonance imaging lesions); the group randomized to HCT developed significantly fewer lesions than the group receiving conventional therapy. The findings of the case series revealed improvements in clinical parameters following HCT compared with baseline. Adverse event rates were high, and most studies reported treatment-related deaths. Controlled trials (with appropriate comparator therapies) reporting on clinical outcomes are needed to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with systemic sclerosis/scleroderma who receive HCT, the evidence includes three RCTs and observational studies. The relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. All three RCTs compared cyclophosphamide conditioning plus autologous HCT with cyclophosphamide alone. Patients in the RCTs were adults < 60 years of age, maximum duration of disease of 5 years, with modified Rodnan skin scores > 15, and internal organ involvement. Patients with severe and irreversible organ involvement were excluded from the trials. Short-term results of the RCTs show higher rates of adverse events and TRM among patients receiving autologous HCT compared with patients receiving chemotherapy alone. However, long-term improvements (four years) in clinical outcomes such as modified Rodnan skin scores and forced vital capacity, as well as overall mortality in patients receiving HCT compared with patients receiving cyclophosphamide alone, were consistently reported in all RCTs. Due to sample size limitations in two of the RCTs, statistical significance was found only in the larger RCT. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes.

For individuals with systemic lupus erythematosus who receive HCT, the evidence includes a systematic review and case series. The relevant outcomes are OS, symptoms, QOL, and TRM and morbidity. Studies were heterogeneous in conditioning regimens and source of cells. The largest series (n = 50) reported an overall 5-year survival rate of 84% and the probability of disease-free survival was 50%. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with juvenile idiopathic or rheumatoid arthritis who receive HCT, the evidence includes registry data and a case series. The relevant outcomes are OS, symptoms, QOL, and TRM and morbidity. The registry included 50 patients with juvenile idiopathic or rheumatoid arthritis. The overall drug-free remission rate was approximately 50% in the registry patients and 69% in the smaller case series. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with chronic inflammatory demyelinating polyneuropathy who receive HCT, the evidence includes case reports. The relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. Additional data are needed from controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with type 1 diabetes who receive HCT, the evidence includes case series and a meta-analysis of 22 studies. The relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. While a substantial proportion of patients tended to become insulin-free after HCT, remission rates were high. A meta-analysis further revealed that HCT is more effective in patients with type 1 diabetes compared with Type 2 diabetes and when HCT is administered soon after the diagnosis. Certain factors limit the conclusions that can be drawn about the overall effectiveness of HCT in treating diabetes; those factors are heterogeneity in the stem cell types, cell number infused, and infusion methods. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with other autoimmune diseases (e.g., Crohn disease, immune cytopenias, relapsing polychondritis) who receive HCT, the evidence includes one RCT and small retrospective studies. The relevant outcomes are OS, symptoms, health status measures, QOL, and TRM and morbidity. The RCT was conducted on patients with Crohn disease. At one year follow-up, one patient in the control group and two patients in the HCT group achieved remission. Data are needed from additional controlled studies to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
Autoimmune Disease Treatment
Immune suppression is a common treatment strategy for many of these diseases, particularly rheumatic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma). Most patients with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive. It is for this group of patients with severe autoimmune disease that alternative therapies have been sought, including hematopoietic cell transplantation (HCT). The primary concept underlying the use of HCT for these diseases is this: ablating and “resetting” the immune system can alter the disease process by inducing a sustained remission that possibly leads to cure.¹

Hematopoietic Cell Transplantation
HCT is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in evidence review 7.01.50.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B and -DR (antigen-D related) loci on each arm of chromosome six. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation
Conventional Conditioning
The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect mediated by non-self-immunologic effector cells. While the slower GVM effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVH disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation
Reduced-Intensity Conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial GVM effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be non-myeloablative.

Regulatory Status
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Policy
Autologous or allogeneic hematopoietic cell transplantation is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY as a treatment of autoimmune diseases, including, but not limited to, the following:

Multiple sclerosis
Systemic lupus erythematosus
Juvenile idiopathic or rheumatoid arthritis
Chronic inflammatory demyelinating polyneuropathy
Type 1 diabetes

Autologous hematopoietic cell transplantation is considered MEDICALLY NECESSARY as a treatment of systemic sclerosis/scleroderma if all of the following conditions are met:

Adult patients < 60 years of age
Maximum duration of condition of 5 years
Modified Rodnan Scale Scores > 15
Internal organ involvement as noted in the Policy Guidelines
History of < 6 months treatment with cyclophosphamide
No active gastric antral vascular ectasia
Do not have any exclusion criteria as noted in the Policy Guidelines

Autologous hematopoietic cell transplantation as a treatment of systemic sclerosis/scleroderma not meeting the above criteria is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY .

Policy Guidelines
Please see the Codes table for details.

Autologous HCT should be considered for patients with systemic sclerosis (SSc) only if the condition is rapidly progressing and the prognosis for survival is poor. An important factor influencing the occurrence of treatment-related adverse effects and response to treatment is the level of internal organ involvement. If organ involvement is severe and irreversible, HCT is not recommended. Below are clinical measurements which can be used to guide the determination of organ involvement.

Patients with internal organ involvement indicated by the following measurements may be considered for autologous HCT:

Cardiac: abnormal electrocardiogram
Pulmonary: diffusing capacity of carbon monoxide (DLCo) < 80% of predicted value; decline of forced vital capacity (FVC) of > 10% in last 12 months; pulmonary fibrosis; ground glass appearance on high resolution chest CT
Renal: scleroderma-related renal disease

Patients with internal organ involvement indicated by the following measurements should not be considered for autologous HCT:

Cardiac: left ventricular ejection fraction < 50%; tricuspid annular plane systolic excursion < 1.8 cm; pulmonary artery systolic pressure > 40 mm Hg; mean pulmonary artery pressure > 25 mmHg
Pulmonary: DLCo < 40% of predicted value; FVC < 45% of predicted value
Renal: creatinine clearance < 40 ml/minute

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function — including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual]; women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Autoimmune Diseases
Autoimmune diseases represent a heterogeneous group of immune-mediated disorders, including multiple sclerosis (MS), systemic sclerosis/scleroderma, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and chronic immune demyelinating polyneuropathy. The National Institutes of Health has estimated that 5% to 8% of Americans have an autoimmune disorder.

The goal of autologous hematopoietic cell transplantation (HCT) in patients with autoimmune diseases is to eliminate self-reactive lymphocytes (lymphoablation) and generate new, self-tolerant lymphocytes. While evidence for the use of allogeneic HCT (allo-HCT) for autoimmune diseases is currently limited, the goal is to possibly eliminate genetic susceptibility to the autoimmune disease, potentially resulting in a cure.

Recent reviews have summarized the research to date using HCT to treat a number of autoimmune diseases.^2,3

In March 2009, patients with an autoimmune disease who had undergone HCT were registered in the European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism database. The database included 1031 patients with the clinical indications of MS (n = 379), systemic sclerosis (n = 207), SLE (n = 92), RA (n = 88), juvenile idiopathic arthritis (JIA; n = 70), idiopathic thrombocytopenic purpura (n = 23), and Crohn disease (n = 23).³

Multiple Sclerosis
Clinical Context and Therapy Purpose
The purpose of HCT in patients who have MS is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with MS.

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medical therapy. Most patients with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive.

Outcomes
The general outcomes of interest are overall survival (OS), health status measures, QOL, treatment-related mortality (TRM), and treatment-related morbidity. Specific outcomes of interest include progression-free survival (PFS) improvement in clinical symptoms, and adverse events.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Characteristic of systematic reviews are presented in Table 1 and results of systematic reviews are presented in Table 2.

A systematic review by Reston et al. (2011) evaluated the safety and efficacy of autologous HCT in patients with progressive MS refractory to conventional medical treatment.^₄ Fourteen studies met inclusion criteria, of which 8 case series met inclusion criteria for the primary outcome of PFS, with a median follow-up of at least 2 years. The other 6 studies were included for a summary of mortality and morbidity rates. The studies differed in the types and intensities of conditioning regimens used before HCT, with 5 studies using an intermediate-intensity regimen and 3 studies using high-intensity regimens. All studies were rated moderate quality. Across the 8 case series, there was substantial heterogeneity. Most patients (77%) had secondary progressive MS, although studies also included patients with primary progressive, progressive-relapsing, and relapsing-remitting MS (RRMS).

Sormani et al. (2017) conducted a systematic review and meta-analysis on the use of autologous HCT for the treatment of patients with severe treatment-refractory MS.⁵ The studies differed in types and intensities of conditioning regimens used before HCT: low (n = 2), intermediate (n = 7), high (n = 4), and mixed (n = 2). Quality assessment of included studies was not discussed. The rates of progression at 2 and 5 years were calculated, as well as treatment-related and overall mortality. The pooled proportion of patients with no evidence of disease activity at 2 years was 83% (range, 70% to 92%) and at 5 years was 67% (range, 59% to 70%).

Ge et al. (2019) reported a systematic review and meta-analysis to assess PFS and disease activity-free survival, as well as TRM and overall deaths, after autologous HCT for MS.⁶ The authors identified 18 eligible studies with a total of 732 participants. Pooled estimated PFS was 75%. Low- and intermediate-intensity treatments had higher PFS than high-intensity treatments. In addition, RRMS benefited from autologous HCT more than other MS subtypes. Patients with gadolinium-enhancing (Gd+) lesions at baseline responded better to autologous HCT. Overall, 9 transplant-related deaths occurred, and estimated TRM was greater with the use of high-intensity treatment regimens and in studies conducted before 2006. Twenty-seven patients died during follow-up, primarily of infection or pneumonia. Several limitations of the meta-analysis include possible publication bias, a lack of RCTs, and differences in autologous HCT procedures, patient characteristics, and duration of follow-up across studies.

Nabizadeh et al. (2022) conducted a systematic review and meta-analysis on the use of autologous HCT in patients with MS.⁷Fifty studies, including 7 RCTs, with a total of 4831 patients were included. The pooled estimated PFS was 73% (95% confidence interval [CI], 69% to 77%; I2 = 89.89%). There was a significant decrease in Expanded Disability Status Scale (EDSS) score after treatment (standardized mean difference [SMD], -0.48; 95% CI, -0.75 to -0.22), and the annualized relapse rate (ARR) was decreased relative to the pretreatment period (SMD, -1.58; 95% CI, -2.34 to -0.78). However, the analysis found a higher incidence of TRM after autologous HCT versus other disease-modifying therapies when evaluating long-term outcome measures; the analysis considered an endpoint of all TRM at the end of a 5-year follow-up duration. Limitations of the meta-analysis include possible publication bias, minimal number of RCTs, lack of studies focusing on specific subtypes of MS, high heterogeneity between included studies, and unspecified duration of follow-up across studies.

Table 1. Characteristics of Meta-Analyses on the Use of Autologous HCT for MS

Study	Dates	Studies	Participants	N (range)	Follow-up
Reston (2011)⁴	Through Feb 2009	1 database 13 cohort	Patients with progressive and treatment-refractory MS	428 (5 to 169)	Median: 24 months
Sormani (2017)⁵	1995 to 2016	1 RCT 14 cohort	Patients with severe and treatment-refractory MS	764 (7 to 178)	Median: 42 months
Ge (2019)⁶	Through 2017	18 uncontrolled observational studies	Patients with severe and refractory MS	732 (14 to 145)	Median: 48 months
Nabizadeh (2022)⁷	Through Feb 2022	7 RCT 1 case series 42 cohort	Patients with MS	4831 (12 to 617)	NR

HCT: hematopoietic cell transplantation; MS: multiple sclerosis; NR: not reported; RCT: randomized controlled trial.

Table 2. Results of Meta-Analyses on the Use of Autologous HCT for MS

Study
Reston (2011)⁴	N	Median follow-up	PFS, % (95% CI)	Sub-population	N	TRM, N (%)	Non-TRM, N (%)
Intermediate-intensity conditioning	102	39 months	79.4 (69.9 to 86.5)	Cohort studies	259	7 (2.7)	6 (2.3)
High-intensity conditioning	61	24 months	44.6 (26.5 to 64.3)	Database	169	9 (5.3)	6 (3.5)
Ge (2019)⁸	N	Median follow-up	PFS, % (95% CI)	Disease activity-free survival , % (95% CI)		TRM, % (95% CI)	Overall mortality , % (95% CI)
Overall	732	48 months	75 (69 to 81)	61 (53 to 69)		1.34 (0.39 to 2.30)	3.58 (2.30 to 4.86)
Patients with RRMS			85 (77 to 92)
Patients with Gd+ lesions			77 (61 to 94)
Patients with Gd- lesions			47 (33 to 62)
Low- and Intermediate-intensity conditioning			80 (75 to 85)			0.97 (-0.05 to 1.98)
High-intensity conditioning			58 (40 to 75)			3.13 (1.18 to 5.08)
Sormani (2017)⁵	N	2-Year PR, % (95% CI)	N	5-Year PR, % (95% CI)	N	Pooled TRM,^a% (95% CI)	Overall mortality , ^b%, (95% CI)
	764	17.1(9.7 to 24.5)	679	23.3 (14.8 to 43.0)	764	2.1 (1.3 to 3.4)	1.0 (0.7 to 1.5)
Nabizadeh (2022)⁷	N	PFS, % (95% CI)	EDSS score change, SMD (95% CI)	ARR change, SMD (95% CI)	EFS, % (95% CI)	OS, % (95% CI)	No evidence of disease activity, % (95% CI)
	4831	73 (69 to 77)	-0.48 (-0.75 to -0.22)	-1.58 (-2.34 to -0.78)	63 (54 to 73)	94 (91 to 96)	68 (59 to 77)

ARR: annualized relapse rate; CI: confidence interval; EDSS: Expanded Disability Status Scale; EFS: event-free survival; Gd+: gadolinium-enhancing; HCT: hematopoietic cell transplantation; MS: multiple sclerosis; NR: not reported; OS: overall survival; PFS: progression free survival; PR: progression rate; RRMS: relapsing remitting multiple sclerosis; SMD: standardized mean difference; TRM: treatment-related mortality.
a Pooled TRM defined as number of deaths within 100 days of transplant/number of transplants.
b Overall mortality defined as total number deaths/number of patient-years.

Randomized Controlled Trials
A few notable RCTs are included here for review. An RCT, Autologous Stem Cell Transplantation in Multiple Sclerosis, which compared HCT with mitoxantrone for treatment of MS, was published by Mancardi et al. (2015).⁹Due to low patient enrollment, this trial’s protocol, initially designed as a phase 3 study evaluating disability progression, was amended to a phase 2 study with a new primary outcome of disease activity, as measured by the number of new T2 magnetic resonance imaging (MRI) lesions in 4 years posttreatment. Eligibility for the trial was limited to the following criteria: secondary progressive or RRMS, a documented worsening of symptoms during the last year, and lack of response to conventional therapy. Twenty-one patients were randomized to autologous HCT (n = 9) or medical therapy (mitoxantrone, n = 12). Follow-up data were collected every 6 months for 48 months. Data were not available for 4 patients; missing data were imputed in the intention-to-treat analysis of the primary outcome. The median number of new T2 MRI lesions was 2.5 in the HCT group and 8 in the conventional therapy group (rate ratio, 0.21; 95% CI , 0.10 to 0.48, p < .001). Among secondary outcomes, the ARR was significantly lower in the HCT group (19%) compared with the conventional therapy group (60%; p < .03). There was no statistically significant difference between groups in the rate of disease progression (defined as increase of > 1 point in EDSS score if baseline was 3.5 to 5.5 or increase of > 0.5 if baseline 5.5 to 6.5) or change in disability status.

Burt et al. (2019) reported an RCT of nonmyeloablative HCT compared to continued disease-modifying therapy on disease progression for patients with RRMS.¹⁰ Between 2005 and 2016, with final follow-up in 2018, 110 patients with RRMS were randomized to receive HCT plus cyclophosphamide and antithymocyte globulin (n = 55) or disease-modifying therapy of higher efficacy or a different class than disease-modifying therapy taken in the previous year (n = 55). To be eligible, the participants had to have at least 2 relapses with disease-modifying therapy in the prior year and an EDSS of 2.0 to 6.0 (EDSS score range 0 to 10, with 10 being worst neurological disability). The primary end point of the study was disease progression, defined as an EDSS score increase of ≥ 1.0 point (minimally clinically important difference, 0.5) after ≥ 1 year on 2 evaluations 6 months apart. Three patients in the HCT group and 34 patients in the disease-modifying therapy group experienced disease progression, with a median follow-up of 2 years (mean, 2.8 years). Too few events in the HCT group prevented calculation of time to progression, but it was 24 months (interquartile range, 18 to 48 months) in the disease-modifying therapy group (hazard ratio [HR], 0.07; 95% CI, 0.02 to 0.24). For the HCT group, the proportion of patients with disease progression was 1.92% (95% CI, 0.27% to 12.9%) at 1 year and 2 years, and by 4 and 5 years it was 9.71% (95% CI, 3.0% to 28.8%). Disease progression for the disease-modifying therapy group was 24.5% (95% CI, 14.7% to 39.1%) at 1 year, and 75.3% (95% CI, 60.4% to 87.8%) by year 5. In the HCT group, the mean EDSS score decreased from a baseline of 3.38 to 2.36 at 1 year. In the disease-modifying therapy group, mean EDSS score increased from 3.31 to 3.98 at 1 year. Between-group difference in change in scores was -1.7 (95% CI, -2.03 to -1.29; p < .001). The results of the study suggest nonmyeloablative HCT is superior to disease-modifying therapy in prolonging time to disease progression in patients with RRMS. Study limitations included sample size, option to cross over from disease-modifying therapy to HCT mid-study and the exclusion of other chemotherapy drugs used in the disease-modifying therapy group.

Nonrandomized Studies
Select nonrandomized studies with at least 2 years of follow-up and more than 20 enrolled patients are described below.

Fassas et al. (2011) reported on the long-term results of a single-center study that investigated the effect of HCT on the treatment of MS (Table 3).¹¹ Progression-free survival and TRM are presented in Table 4. The median time to progression was 11 years (range, 0 to 22 years) for patients with active central nervous system disease and 2 years for patients without (range, 0 to 6 years). Improvements by 0.5 to 5.5 (median, 1) EDSS points were observed in 16 cases, lasting for a median of 2 years. In 9 of these patients, EDSS scores did not progress above baseline scores. Gadolinium-enhancing lesions were significantly reduced after mobilization but were maximally and persistently diminished post-HCT.

Shevchenko et al. (2012) reported on the results of a prospective, open-label, single-center study that analyzed the safety and efficacy of autologous HCT with a reduced-intensity conditioning (RIC) regimen with different types of MS (Tables 3 and 4).¹²Patients underwent early, conventional, and salvage/late transplantation. Efficacy was evaluated based on clinical and QOL outcomes. All patients, except 1, responded to treatment. At long-term follow-up (mean, 46 months), the overall clinical response regarding disease improvement or stabilization was 80%. The estimated PFS rate at 5 years was 92% in the group after early transplant and 73% in the group after conventional/salvage transplant (p = .01). No active, new, or enlarging lesions were found on MRI without disease progression. All patients who did not have disease progression did not receive therapy during the post-transplantation period. Hematopoietic cell transplantation was accompanied by a significant improvement in QOL, with statistically significant changes in most QOL parameters (p < .05). A subsequent 2015 publication reported on 64 patients participating in this trial who had at least 36 months of follow-up (median, 62 months); another 35 patients had a shorter follow-up, and the remainder were lost to follow-up.¹³ Thirty (47%) of the 64 patients improved by at least 0.5 points on the EDSS score compared with baseline. Among the other patients, 29 (45%) were stable, and 5 (7%) experienced worsening disease.

Mancardi et al. (2012) reported on 74 consecutive patients with MS treated with autologous HCT following an intermediate-intensity conditioning regimen during the period from 1996 to 2008 (Table 3).¹⁴ Thirty-six patients had secondary progressive disease and 25 had RRMS. Clinical and MRI outcomes were reported (Table 4). The median follow-up was 48.3 months (range, 0.8 to 126 months). After 5 years, 66% of patients remained stable or improved. Among patients with follow-up more than 1 year, 8 (31%) of 25 subjects with RRMS had a 6- to 12-month confirmed EDSS score improvement more than 1 point after HCT compared with 1 (3%) of 36 patients with a secondary progressive disease course (p = .009). Among the 18 cases with a follow-up of more than 7 years, 8 (44%) remained stable or had sustained improvement, while 10 (56%), after an initial period of stabilization or improvement (median duration, 3.5 years), showed a slow disability progression.

A single-center case series by Burt et al. (2015) reported on 151 patients, 123 with RRMS and 28 with secondary progressive MS (Tables 3 and 4).¹⁵ Patients were treated with nonmyeloablative HCT between 2003 and 2014. Six patients were not included in the outcome analysis (lost to follow-up and nonreproducible neurologic findings). The remaining 145 patients were followed for a median of 2 years (range, 6 months to 5 years). Change in EDSS score was the primary outcome. A decrease of at least 1.0 point was considered a significant improvement and an increase of at least 1.0 point was considered a significant progression. There was a statistically significant improvement in EDSS score for the group as a whole compared with the pretransplant mean score of 4.0, decreasing to a mean EDSS score of 2.5 at 3, 4, and 5 years. In post hoc analysis, patients most likely to have statistically significant improvements in EDSS scores were those with RRMS, with a duration of disease of 10 years or less, and those without sustained fever during HCT.

A multicenter case series by Burman et al. (2014) reported on 48 patients with aggressive RRMS (defined as a disease with high relapse frequency, and who failed conventional therapy) (Tables 3 and 4).¹⁶ Patients underwent autologous HCT. At the 5-year follow-up, relapse-free survival (RFS) was 87%, and the EDSS score PFS (defined as a deterioration in EDSS score of < 0.5 points) was 77%.

Atkins et al. (2016) published a phase 2 trial investigating the use of immunoablation and autologous HCT for the treatment of aggressive MS (Table 3).¹⁷ Inclusion criteria were: poor prognosis, ongoing disease activity, and EDSS score between 3.0 and 6.0. Twenty-four patients were enrolled and PFS and TRM are presented in Table 4. During the extended follow-up period, without the use of disease-modifying drugs, no signs of central nervous system inflammation were detected clinically or radiologically. Clinical relapses did not occur among the 23 surviving patients in 179 patient-years of follow-up. Moreover, 33% of the patients experienced grade 2 toxic effects and 58% experienced grade 1 transplantation-related toxic effects.

Results from the High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis trial were published by Nash et al. (2017) (Tables 3 and 4).¹⁸The trial evaluated 24 patients with MS who were treated with high-dose immunosuppression and autologous HCT. Outcomes were PFS (91%; 90% CI, 75% to 97%), clinical RFS (87%; 90% CI, 69% to 95%), and MRI activity-free survival (86%; 90% CI, 68% to 95%). Patients experienced high rates of adverse events: 92% had grade 3, and 100% had grade 4 adverse events. The majority of adverse events occurred between the start of conditioning and day 29 in the trial.

Muraro et al. (2017) conducted a retrospective cohort study of patients with MS treated with HCT between 1995 and 2006 (Table 3).¹⁹ Data was collected from 25 centers in 13 European countries. Results are presented in Table 4. Factors associated with neurological progression included age, progressive versus relapsing MS, and > 2 previous therapies.

Kvistad et al. (2019) performed a retrospective cohort study of 30 patients in Norway with RRMS treated with HCT between 2015 and 2018 (Table 3).²⁰ Results for PFS and TRM are presented in Table 4. Additionally, 13 (43%) patients experienced sustained improvement in EDSS score of 1 or more, and 25 patients (83%) experienced no evidence of disease activity.

Boffa et al. (2021) performed a retrospective cohort study of 210 patients in Italy with RRMS, secondary progressive MS, or primary progressive MS treated with HCT between 1997 and 2019 (Table 3).²¹ Results for the primary outcome of disability worsening-free survival are presented in Table 4. Additionally, RFS at 5 and 10 years after transplant was 82.9% (95% CI, 76.6% to 89.2%) and 71.2% (95% CI, 61.8% to 80.6%), respectively.

Burt et al. (2021) performed a retrospective cohort study of 414 patients with RRMS and 93 patients with newly diagnosed secondary-progressive MS treated with HCT at a single center in the US between 2003 and 2019 (Table 3).²² Results for PFS and TRM are presented in Table 4. Additionally, RFS at 5 years for patients with RRMS and secondary-progressive MS was 80.1% and 98.1%, respectively.

Table 3. Characteristics of Observational Studies of HCT for MS (≥ 2 years Follow-Up)

Study	Study Design	Country	Participants	N	Median years (range) follow-up
Fassas (2011)¹¹	Case series	Greece	Patients with aggressive MS treated with HCT	35	11 (2 to 15)
Shevchenko (2012)¹²Shevchenko (2015)¹³	Case series	Russia	Patients with progressive MS or RRMS treated with HCT	99	4 (NR)
Mancardi et al. (2012)¹⁴	Case series	Italy	Patients with severe MS treated with HCT	74	4 (0.8 to 10)
Burman (2014)¹⁶	Case series	Sweden	Patients with aggressive MS treated with HCT	41	4 (1 to 9)
Burt (2015)¹⁵	Case series	United States	Patients with RRMS treated with HCT	151	2 (0.5 to 5)
Atkins (2016)¹⁷	Case series	Canada	Patients with relapsing MS treated with HCT	24	6.7 (4 to 13)
Nash (2017)¹⁸	Case series	United States	Patients with RRMS or progressive MS treated with HCT	24	5.2 (1 to 6)
Muraro (2017)¹⁹	Retrospective cohort	Europe (13 countries)	Patients with aggressive treatment-refractory MS treated with HCT	281	6.6 (0.2 to 16)
Kvistad (2019)²⁰	Retrospective cohort	Norway	Patients with RRMS or progressive MS treated with HCT	30	26 (11 to 48)
Boffa (2021)²¹	Retrospective cohort	Italy	Patients with RRMS , secondary progressive MS, or primary progressive MS treated with HCT	210	6.2 (NR)
Burt (2021)²²	Retrospective cohort	United States	Patients with RRMS or newly diagnosed secondary progressive MS treated with HCT	507	3 (NR)

HCT: hematopoietic cell transplantation; MS: multiple sclerosis; NR: not reported; RRMS: relapsing-remitting multiple sclerosis.

Table 4. Results of Observational Studies of HCT for MS (≥ 2 years Follow-Up)

Study	Follow up	PFS, % (95% CI)	TRM, N (%)
Fassas (2011)¹¹	15 years	All: 25 (NR) Active MRI lesions: 44 (NR) No active MRI lesions: 10 (NR)	2 (5.7)
Shevchenko (2012)¹² Shevchenko (2015)¹³	8 years	80 (68 to 88)	0
Mancardi et al. (2012)¹⁴	4 years	NR	2 (2.7)
Burman (2014)¹⁶	5 years	68 (NR)	0
Burt (2015)¹⁵	2 years 4 years	92 (85 to 96) 87 (78 to 93)	0
Atkins (2016)¹⁷	3 years	70 (47 to 84)	1 (4.2)
Nash (2017)¹⁸	5 years	91 (75 to 97)	0
Muraro (2017)¹⁹	5 years	All: 46 (42 to 54) Relapsing: 73 (57 to 88)	8 (2.8)
Kvistad (2019)²⁰	2 years	7 (NR)	0
Boffa (2021)²¹	5 and 10 years	5 years^a: 79.5 (72.0 to 86.6); 10 years^a: 65.5 (55.3 to 75.7)	3 (1.4)
Burt (2021)²²	4 years	RRMS: 95 Secondary progressive MS: 66	1 (0.19)

a This study measured disability worsening-free survival.
CI: confidence intervals; HCT: hematopoietic cell transplantation; MRI: magnetic resonance imaging; MS: multiple sclerosis; NR: not reported; PFS: progression-free survival; RRMS: relapsing-remitting multiple sclerosis; TRM: treatment-related mortality.

Section Summary: Multiple Sclerosis
Evidence for the use of HCT in patients with MS consists of RCTs, systematic reviews, and many single-arm studies. Several systematic reviews for HCT are available, but the vast majority of data comes from observational studies without a control group, prohibiting conclusions comparing HCT with disease-modifying therapy. One RCT compared HCT (n = 9) with mitoxantrone (n = 12). The primary outcome was the number of new T2 lesions detected by MRI. The HCT group developed statistically fewer new T2 lesions than the mitoxantrone group. The other RCT compared nonmyeloablative HCT results in patients with continued disease-modifying therapy and found a benefit to HCT in prolonging time to disease progression. Outcomes in the single-arm studies included PFS, RFS, disease activity-free survival, disability worsening-free survival, disease stabilization, number of new lesions, and improvements in EDSS scores. While improvements were seen in all outcomes compared with baseline, there were no comparative treatments. Adverse event rates were high with studies reporting treatment-related death rates ranging from 0 to 4%.

Systemic Sclerosis (Scleroderma)
Clinical Context and Therapy Purpose
The purpose of HCT in patients who have systemic sclerosis (scleroderma) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with systemic sclerosis or scleroderma.

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medical therapy. Most patients with autoimmune disorders such as systemic sclerosis or scleroderma respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive.

Outcome
The general outcomes of interest are OS, symptoms, health status measures, QOL, TRM, and treatment-related morbidity. Specific outcomes of interest include PFS, OS, improvement in clinical symptoms, adverse events, and TRM.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A review by Milanetti et al. (2011) summarized 8 phase 1 and 2 clinical studies using autologous HCT to treat systemic sclerosis.²³ The number of patients in each study ranged from 6 to 57. The proportion of patients across the studies achieving a 25% decrease in the Rodnan Skin Score (RSS) ranged from 60% to 100%. Pooled analyses were not conducted.

Host et al. (2017) conducted a systematic review of autologous HCT for the treatment of systemic sclerosis.²⁴The literature search, conducted through March 2016, identified 9 studies (2 RCTs and 7 observational studies) for inclusion. The RCTs reported improvements in PFS and event-free survival (EFS) and all studies reported improvements in modified Rodnan skin score (mRSS). However, TRM rates ranged from 0% to 23%, with higher rates found with higher doses of cyclophosphamide or myeloablative conditioning regimens. Pooled analyses were not conducted.

Shouval et al. (2018) conducted a meta-analysis of 4 studies (3 RCTs and 1 retrospective comparative study) on the use of autologous HCT compared with cyclophosphamide alone for the treatment of systemic sclerosis.²⁵ Quality assessment of the 3 RCTs found that 2 of the RCTs had low-risk in the randomization methods and outcome reporting, 1 RCT was unclear in randomization methods, and all 3 were high-risk since masking of patients and outcome assessors was not conducted. Meta-analyses of the RCTs showed that all-cause mortality favored HCT (risk ratio [RR], 0.6; 95% CI , 0.4 to 0.9) and TRM favored cyclophosphamide alone ( RR, 10.8; 95% CI , 1.4 to 85.7).

Higashitani et al. (2022) conducted a systematic review and meta-analysis of survival outcomes of HCT in patients with systemic sclerosis.²⁶ There were 22 studies included (3 RCTs; 19 observational cohorts). The pooled frequency of transplant-related death (N = 700) was 6.30% (95% CI, 4.21 to 8.38). However, the authors note that the estimated frequency of treatment-related deaths has been declining over the last decade.

Bruera et al. (2022) conducted a systematic review of autologous HCT for the treatment of systemic sclerosis.²⁷ There were 3 RCTs (N = 125) included (described below) with 3 different transplant modalities (non-myeloablative non-selective; non-myeloablative selective; myeloablative selective) and the comparator in all studies was cyclophosphamide. No study demonstrated an overall mortality benefit of autologous HCT when compared wtih cyclophosphamide; however, non-myeloablative selective HCT demonstrated OS benefits (using Kaplan-Meier curves) at 10 years and myeloablative selective HCT demonstrated OS benefits at 6 years. Event-free survival was improved with non-myeloablative selective HCT at 48 months (HR, 0.34; 95% CI, 0.16 to 0.74; moderate-certainty evidence) compared with cyclophosphamide; there was no improvement in EFS with myeloablative selective HCT at 54 months (HR, 0.54; 95% CI, 0.23 to 1.27; moderate-certainty evidence). All HCT transplant modalities reported improvement of mRSS compared with cyclophosphamide; however, there was low-certainty evidence that these modalities of HCT improved patient physical function.

Randomized Controlled Trials
An open-label, randomized, controlled phase 2 trial (Trial of High Dose Cyclophosphamide and Rabbit Antithymocyte Globulin (rATG) With Hematopoietic Stem Cell Support in Patients With Systemic Scleroderma: A Randomized Trial [ASSIST]; Burt et al. [2011]) evaluated the safety and efficacy of autologous nonmyeloablative HCT compared with the standard of care (cyclophosphamide) (Table 5).²⁸ The primary outcome was an improvement at 12 months, which was defined as a decrease in mRSS (< 25% for those with initial mRSS > 14) or an increase in forced vital capacity (FVC) of more than 10% (Table 6). Patients in the control group with disease progression (> 25% increase in mRSS or decrease of > 10% in FVC) despite treatment with cyclophosphamide could switch to HCT 12 months after enrollment. Patients allocated to HCT (n = 10) improved at or before the 12-month follow-up compared with none of the 9 patients allocated to cyclophosphamide (p < .001). Treatment failure (i.e., disease progression without interval improvement) occurred in 8 of 9 controls but did not occur in any of the 10 patients treated by HCT (p < .001). After long-term follow-up (mean, 2.6 years) of patients allocated to HCT, all but 2 patients had sustained improvement in mRSS and FVC, with the longest follow-up of 60 months. Seven patients allocated to cyclophosphamide switched treatment groups at a mean of 14 months after enrollment and underwent HCT without complication; all improved after HCT. Four of these patients, followed for at least 1 year, had a mean (standard deviation [SD]) decrease in mRSS from 27 (SD = 15.5) to 15 (SD = 7.4), an increase in FVC from 65% (20.6%) to 76% (26.5%), and an increase in total lung capacity from 81% (14.0%) to 88% (13.9%). Data for 11 patients, with a follow-up of 2 years after HCT, suggested that the improvements in mRSS (p < .001) and FVC (p < .03) persisted.

Results of the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial (ISRCTN54371254) were published by van Laar et al. (2014) (Tables 5 and 6).²⁹ The ASTIS trial was a phase 3 RCT comparing autologous HCT with cyclophosphamide for the treatment of systemic scleroderma. A total of 156 patients were recruited between March 2001 and October 2009. Median follow-up was 5.8 years (interquartile range, 4.1 to 7.8 years). The primary endpoint was EFS, defined as the time in days from randomization until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney). Main secondary endpoints included TRM, toxicity, and disease-related changes in mRSS, organ function, body weight, and QOL scores. The internal validity (risk of bias) of ASTIS was assessed according to the U.S. Preventive Services Task Force criteria for randomized trials. The trial was rated as poor-quality according to this framework because of 2 flaws: outcome assessment was not masked to patients or assessors, and 18 (24%) of 75 patients in the control group discontinued intervention because of death, major organ failure, adverse events, or nonadherence. Furthermore, the trial design permitted crossover after the second year, but whether any patients did so and were analyzed as such is not mentioned. Finally, the authors reported that the use of unspecified concomitant medications or other supportive care measures was allowed at the discretion of the investigators, adding further uncertainty to the results. Of the 53 primary endpoint events recorded, 22 were in the HCT group (19 deaths, 3 irreversible organ failures; 8 patients died of treatment-related causes in the first year, 9 of disease progression, 1 of cerebrovascular disease, 1 of malignancy) and 31 were in the control group (23 deaths, 8 irreversible organ failures [7 of whom died later]; 19 patients died of disease progression, 4 of cardiovascular disease, 5 of malignancy, 2 of other causes). The data showed patients treated with HCT experienced more events in the first year but appeared to have better long-term EFS than the controls, with Kaplan-Meier curves for OS crossing at about 2 years after treatment, with the OS rate at that time estimated at 85%. According to the Kaplan-Meier curves, at 5 years, the OS rate was estimated at 66% in the control group and estimated at 80% in the HCT group (p-value unknown). Time-varying HRs (modeled with treatment by time interaction) for EFS were 0.35 (95% CI, 0.15 to 0.74) at 2 years and 0.34 (95% CI, 0.16 to 0.74) at 4 years, supporting a benefit of HCT compared with pulsed cyclophosphamide. Severe or life-threatening grade 3 or 4 adverse events were reported in 51 (63%) of the HCT group and 30 (37% by intention-to-treat, p = .002) of the control group.

Sullivan et al. (2018) conducted an RCT comparing autologous HCT with cyclophosphamide for the treatment of scleroderma (SCOT — A Randomized, Open-Label, Phase II Multicenter Study of High-Dose Immunosuppressive Therapy Using Total Body Irradiation, Cyclophosphamide, ATGAM, and Autologous Transplantation With Auto-CD34 + HPC Versus Intravenous Pulse Cyclophosphamide for the Treatment of Severe Systemic Sclerosis [SCSSc-01]) (Table 5).³⁰ The trial was originally designed for 226 patients, but due to low accrual, a total of 75 patients participated. Of the 36 patients randomized to receive HCT, 27 completed the trial per protocol (3 died and 6 withdrew prematurely). Of the 39 patients randomized to receive cyclophosphamide alone, 19 completed the trial per protocol (11 died and 9 withdrew prematurely). The primary outcome was a global rank composite score. This score does not measure disease activity or severity but performs a pairwise comparison of the following: death, EFS, FVC, Disability Index of the Health Assessment Questionnaire, and the mRSS. There were more percent pairwise comparisons favoring HCT over cyclophosphamide alone at 4- and 4.5-years follow-up (Table 6). The following disease progression events were significantly higher among patients receiving cyclophosphamide alone: initiating disease-modifying antirheumatic drugs, congestive heart failure leading to treatment, and pulmonary arterial hypertension. The following disease progression events were not significantly different among the 2 treatment groups: arrhythmia, pericardial effusion, renal crisis, and myositis. Comparisons in mortality rates are presented in Table 6.

Table 5. Characteristics of RCTs of HCT for Systemic Sclerosis

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Burt (2011);²⁸ASSIST	United States	1	2006 to 2009	Adult patients < 60 yrs with diffuse systematic sclerosis; mRSS ≥ 15; internal organ involvement	High-dose intravenous cyclophosphamide 200 mg/kg; intravenous rabbit antithymocyte-globulin 6.5 mg/kg total dose; autologous HCT (n = 10)	6 monthly treatments with intravenous pulsed cyclophosphamide (1000 mg/m²) (n = 9)
Van Laar (2014);²⁹ASTIS	9 European countries and Canada	29	2001 to 2009	Adult patients with diffuse cutaneous systematic sclerosis; maximum duration 4 years; minimum mRSS ≥ 15; internal organ involvement	High-dose intravenous cyclophosphamide 200 mg/kg; intravenous rabbit antithymocyte-globulin 7.5 mg/kg total dose; autologous HCT (n = 79)	12 monthly treatments with intravenous pulsed cyclophosphamide (750 mg/m²) (n = 77)
Sullivan (2018);³⁰SCOT	United States and Canada	26	2005 to 2011	Adult patients with scleroderma; maximum duration 5 years; active interstitial lung disease and scleroderma-related renal disease	Total body irradiation (800 cGy); cyclophosphamide (120 mg/kg); equine antithymocyte globulin (90 mg/kg); autologous HCT (n = 36)	12 monthly treatments with intravenous pulsed cyclophosphamide (n = 39)

HCT: hematopoietic cell transplantation; mRSS: modified Rodnan skin scores; RCT: randomized controlled trial.

Table 6. Results of RCTs of HCT for Systemic Sclerosis

Study	Efficacy Outcomes				Adverse Events	TRM n (%)
Burt (2011);²⁸ ASSIST	mRSS at 1 year mean (SD)		FVC at 1 year Mean % (SD)
Autologous HCT	15 (7.9)		74 (15.7)		NR	0
cyclophosphamide	22 (14.2)		61 (19.8)		NR	0
van Laar (2014);²⁹ ASTIS	Events. 1 yr	Events. 4 yrs	Deaths, 1 yr	Deaths, 4 yrs	≥ Grade 3	TRM n (%)
Autologous HCT	13	15	11	12	63%	8 (10.1)
cyclophosphamide	8	20	7	20	37%	0
Relative Risk (95% CI)	1.6 (0.7 to 4.4)	0.7 (0.4 to 1.3)	1.5 (0.4 to 5.4)	0.6 (0.3 to 1.1)
Sullivan (2018);³⁰ SCOT	Global Rank Composite Score, at 4 Years		Global Rank Composite Score, at 4.5 Years		≥ Grade 3 Rate/person-yr	TRM n (%)
Autologous HCT	68%		67%		2.0	2 (5.5)
cyclophosphamide	32%		33%		1.2	0
p-value	.008		.01		< .001
	Death or Respiratory, Renal, or Cardiac Failure, n (%)		Death from any Cause, n (%)
Autologous HCT	At 4 years: 10 (28)		At 4.5 years: 6 (17)
cyclophosphamide	At 4 years: 20 (51)		At 4.5 years: 11 (28)
p-value	.06		.28

CI: confidence interval; FVC: forced vital capacity; HCT: hematopoietic cell transplantation; mRSS: modified Rodnan skin scores; NR: not reported; RCT: randomized controlled trial; SD: standard deviation; TRM: treatment-related mortality.

Nonrandomized Studies
Vonk et al. (2008) reported on the long-term results of 28 patients with severe diffuse cutaneous systemic sclerosis who underwent autologous HCT from 1998 to 2004.³¹ 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 to 7.5 years), 81% (n = 21 of 26) of the patients demonstrated a clinically beneficial response. Skin sclerosis was measured with themRSS , and a significant (i.e., > 25%) decrease (i.e., improvement) was achieved in 19 of 26 patients after 1 year and in 15 of 16 after 5 years. At study baseline, 65% of patients had significant lung involvement; all pulmonary function parameters remained stable after transplant at 5- and 7-year follow-ups. Based on the World Health Organization Performance Status, which reflects the effect of HCT on the combination of functional status, skin, lung, heart, and kidney involvement, the percentage of patients with a Performance Status score of 0 increased to 56% from 4% at baseline. The estimated survival rate 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 the EFS rate (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%.³²

Nash et al. (2007) reported on 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 HCT.³³ Of the 34 patients, 27 (79%) survived 1 year and were evaluable for response (there were 8 transplant-related deaths and 4 systemic sclerosis-related deaths). Of the 27 evaluable patients, 17 (63%) had sustained responses at a median follow-up of 4 years (range, 1 to 8 years). Skin biopsies showed a statistically significant decrease in dermal fibrosis compared with baseline (p < .001) and, in general, lung, heart, and kidney function remained stable. Overall function as assessed in 25 patients using the Disability Index of the modified Health Assessment Questionnaire showed improvement in 19, and disease response was observed in the skin of 23 of 25 and lungs of 8 of 27 patients. Estimated OS and PFS rates were both 64% at 5 years.

Henes et al. (2012) reported on 26 consecutive patients with systemic sclerosis scheduled for autologous HCT between 1997 and 2009.³⁴ The main outcome variable was a response to treatment (reduction of mRSS by 25%) at 6 months. Secondary endpoints were transplant-related mortality and PFS. At 6 months, significant skin and lung function improvement assessed on the mRSS was achieved in 78.3% of patients. The overall response rate was 91%, and some patients even improved after month 6. Three patients died between mobilization and conditioning treatment: 2 were due to severe disease progression and 1 treatment-related. Seven patients relapsed during the 4.4 years of follow-up. The PFS rate was 74%. Four patients died during follow-up, with the most frequent causes of death being pulmonary and cardiac complications of systemic sclerosis.

Henes et al. (2020) described results from a prospective non-interventional study of 80 patients with systemic sclerosis between 2012 and 2016.³⁵ After a median follow-up of 24 months after HCT, the primary endpoint of PFS was 81.8%, and secondary endpoints of OS, response, and incidence of progression were 90%, 88.7%, and 11.9%, respectively. The incidence of non-relapse mortality at 100 days was 6.25%, and 4 patients experienced death from cardiac events, including 3 due to toxicity of cyclophosphamide used in conditioning regimens.

van Bijnen et al. (2020) performed a retrospective cohort study of 92 patients in the Netherlands with systemic sclerosis treated with HCT between 1998 and 2017.³⁶ After a median follow up of 4.6 years, EFS at 5, 10, and 15 years was 78%, 76%, and 66%, respectively. From baseline to 5 years of follow up, median values decreased for mRSS from 26 to 6, and increased for FVC from 84% to 94%. Disease progression occurred in 22 (24%) patients. Twenty patients died, and 10 deaths were classified as TRM.

Section Summary: Systemic Sclerosis (Scleroderma)
Evidence for the use of HCT in patients with systemic sclerosis/scleroderma consists of systematic reviews, 3 RCTs, and several nonrandomized studies. All 3 RCTs report long-term improvements in clinical outcomes such as mRSS and FVC, as well as overall mortality in patients receiving autologous HCT compared with patients receiving chemotherapy alone. However, due to small sample sizes in 2 of the RCTs, only the large RCT shows statistical significance. Treatment-related mortality and adverse events are higher among the patients receiving HCT compared with patients receiving chemotherapy alone.

Systemic Lupus Erythematosus
Clinical Context and Therapy Purpose

The purpose of HCT in patients who have SLE is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with SLE.

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medical therapy. Most patients with autoimmune disorders such as SLE respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive.

Outcomes
The general outcomes of interest include OS, symptoms, QOL, TRM, and treatment-related morbidity. Specific outcomes of interest include PFS, OS, improvement in clinical symptoms, adverse events, and TRM.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Review
Leone et al. (2018) conducted a systematic review of clinical and laboratory studies using autologous HCT for patients with SLE.³⁷ The literature search, conducted through 2014, identified 25 studies (n = 279 patients): 2 prospective, 10 retrospective, and 13 case reports. Quality assessment of included studies was not discussed in the publication. Heterogeneity between studies was high (I2 = 87%). The only pooled analysis conducted was on 5 studies reporting deaths, resulting in overall mortality of 8.3% in a mean follow-up of 36 months.

Case Series
Select case series from the systematic review by Leone et al. (2018) and series published after the review are described below.

Burt et al. (2006) published results from the largest single-center series using HCT for SLE in the United States.³⁸ Between 1997 through 2005, investigators enrolled 50 patients (mean age, 30 years; 43 women, 7 men) with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement in a single-arm trial. All subjects had at least 4 of 11 American College of Rheumatology criteria for SLE and required more than 20 mg/d of prednisone or its equivalent, despite the use of cyclophosphamide. Patients underwent autologous HCT following a lymphoablative conditioning regimen. Two patients died after mobilization, yielding a TRM rate of 4% (2/50). After a mean follow-up of 29 months (range, 6 months to 7.5 years), the 5-year OS rate was 84%, and the probability of disease-free survival (DFS) was 50%. Several parameters of SLE activity improved, including renal function, SLE Disease Activity Index score, antinuclear antibody, anti-double-stranded DNA, complement C3 and C4 levels, and carbon monoxide diffusion lung capacity. The investigators suggested these results justified a randomized trial comparing immunosuppression plus autologous HCT with continued standard of care.

Song et al. (2011) reported on the efficacy and toxicity of autologous HCT for 17 patients with SLE after 7 years follow-up.³⁹ The OS and PFS rates were used to assess the efficacy and toxicity levels of the treatment. The median follow-up was 89 months (range, 33 to 110 months). The probabilities of 7-year OS and PFS were 82.4% and 64.7%, respectively. The principal adverse events included allergy, infection, elevated liver enzymes, bone pain, and heart failure. Two patients died, 1 due to severe pneumonia and the other due to heart failure at 33 and 64 months after transplantation, respectively. The authors concluded that their 7-year follow-up results suggested that autologous HCT was beneficial for SLE patients.

Leng et al. (2017) reported on 24 patients with severe SLE who received high-dose immunosuppressive therapy and HCT.⁴⁰ Patients were followed for 10 years. One patient died following treatment. At the 6-month follow-up, 2 patients had achieved partial remission, and 21 patients had achieved remission. At the 10-year follow-up, the OS rate was 86%; 16 patients remained in remission, 4 were lost to follow-up, 2 had died, and 1 had active disease.

Cao et al. (2017) reported on 22 patients with SLE who underwent autologous peripheral blood HCT.⁴¹ At 5-year follow-up, PFS was 68% and OS was 95%. At last follow-up, 10 patients had relapsed. Adverse events included infections, secondary autoimmunity, lymphoma, and malignancy. The authors noted difficulty in distinguishing between conditions caused by relapse or by the transplantation.

Burt et al. (2018) reported on 30 patients with refractory, chronic, corticosteroid-dependent SLE who underwent autologous HCT.⁴² Outcomes were measured at 6 months and yearly through 5 years. Disease remission was achieved by 24 patients. The SLE Disease Activity Index and QOL 36-Item Short-Form Health Survey improved significantly at each follow-up compared with baseline. No TRM was reported. Five grade 4 and 60 grade 3 adverse events were reported.

Section Summary: Systemic Lupus Erythematosus
Evidence for the use of autologous HCT to treat patients with SLE consists of a systematic review and numerous case series. The systematic review did not conduct a quality assessment and reported high heterogeneity among the studies. A 4% TRM rate was reported in 2 studies. High rates of remission were reported at various follow-up times and adverse event rates were high. While HCT has shown beneficial effects on patients with SLE, further investigation of more patients is needed.

Juvenile Idiopathic or Rheumatoid Arthritis
Clinical Context and Therapy Purpose
The purpose of HCT in patients who have JIA or RA is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with JIA or RA.

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medication therapy or biologic therapy. Most patients with autoimmune disorders such as JIA or RA respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive.

Outcomes
The general outcomes of interest are OS, symptoms, QOL, TRM, and treatment-related morbidity. Specific outcomes of interest include PFS, OS, improvement in clinical symptoms, adverse events, and TRM.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Registry Data
A review article by Saccardi et al. (2008) on HCT for autoimmune diseases has summarized the experience with JIA and RA as follows.⁴³ More than 50 patients with JIA have been reported to the European Society for Blood and Marrow Transplantation (EBMT) Registry. The largest cohort study initially used a single conditioning regimen and, thereafter, a modified protocol. Overall drug-free remission rate was approximately 50%. Some late relapses have been reported, and only partial correction of growth impairment has been seen. The frequency of HCT for RA has decreased significantly since 2000, due to the introduction of new biologic therapies. Most patients who have undergone HCT have had persistence or relapse of disease activity within 6 months of transplant.

Case Series
Silva et al. (2018) reported on 16 patients with JIA refractory to standard therapy or who had failed autologous HCT, who underwent allo-HCT.⁴⁴ Patients experienced significant improvements in arthritis and QOL, with 11 children achieving drug-free remission at last follow-up. At a median follow-up of 29 months, 1 patient died of probable sepsis following elective surgery and 1 died of invasive fungal infection, for a TRM rate of 12.5%.

Section Summary: Juvenile Idiopathic or Rheumatoid Arthritis
Evidence for the use of HCT on patients with JIA consists of data from an EBMT Registry (N > 50) and a case series. Different conditioning regimens were used among the patients in the registry, with remission rates averaging 50%. However, relapse has been reported within 6 months in many cases, and new biologic therapies that provide improved outcomes are available for these patients. The case series of patients with refractory JIA reported a high rate of drug-free remission (69%), with a TRM rate of 12.5%.

Chronic Inflammatory Demyelinating Polyneuropathy
Clinical Context and Therapy Purpose
The purpose of HCT in patients who have chronic inflammatory demyelinating polyneuropathy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with chronic inflammatory demyelinating polyneuropathy.

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medication therapy. Most patients with autoimmune disorders such as chronic inflammatory demyelinating polyneuropathy respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive.

Outcomes
General outcomes of interest are OS, symptoms, health status measures, QOL, TRM, and treatment-related morbidity. Specific outcomes of interest include PFS, OS, improvement in clinical symptoms, adverse events, and TRM.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Several review articles have summarized experience with HCT in the treatment of chronic inflammatory demyelinating polyneuropathy.^45,46,47 In general, the evidence includes a few case reports describing outcomes for autologous HCT in patients who failed standard treatments such as corticosteroids, intravenous immunoglobulins, and plasma exchange. While improvements were reported, some with long-term follow-up, the numbers of patients undergoing the procedure are small, and the potential for serious adverse events is a concern.

Nonrandomized Studies
Burt et al. (2020) reported results from a single-center, open-label prospective cohort of 60 patients with chronic inflammatory demyelinating polyneuropathy treated with HCT (Table 7).⁴⁸Patients were required to have failed 2 of 3 first-line treatments (corticosteroids, intravenous immune globulin, or plasmapheresis). Results for key endpoints are reported in Table 8. No TRM occurred, and 3 (4.5%) patients experienced grade 4 toxicities (hypokalemia, use of continuous positive airway pressure for dyspnea, and use of total parenteral nutrition for nausea and vomiting).

Table 7. Characteristics of Observational Studies of HCT for Chronic Inflammatory Demyelinating Polyneuropathy

Study	Study Design	Country	Participants	N	Follow-Up, median years (range)
Burt (2020)⁴⁸	Prospective cohort	United States	Patients with chronic inflammatory demyelinating polyneuropathy who failed at least 2 of 3 first-line treatments	60	4.5 (2 to 5)

HCT: hematopoietic cell transplantation.

Table 8. Results of Observational Studies of HCT for Chronic Inflammatory Demyelinating Polyneuropathy

Study	OS, % (95% CI)	Medication-free remission (%)	Ambulation-free assistance (%)
Burt (2020)⁴⁸	97 (NR)	1 year: 80 2 years: 78 3 years: 76 4 years: 78 5 years: 83	1 year: 82 2 years: 82 3 years: 81 4 years: 86 5 years: 83

CI: confidence interval; HCT: hematopoietic cell transplantation; NR: not reported; OS: overall survival.

Section Summary: Chronic Inflammatory Demyelinating Polyneuropathy
Evidence for the use of HCT to treat patients with chronic inflammatory demyelinating polyneuropathy is limited to a recent observational study and case reports. Additional investigations are needed due to the toxicity associated with this procedure.

Type 1 Diabetes
Clinical Context and Therapy Purpose
The purpose of HCT in patients who have type 1 diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with type 1 diabetes.

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medication therapy. Most patients with type 1 diabetes are managed with insulin therapy.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCT.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Sun et al. (2020) published a meta-analysis on the use of HCT to treat type 1 diabetes using data from RCTs published to March 2019 (Tables 9 and 10).⁴⁹The authors included randomized and non-randomized studies in the systematic review, but performed a quantitative meta-analysis using only data from randomized studies; these results are presented in Tables 10 and 11. Most domains of bias in the RCTs were rated as low or unclear risk. Results of the meta-analysis found that, compared with insulin therapy, HCT therapy significantly reduced HbA1c levels, increased fasting C-peptide levels (C-peptide measures islet cell mass, and an increase after HCT indicates preservation of islet cells), and reduced insulin dosages at 6 months of treatment, while not significantly increasing risk of adverse events. The authors concluded HCT for type 1 diabetes may improve glycemic control and beta cell function without increasing risk of adverse events.

El-Badawy and El-Badri (2016) published a meta-analysis on the use of HCT to treat diabetes (Tables 9 and 10).⁵⁰ The literature search, conducted through August 2015, identified 22 studies for inclusion; study design of included studies was not consistently reported. Fifteen of the studies (n = 300 patients) involved patients with type 1 diabetes; 7 studies (n = 224 patients) involved patients with type 2 diabetes. Results for the cohort of patients with Type 1 diabetes are presented in Table 11. The quality of the selected studies was assessed using Cochrane criteria; however, results of the risk of bias assessment were not reported in the publication. The mean follow-up in the studies ranged from 6 to 48 months (median, 12 months). Table 12 presents comparisons of C-peptide levels and hemoglobin A1c levels after 12-month follow-up. Adverse events were reported in 22% of the patients, with no reported mortality. Reviewers concluded that remission of diabetes is possible and safe with stem cell therapy, patients with previously diagnosed ketoacidosis are not good candidates for HCT, and that early-stage patients may benefit more from HCT. Large-scale well-designed randomized studies considering stem cell type, cell number, and infusion method are needed.

Table 9. Comparison of Studies Included in Systematic Reviews of Studies of Patients With Diabetes Treated With HCT

Study	Sun (2020)⁴⁹	El-Badawy and El-Badri (2011)⁵⁰
Cai (2016)	⚫
Carlsson (2015)	⚫	⚫
Ghodsi (2012)	⚫
Hu (2013)	⚫	⚫
Zhang (2016)	⚫	⚫
Gu (2018)	⚫	⚫
Gu (2014)	⚫	⚫
Hou (2014)	⚫	⚫
Walicka (2018)	⚫	⚫
Wang (2013)	⚫	⚫
Ye (2017)	⚫	⚫
Yu (2011)	⚫	⚫
Zhao (2012)	⚫	⚫
Thakkar (2015)		⚫
D'Addio (2014)		⚫
Haller (2013)		⚫
Bhansali (2013)		⚫
Giannopoulou (2013)		⚫
Mesples (2013)		⚫
Li (2012)		⚫
Zhang (2012)		⚫
Gu (2012)		⚫
Haller (2011)		⚫
Snarski (2010)		⚫
Vanikar (2010)		⚫
Couri (2009)		⚫
Haller (2009)		⚫
Liu (2014)		⚫
Wu (2014)		⚫
Tong (2013)		⚫
Hu (2012)		⚫
Jiang (2011)		⚫
Bhansali (2009)		⚫

HCT: hematopoietic cell transplantation.

Table 10. Summary of Systematic Reviews of Studies of Patients With Diabetes Treated with HCT

Study	Dates	Studies	Participants	N (range)	Duration
Sun (2020)⁴⁹	To March 2019	13 (5 RCTs, 8 non-randomized studies)	Patients with Type 1 diabetes	396 (3 to 28) (RCTs and non-randomized studies) 154 (20 to 42) (RCTs only)	12 to 50 months
El-Badawy and El-Badri (2011)⁵⁰	To August 2015	22	Patients with Type 1 diabetes (15 studies; n = 300); patients with Type 2 diabetes (7 studies; n = 224)	524 (8 to 118)	6 to 48 months

HCT: hematopoietic cell transplantation; RCT: randomized controlled trial.

Table 11. Results of Systematic Reviews of Studies of Patients With Diabetes Treated With HCT

Study	Efficacy Outcomes			Adverse Event
	C-peptide levels	HbA1c	Insulin dosage	Infection	Gastrointestinal symptoms
Sun (2020)⁴⁹
Total N	151	71	93	88	88
Pooled effect (95% CI)	MD, -1.20 (-1.91 to -0.49)	MD, -1.20 (-1.91 to -0.49)	SMD, -3.35 (-7.02 to 0.32)	Relative risk, 0.97 (0.40 to 2.34)	Relative risk, 0.69 (0.14 to 3.28)
I² (p)	96% (.00001)	96% (.00001)	96% (< .00001)	45% (.95)	0% (.64)
Range of N	18 to 42	18 to 42	18 to 42	NR	NR
Range of effect sizes	-0.10 to -2.07	-0.10 to -2.07	0 to -6.38	NR	NR
El-Badawy and El-Badri (2011)⁵⁰
Total N	199	193	NR	NR	NR
Pooled effect (95% CI)	SMD vs. baseline, -0.57 (-0.79 to -0.35)	SMD vs. baseline, 1.09 (0.83 to 1.35)
I² (p)	90% (< .00001)	96% (< .00001)
Range of N	7 to 65	7 to 65
Range of effect sizes	-1.37 to 1.07	0.05 to 3.87

CI: confidence interval; HbA1c: hemoglobin A1C; HCT: hematopoietic cell transplantation; MD: mean difference; NR: not reported; SMD: standardized mean difference.

Table 12. Standardized Mean Differences From Baseline in C-Peptide and HbA1C Levels in Patients With Diabetes Treated With HCT After 12 Months of Follow-Up

Diabetes Subgroups	No. of Studies	No. of Patients	SMD (95% CI) C-Peptide	No. of Studies	No. of Patients	SMD (95% CI) HbA_1c
Type 1
UCB	4	56	1.07 (0.67 to 1.48)	4	61	0.05 (-0.30 to 0.41)
UC-MSC	1	15	-0.91 (-1.67 to -0.16)	1	15	1.19 (0.41 to 1.98)
BM-HSC	4	97	-1.37 (-1.69 to -1.05)	3	96	3.87 (3.29 to 4.44)
BM-MSC	1	10	-1.18 (-2.15 to -0.22)	NA	NA	NA
IS-ADSc + BM-HSC	2	21	-1.01 (-1.73 to -0.30)	2	21	0.93 (0.27 to 1.59)
Total	12	199	-0.57 (-1.73 to -0.35)	10	193	1.09 (0.83 to 1.35)

Adapted from El-Badawy and El-Badri (2016).50,
BM-HSC: bone marrow hematopoietic stem cells; BM-MSC: bone marrow mesenchymal stem cells; CI: confidence interval; HbA1C: hemoglobin A1c; HCT: hematopoietic cell transplantation; IS-ADSc: insulin secreting-adipose derived stem cells; NA: not applicable; SMD: standard mean difference; UCB: umbilical cord blood; UC-MSC: umbilical cord mesenchymal stem cells.

Case Series
Several case series have evaluated autologous HCT in patients with new-onset Type 1 diabetes; there were no published comparative studies. Although a substantial proportion of patients tended to become insulin-free after HCT, remission rates were high.

Cantu-Rodriguez et al. (2016) published a study of 16 patients with Type 1 diabetes who received a less toxic conditioning regimen and transplantation.⁵¹ The outpatient procedures were completed without severe complications. At the 6-month follow-up, 3 (19%) were nonresponders, 6 (37%) partially independent from insulin, and 7 (44%) were completely independent of insulin. Hemoglobin A1C levels decreased by a mean of -2.3% in the insulin-independent group.

Xiang et al. (2015) published data on 128 patients ages 12 to 35 years who had been diagnosed with Type 1 diabetes no more than 6 weeks before study enrollment.⁵² After a mean follow-up of 28.5 months (range, 15 to 38 months), 71 (55%) patients were considered to be insulin-free. These patients had a mean remission period of 14.2 months. The other 57 (45%) patients were insulin-dependent. The latter group included 27 patients with no response to treatment and another 30 patients who relapsed after a transient remission period. Adverse events included ketoacidosis and renal dysfunction (1 patient each); there was no transplant-related mortality. In multiple logistic regression analysis, factors independently associated with becoming insulin-free after autologous HCT were younger age at onset of diabetes, lower tumor necrosis factor α levels, and higher fasting C-peptide levels.

A case series by Snarski et al. (2016) reported on 24 patients with a diagnosis of type 1 diabetes who underwent autologous HCT.⁸ Mean age was 26.5 years (range, 18 to 34 years). After treatment, 20 (87%) of 23 patients went into diabetes remission, defined as being insulin-free with normoglycemia for at least 9.5 months. The median time of remission was 31 months (range, 9.5 to 80 months). Mean insulin doses remained significantly lower than baseline doses at 2 and 3 years, but the insulin doses returned to pre-HCT levels at years 4 and 5. Among 20 patients remaining in follow-up at the time of data analysis for publication, 4 (20%) remained insulin-free. In an update published by Walicka et al. (2018), after 6 years of follow-up, 1 patient remained insulin-free.⁵³Adverse events include neutropenic fever in 12 (50%) patients. There were 4 cases of sepsis, including a fatal case of Pseudomonas aeruginosa sepsis. There was also a case of pulmonary emphysema after insertion of a central venous catheter.

Section Summary: Type 1 Diabetes
Evidence for the use of HCT to treat diabetes consists of several case series and 2 meta-analyses. The meta-analyses revealed that HCT may improve HbA1 and C-peptide levels compared with baseline values and compared with insulin. One meta-analysis found that HCT is more effective in patients with type 1 diabetes compared with type 2 diabetes, and when the treatment is administered soon after the diagnosis. Certain factors limit the conclusions that can be drawn about the overall effectiveness of HCT to treat diabetes due to heterogeneity in the stem cell types, cell number infused, and infusion methods. Case series reported short-term effectiveness in achieving insulin independence; however, long-term studies showed that a majority of patients returned to insulin within 4 to 6 years.

Other Autoimmune Diseases
Clinical Context and Therapy Purpose
The purpose of HCT in patients who have other autoimmune diseases is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with other autoimmune diseases (e.g., Crohn disease, immune cytopenias, relapsing polychondritis).

Interventions
The therapy being considered is HCT.

Comparators
Comparators consist of conventional medication therapy. Most patients with autoimmune disorders respond to conventional therapies, which consist of anti-inflammatory agents, immunosuppressants, and immunomodulating drugs; however, conventional drug therapies are not curative, and a proportion of patients suffer from autoimmune diseases that range from severe to recalcitrant to rapidly progressive.

Follow-up for 1 year is standard to measure treatment-related adverse events and mortality. Several years of follow-up are necessary to determine the efficacy of treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Crohn Disease
Phase 2/3 protocols are being developed for Crohn disease.

Hawkey et al. (2015) have the only RCT (ASTIC trial; NCT00297193) evaluating the effect of HCT on Crohn disease.⁵⁴ Patients were randomized to receive either immunoablation and HCT (n = 23) or control (HCT deferred for 1 year, n = 22). The primary endpoint was remission defined as Crohn Disease Activity Index < 150; no use of corticosteroids or immunosuppressive drugs or biologics for 3 months; and no endoscopic or radiologic evidence of active disease. At 1 year follow-up, 2 patients in the treatment group and 1 patient in the control group achieved remission (p = .6). Adverse events were reported in 76 patients receiving HCT and in 38 controls. One HCT patient died.

Lindsay et al. (2017) reported additional analyses on the ASTIC trial participants, combining the treated patients and the control patients who underwent deferred HCT.⁵⁵ Outcomes were 3-month steroid-free clinical remission at 1 year and degree of endoscopic healing at 1 year. Three-month steroid-free clinical remission was achieved by 13 of 34 (38%; 95% CI, 22% to 55%) patients who had data available. Complete endoscopic healing was seen in 19 of 38 patients (50%; 95% CI, 34% to 66%). However, serious adverse events were experienced in 23 of 40 patients.

Brierley et al. (2018) published a review of patients in the EBMT Registry undergoing autologous HCT for Crohn disease (n = 82) who had failed a median of 6 lines of drug therapy.⁵⁶ At a median follow-up of 41 months, 68% achieved either complete remission or significant improvement in symptoms. One patient died of causes relating to the transplant (cytomegalovirus infection, sepsis, and organ failure). At a median of 10 months follow-up, 73% resumed medical therapy for Crohn disease.

Additional Autoimmune Diseases
For the remaining autoimmune diseases (e.g., immune cytopenias, relapsing polychondritis), sample sizes are too small to draw conclusions.

A case series of 7 patients with myasthenia gravis was reported by Bryant et al. (2016).⁵⁷ Using the Myasthenia Gravis Foundation of America clinical classification, all patients achieved complete stable remission, with follow-up from 29 to 149 months. The authors concluded that these positive long-term results warranted further investigation of HCT for patients with myasthenia gravis.

Section Summary: Other Autoimmune Diseases
Evidence for the use of HCT to treat Crohn disease consists of 1 RCT and a retrospective review of registry data. While remission was experienced by some patients receiving HCT, adverse event rates were high, and many patients had a recurrence of symptoms within 1 year.

Evidence for the use of HCT to treat other autoimmune diseases consists of case series. Information from larger prospective studies is needed.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society for Transplantation and Cellular Therapy
In 2020, the American Society for Transplantation and Cellular Therapy (formerly the American Society for Blood and Marrow Transplantation) published consensus guidelines on the use of hematopoetic cell transplantation (HCT) to treat specific conditions in and out of the clinical trial setting.⁵⁸ Table 13 summarizes recommendations for specific indications addressed in this guideline.

Table 13. Recommendations for the Use of HCT To Treat Autoimmune Diseases

Indications for HCT in Pediatric Patients (Generally < 18 y)	Allogeneic HCT^a	Autologous HCT^a
Juvenile rheumatoid arthritis	D	R
Systemic sclerosis	D	R
Other autoimmune and immune dysregulation disorders	R	N
Indications for HCT in Adults > 18 y
Multiple sclerosis	N	C
Systemic sclerosis	N	S
Rheumatoid arthritis	N	D
Systemic lupus erythematosus	N	D
Crohn disease	N	D
Polymyositis-dermatomyositis	N	D

HCT: hematopoietic cell transplantation.
a “Standard of care (S): This category includes indications that are well defined and are generally supported by evidence in the form of high quality clinical trials and/or observational studies (e.g., through CIBMTR or EBMT).” “Standard of care, clinical evidence available (C): This category includes indications for which large clinical trials and observational studies are not available. However, HCT/immune effector cell therapy (IECT) has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multi-center cohort studies. HCT/IECT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care’.” "Standard of care, rare indication (R): Indications included in this category are rare diseases for which clinical trials and observational studies with sufficient number of patients are not currently feasible because of their very low incidence. However, single-center or multicenter or registry studies in relatively small cohorts of patients have shown HCT/IECT to be effective treatment with acceptable risks of morbidity and mortality. For patients with diseases in this category, HCT/IECT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits." “Developmental; (D): Developmental indications include diseases where pre-clinical and/or early phase clinical studies show HCT/IECT to be a promising treatment option. HCT/IECT is best pursued for these indications as part of a clinical trial. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care, Clinical Evidence Available’ or ‘Standard of Care’.” “Not generally recommended (N): HCT/IECT is not currently recommended for these indications where evidence and clinical practice do not support the routine use of HCT/IECT. However, this recommendation does not preclude investigation of HCT/IECT as a potential treatment and may be pursued for these indications within the context of a clinical trial."

U.S. Preventive Services Task Force Recommendations
Not applicable

Table 14. Nationally Covered and Noncovered Indications for HCT

Covered and Noncovered Indications
Nationally covered indications
Allogeneic HCT
“Effective ... 1978, for the treatment of leukemia, leukemia in remission, or aplastic anemia when it is reasonable and necessary”
“Effective ... 1985, for the treatment of severe combined immunodeficiency disease (SCID) and for the treatment of Wiskott-Aldrich syndrome”
“Effective ... 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”
Autologous HCT
"Effective...1989, [autologous HCT] is considered reasonable and necessary … 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 leukocyte 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."
"Effective...2000, single [autologous HCT] 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. Adequate cardiac, renal, pulmonary, and hepatic function."
"Effective...2005, when recognized clinical risk factors are employed to select patients for transplantation, high dose melphalan (HDM) together with [autologous HCT] 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 Cardiac left ventricular ejection fraction (EF) greater than 45%"
Nationally noncovered indications
Allogeneic HCT
"Effective ... 1996, through January 26, 2016, allogeneic [HCT] is not covered as treatment for multiple myeloma."
Autologous HCT
"Insufficient data exist to establish definite conclusions regarding the efficacy of [autologous HCT] 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 [autologous HCT]) for patients with multiple myeloma; Effective ... 2000, non primary AL amyloidosis; and, Effective ... 2000 through March 14, 2005, primary AL amyloidosis for Medicare beneficiaries age 64 or older. In these cases, [autologous HCT] is not considered reasonable and necessary...and is not covered under Medicare."

HCT: hematopoietic cell transplantation.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 15.

Table 15. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02674217	Outpatient Hematopoietic Grafting in Patients with Multiple Sclerosis Employing Autologous Non-cryopreserved Peripheral Blood Stem Cells: a Feasibility Study	1000	Dec 2025
	ion
NCT01895244	High-dose Chemotherapy and Transplantation of 43+ Selected Stem Cells for Progressive Systemic Sclerosis - Modification According to Manifestation	44	Sep 2024
NCT03477500	Randomized Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab for Patients with Relapsing Remitting Multiple Sclerosis	100	Mar 2026
NCT04047628	A Multicenter Randomized Controlled Trial of Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Treatment-Resistant Relapsing Multiple Sclerosis (ITN077AI)	156	Oct 2029
NCT03219359	Maintenance in Autologous Stem Cell Transplant for Crohn's Disease (MASCT - CD)	50	Sep 2028
NCT00716066	High-Dose Immunosuppressive Therapy Using Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) + Thymoglobulin Followed by Syngeneic or Autologous Hematopoietic Cell Transplantation for Patients With Autoimmune Neurologic Diseases	40	Jun 2033
NCT05029336	Autologous Stem Cell Transplant (ASCT) for Autoimmune Diseases	20	May 2031
NCT03000296	Autologous Unselected Hematopoietic Stem Cell Transplantation for Refractory Crohn’s Disease	50	Dec 2024
Unpublished
NCT03562208^a	Autologous Bone Marrow Transplant in Chronic Insulin Dependent Diabetic Patients Phase II Clinical Trial	100	Jun 2020
NCT03069170	Safety and Efficacy of Immuno-Modulation and Autologous Bone-Marrow Derived Stem Cell Transplantation for the Treatment of Multiple Sclerosis	50	Jan 2021
NCT03113162	Evaluation of the Safety and Efficacy of Reduced-Intensity Immunoablation and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Multiple Sclerosis	15	May 2022
NCT00750971	An Open-Label, Phase II Multicenter Cohort Study of Immunoablation with Cyclophosphamide and Antithymocyte-Globulin and Transplantation of Autologous CD34-Enriched Hematopoietic Stem Cells versus Currently Available Immunosuppressive /Immunomodulatory Therapy for Treatment of Refractory Systemic Lupus Erythematosus	30	Aug 2020

NCT: national clinical trial.
a Denotes industry sponsored or co-sponsored trial.

References

Nikolov NP, Pavletic SZ. Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease. Nat Clin Pract Rheumatol. Apr 2008; 4(4): 184-91. PMID 18285764
Milanetti F, Abinun M, Voltarelli JC, et al. Autologous hematopoietic stem cell transplantation for childhood autoimmune disease. Pediatr Clin North Am. Feb 2010; 57(1): 239-71. PMID 20307720
Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United States. Biol Blood Marrow Transplant. Jan 2010; 16(1 Suppl): S48-56. PMID 19895895
Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler. Feb 2011; 17(2): 204-13. PMID 20921236
Sormani MP, Muraro PA, Schiavetti I, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. May 30 2017; 88(22): 2115-2122. PMID 28455383
Ge F, Lin H, Li Z, et al. Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis. Neurol Sci. Mar 2019; 40(3): 479-487. PMID 30535563
Nabizadeh F, Pirahesh K, Rafiei N, et al. Autologous Hematopoietic Stem-Cell Transplantation in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Neurol Ther. Dec 2022; 11(4): 1553-1569. PMID 35902484
Snarski E, Milczarczyk A, Hałaburda K, et al. Immunoablation and autologous hematopoietic stem cell transplantation in the treatment of new-onset type 1 diabetes mellitus: long-term observations. Bone Marrow Transplant. Mar 2016; 51(3): 398-402. PMID 26642342
Mancardi GL, Sormani MP, Gualandi F, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. Mar 10 2015; 84(10): 981-8. PMID 25672923
Burt RK, Balabanov R, Burman J, et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. Jan 15 2019; 321(2): 165-174. PMID 30644983
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): 1066-70. PMID 21422458
Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. Nov 2012; 40(11): 892-8. PMID 22771495
Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician's and patient's perspectives. Ann Hematol. Jul 2015; 94(7): 1149-57. PMID 25711670
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): 835-42. PMID 22127896
Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. Jan 20 2015; 313(3): 275-84. PMID 25602998
Burman J, Iacobaeus E, Svenningsson A, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. Oct 2014; 85(10): 1116-21. PMID 24554104
Atkins HL, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. Aug 06 2016; 388(10044): 576-85. PMID 27291994
Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. Feb 28 2017; 88(9): 842-852. PMID 28148635
Muraro PA, Pasquini M, Atkins HL, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. Apr 01 2017; 74(4): 459-469. PMID 28241268
Kvistad SAS, Lehmann AK, Trovik LH, et al. Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway. Mult Scler. Dec 2020; 26(14): 1889-1897. PMID 31833798
Boffa G, Massacesi L, Inglese M, et al. Long-term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. Feb 22 2021; 96(8): e1215-e1226. PMID 33472915
Burt RK, Han X, Quigley K, et al. Real-world application of autologous hematopoietic stem cell transplantation in 507 patients with multiple sclerosis. J Neurol. May 2022; 269(5): 2513-2526. PMID 34633525
Milanetti F, Bucha J, Testori A, et al. Autologous hematopoietic stem cell transplantation for systemic sclerosis. Curr Stem Cell Res Ther. Mar 2011; 6(1): 16-28. PMID 20955159
Host L, Nikpour M, Calderone A, et al. Autologous stem cell transplantation in systemic sclerosis: a systematic review. Clin Exp Rheumatol. 2017; 35 Suppl 106(4): 198-207. PMID 28869416
Shouval R, Furie N, Raanani P, et al. Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant. May 2018; 24(5): 937-944. PMID 29374527
Higashitani K, Takase-Minegishi K, Yoshimi R, et al. Benefits and risks of haematopoietic stem cell transplantation for systemic sclerosis: A systematic review and meta-analysis. Mod Rheumatol. Mar 02 2023; 33(2): 330-337. PMID 35285885
Bruera S, Sidanmat H, Molony DA, et al. Stem cell transplantation for systemic sclerosis. Cochrane Database Syst Rev. Jul 29 2022; 7(7): CD011819. PMID 35904231
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, randomised phase 2 trial. Lancet. Aug 06 2011; 378(9790): 498-506. PMID 21777972
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): 2490-8. PMID 25058083
Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. Jan 04 2018; 378(1): 35-47. PMID 29298160
Vonk MC, Marjanovic Z, van den Hoogen FH, et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. Jan 2008; 67(1): 98-104. PMID 17526554
Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, et al. Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med. Jan 2005; 118(1): 2-10. PMID 15639201
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. Aug 15 2007; 110(4): 1388-96. PMID 17452515
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): 269-75. PMID 22247352
Henes J, Oliveira MC, Labopin M, et al. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Haematologica. Feb 01 2021; 106(2): 375-383. PMID 31949011
van Bijnen S, de Vries-Bouwstra J, van den Ende CH, et al. Predictive factors for treatment-related mortality and major adverse events after autologous haematopoietic stem cell transplantation for systemic sclerosis: results of a long-term follow-up multicentre study. Ann Rheum Dis. Aug 2020; 79(8): 1084-1089. PMID 32409324
Leone A, Radin M, Almarzooqi AM, et al. Autologous hematopoietic stem cell transplantation in Systemic Lupus Erythematosus and antiphospholipid syndrome: A systematic review. Autoimmun Rev. May 2017; 16(5): 469-477. PMID 28279836
Burt RK, Traynor A, Statkute L, et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. Feb 01 2006; 295(5): 527-35. PMID 16449618
Song XN, Lv HY, Sun LX, et al. Autologous stem cell transplantation for systemic lupus erythematosus: report of efficacy and safety at 7 years of follow-up in 17 patients. Transplant Proc. Jun 2011; 43(5): 1924-7. PMID 21693301
Leng XM, Jiang Y, Zhou DB, et al. Good outcome of severe lupus patients with high-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation: a 10-year follow-up study. Clin Exp Rheumatol. 2017; 35(3): 494-499. PMID 28240594
Cao C, Wang M, Sun J, et al. Autologous peripheral blood haematopoietic stem cell transplantation for systemic lupus erythematosus: the observation of long-term outcomes in a Chinese centre. Clin Exp Rheumatol. 2017; 35(3): 500-507. PMID 28375828
Burt RK, Han X, Gozdziak P, et al. Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome. Bone Marrow Transplant. Jun 2018; 53(6): 692-700. PMID 29855561
Saccardi R, Di Gioia M, Bosi A. Haematopoietic stem cell transplantation for autoimmune disorders. Curr Opin Hematol. Nov 2008; 15(6): 594-600. PMID 18832930
M F Silva J, Ladomenou F, Carpenter B, et al. Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis. Blood Adv. Apr 10 2018; 2(7): 777-786. PMID 29618462
Kazmi MA, Mahdi-Rogers M, Sanvito L. Chronic inflammatory demyelinating polyradiculoneuropathy: a role for haematopoietic stem cell transplantation?. Autoimmunity. Dec 2008; 41(8): 611-5. PMID 18958756
Lehmann HC, Hughes RA, Hartung HP. Treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Handb Clin Neurol. 2013; 115: 415-27. PMID 23931793
Peltier AC, Donofrio PD. Chronic inflammatory demyelinating polyradiculoneuropathy: from bench to bedside. Semin Neurol. Jul 2012; 32(3): 187-95. PMID 23117943
Burt RK, Balabanov R, Tavee J, et al. Hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol. Nov 2020; 267(11): 3378-3391. PMID 32594300
Sun SY, Gao Y, Liu GJ, et al. Efficacy and Safety of Stem Cell Therapy for T1DM: An Updated Systematic Review and Meta-Analysis. J Diabetes Res. 2020; 2020: 5740923. PMID 33102605
El-Badawy A, El-Badri N. Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis. PLoS One. 2016; 11(4): e0151938. PMID 27073927
Cantú-Rodríguez OG, Lavalle-González F, Herrera-Rojas MÁ, et al. Long-Term Insulin Independence in Type 1 Diabetes Mellitus Using a Simplified Autologous Stem Cell Transplant. J Clin Endocrinol Metab. May 2016; 101(5): 2141-8. PMID 26859103
Xiang H, Chen H, Li F, et al. Predictive factors for prolonged remission after autologous hematopoietic stem cell transplantation in young patients with type 1 diabetes mellitus. Cytotherapy. Nov 2015; 17(11): 1638-45. PMID 26318272
Walicka M, Milczarczyk A, Snarski E, et al. Lack of persistent remission following initial recovery in patients with type 1 diabetes treated with autologous peripheral blood stem cell transplantation. Diabetes Res Clin Pract. Sep 2018; 143: 357-363. PMID 30036612
Hawkey CJ, Allez M, Clark MM, et al. Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial. JAMA. Dec 15 2015; 314(23): 2524-34. PMID 26670970
Lindsay JO, Allez M, Clark M, et al. Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol Hepatol. Jun 2017; 2(6): 399-406. PMID 28497755
Brierley CK, Castilla-Llorente C, Labopin M, et al. Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation. J Crohns Colitis. Aug 29 2018; 12(9): 1097-1103. PMID 29788233
Bryant A, Atkins H, Pringle CE, et al. Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation. JAMA Neurol. Jun 01 2016; 73(6): 652-8. PMID 27043206
Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247-1256. PMID 32165328
Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Stem Cell Transplantation (Formerly 110.8.1) (110.23). 2016; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=366. Accessed November 14, 2023.

Coding Section

Codes	Number	Description
CPT	38204	Management of recipient hematopoietic progenitor cell donor search and cell acquisition
	38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
	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, per donor
	38209	thawing of previously frozen harvest with washing, per donor
	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	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
	38241	autologous transplantation
HCPCS	Q0083-Q0085	Chemotherapy, administer code range
	J9000-J9999	Chemotherapy drug code range
	S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic, and emergency services)
ICD-10-CM		Investigational for all relevant diagnoses
	E10.10-E10.9	Type 1 diabetes mellitus code range
	G35	Multiple sclerosis
	M05.10-M06.9	Rheumatoid arthritis code range
	M08.00-M08.99	Juvenile arthritis code range
	M32.0-M32.9	Systemic lupus erythematosus code range
	M34.0-M34.9	Systemic sclerosis [scleroderma] code range
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services
	30243G0, 30243X0,30243Y0	Administration, circulatory, transfusion, central vein, percutaneous, autologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	30243G2, 30243X2, 30243Y2	Administration, circulatory, transfusion, central vein, percutaneous, allogeneic related, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	30243G3, 30243X3, 30243Y3	Administration, circulatory, transfusion, central vein, percutaneous, allogeneic unrelated, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	30243G4, 30243X4, 30243Y4	Administration, circulatory, transfusion, central vein, percutaneous, allogeneic unspecified, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ	Surgical, lymphatic and hemic systems, extraction, bone marrow, code list
Type of Service	Therapy
Place of Service	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2024 Forward

08/23/2024 Annual review, no change to policy intent. Updating references

07/12/2024 Annual review, no change to policy intent. Adding CPT code 38204

01012024 NEW POLICY

Policy List

Edit Policy

{{ navigationConstituentPage.title || { 'medicalpolicyhb': 'Healthy Blue Medical Policies', 'medicalpolicyih': 'InStil Health Medical Policies' }[navigationSitePage.urlName] || 'Medical Policies' }}

Hematopoietic Stem Cell Transplantation for Autoimmune Diseases - CAM 80125HB