CurrentAetnaPolicy 0606

Hematopoietic Cell Transplantation for Autoimmune Diseases and Miscellaneous Indications

Governs medical necessity and coverage determinations for autologous and allogeneic hematopoietic cell transplantation for autoimmune diseases and miscellaneous indications, including accepted indications (e.g., rapidly progressive systemic sclerosis) and a list of conditions considered experimental/investigational.

Policy Summary

PayerAetna

PolicyHematopoietic Cell Transplantation for Autoimmune Diseases and Miscellaneous Indications

Policy CodePolicy 0606

Change TypeNo material change noted

Effective DateApr 23, 2002

Next Review DateJun 27, 2024

Key ActionObtain prior authorization and document disease severity, prior therapies, and required organ-function testing when requesting hematopoietic cell transplantation.

SourceLink

04/23/2002Policy effective (original)

08/31/2023Last review

06/27/2024Next review

83% (2 yr)NEDA rate

2.1%Pooled TRM

FVC/DLCO <70%

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Inclusion lung threshold

Coverage Criteria and Evidence Summary

Medical necessity criteria for autologous HCT in systemic sclerosis

Autologous hematopoietic cell transplantation is considered medically necessary for adults with rapidly progressive systemic sclerosis when ALL of the following are met:

Primary indication: Adult (18 to 69 years) with rapidly progressive systemic sclerosis at risk of organ failureage 18-69

Supported by trial inclusion criteria

Disease-specific criteria (any one required): 1) Active interstitial lung disease (defined by broncho-alveolar cell composition or ground-glass opacities on chest CT) plus either FVC or DLCO < 70% of predicted; OR 2) Previous scleroderma-related renal diseaseFVC or DLCO < 70% if ILD present

From policy medical necessity statement and trial inclusion

Selection and exclusion: Member meets the transplanting institution's selection criteria, or if none exist, does not have any of the following exclusions: creatinine clearance < 40 mL/min; DLCO < 40% predicted; FVC < 45% predicted; pulmonary arterial hypertension; LVEF < 50%; active gastric antral vascular ectasia; >6 months prior cyclophosphamide (trial context)see listed organ-function exclusions

Exclusion criteria drawn from policy and trial exclusions

Coverage evidence considerations

Summary of the evidence base and its limitations:

Efficacy evidence summary: AHSCT/non-myeloablative HSCT has demonstrated clinical benefits in relapsing‑remitting MS (improved EDSS, relapse- and progression-free survival, reduced MRI lesion burden) and variable results in Crohn's disease and type 1 diabetes (some patients achieved remission or insulin‑independence); much of the data derive from nonrandomized series, single-center cohorts, and small trials.

See Mancardi 2015; Burt et al. 2015; Voltarelli 2007; Hernanz 2019

Evidence limitations: Large, well-designed randomized controlled trials demonstrating long-term benefit across autoimmune indications are limited; heterogeneity of conditioning regimens, small sample sizes, and nonrandomized designs constrain generalizability.

Authors call for further RCTs and longer follow-up

Covered when ALL criteria met

AHSCT may be considered when ALL of the following selection criteria are documented:

Eligibility for AHSCT in MS (evidence-based selection): 1) Relapsing‑remitting MS with highly active disease despite disease‑modifying therapy; 2) EDSS within ranges used in trials (commonly ~3.0–6.0); 3) documented clinical relapses and MRI activity despite prior DMTs; 4) age and comorbidity profile compatible with transplant; 5) treatment to be performed in experienced transplant centers with appropriate follow-up.EDSS ~3.0–6.0 (trial ranges)

Derived from trial inclusion criteria and authors' conclusions; numeric thresholds varied by study.

Risk factors requiring caution

Features associated with higher risk or poorer outcomes that require caution or may contraindicate HSCT:

High-risk features: Older age; progressive MS phenotype (primary or secondary) without inflammatory activity; higher baseline EDSS; more than two prior disease‑modifying therapies; significant cardiac or other comorbidities that increase transplant risk.

Associated with higher progression and transplant‑related mortality in pooled and cohort studies.

AHSCT in Multiple Sclerosis

Evidence-based considerations for use of AHSCT in multiple sclerosis:

AHSCT for MS - evidence and selection: AHSCT shows high effectiveness for highly active or aggressive relapsing MS in multiple nonrandomized studies and some randomized trials; factors linked to better outcomes include relapsing‑remitting phenotype, younger age, lower baseline EDSS, and shorter disease duration. Definitive comparisons with high‑efficacy DMTs are pending ongoing RCTs.

Support from cohort studies, systematic reviews, and some randomized trials; heterogeneity in conditioning regimens limits direct comparison.

AHSCT versus other DMTs in active SPMS

Comparative outcomes reported for active secondary progressive MS:

SPMS cohort findings: In a propensity‑score matched analysis of active SPMS, AHSCT was associated with longer time to 6‑month confirmed disability progression (HR 0.50) and higher likelihood of sustained disability improvement (34.7% vs 4.6% at 3 years); applicability is limited to relatively young SPMS patients with clinical inflammatory activity.

Class III evidence from matched cohort analyses.

Allogeneic HSCT in RBDEB

Allogeneic HSCT findings in recessive dystrophic epidermolysis bullosa (RBDEB):

RBDEB outcomes: Allogeneic marrow transplantation in a small pediatric series increased type VII collagen deposition and donor cell presence in skin with improved wound healing for most patients but was associated with transplant‑related mortality in some cases; larger studies and longer follow‑up are needed.

Preliminary small‑cohort evidence; significant risks reported.

HSCT in SLE and APS

Pooled and observational findings for HSCT in SLE and APS:

SLE/APS pooled outcomes: Pooled series (25 studies; 279 SLE patients, 54 with APS) reported disease‑activity control and some survival benefit in many reports; infections were common (30.8%, 86 infections) with 3 infection‑related deaths; some APS patients (73%) could discontinue anticoagulation after HSCT. Due to AE rates, HSCT is confined to selected refractory cases.

Heterogeneous, mostly nonrandomized data; further studies needed.

Myeloproliferative neoplasms (PV/ET/PMF)

Role of HSCT in myeloproliferative neoplasms (PV/ET/PMF):

PV and related disorders: Stem‑cell transplant is not a routine therapy for PV or ET per guidelines; allogeneic transplant is considered primarily for primary myelofibrosis or selected high‑risk cases where unmet need exists.

Guidelines and reviews do not support routine transplant for PV/ET.

MSC role and evidence

Summary of MSC applications and outstanding questions:

MSC applications and uncertainties: MSCs have immunomodulatory effects useful for GVHD prevention/treatment, engraftment support, and tissue repair; unresolved issues include optimal source (bone marrow vs umbilical cord/Wharton's jelly), dosing, culture quality control, and effects on relapse and infection rates—further research required.

Multiple reviews highlight benefits and unresolved safety/quality questions.

SLE / Anti-Phospholipid Syndrome

Reiteration of SLE/APS evidence and policy implications:

SLE/APS HSCT evidence considerations: Although many reports show disease‑activity improvement after HSCT, at least one study reported no net benefit versus immunosuppression; infection rates and other AEs limit HSCT to selected refractory patients and warrant further study before broader adoption.

Pooled literature includes heterogeneous study designs and outcomes.

Autoimmune-induced liver cirrhosis (MSCT)

Allogeneic MSC transplantation for autoimmune disease–induced cirrhosis — trial summary:

MSCT cirrhosis considerations: A small trial (26 patients) of peripheral‑vein allogeneic MSC infusion reported improvements in albumin, bilirubin, and MELD score at some time points with no serious immediate infusion‑related AEs; authors recommend larger trials before broader use.

Evidence insufficient for routine coverage; investigational status suggested.

LRBA deficiency / IBD

Allogeneic HSCT in LRBA deficiency presenting with severe infantile IBD:

LRBA deficiency HSCT considerations: Allo‑HSCT in a child with LRBA deficiency produced complete remission over 6 years; genetic diagnosis, donor selection, conditioning intensity, and chimerism targets require careful consideration and further data to guide candidate selection.

Genetic diagnosis essential prior to consideration; evidence limited to case reports/series.

Pemphigus

Autologous peripheral HSCT evidence in pemphigus:

Pemphigus APHSCT findings: In a 12‑patient series of life‑threatening or refractory pemphigus, APHSCT produced 92% overall survival and 75% complete clinical remission with expected AEs; evidence is limited but suggests potential benefit in refractory severe disease.

Consider only for refractory, severe cases given small series.

Lupus nephritis

Evidence for MSCs and other stem-cell approaches in lupus nephritis:

LN MSC evidence: Small compassionate‑use reports and reviews show improvements in proteinuria and SLEDAI scores with MSCs in individual cases, but UpToDate and major guidelines do not list stem‑cell transplantation as a standard therapy for lupus nephritis.

Insufficient evidence for routine coverage; investigational in many sources.

Multiple system atrophy

Autologous MSCs in Multiple System Atrophy (MSA):

MSA MSC findings: Randomized and phase I/II studies report possible slowing of progression and imaging/clinical signals with MSC therapy; intrathecal administration may cause dose‑limiting painful implantation responses, and intra‑arterial infusion has been associated with small ischemic lesions—overall investigational.

Safety signals and limited efficacy data; further trials required.

Autism spectrum disorder (UCB)

Umbilical cord blood infusions for autism spectrum disorder — trial evidence:

Autologous/allogeneic UCB for ASD: Phase I and randomized trials show UCB infusions are generally safe but do not improve primary outcomes (socialization) in the full trial populations; subgroup or secondary endpoint signals exist for some children without intellectual disability, but evidence is insufficient for routine use.

Investigational; not listed as standard therapy in UpToDate reviews.

Stiff-person spectrum disorder

Autologous non‑myeloablative HSCT for Stiff‑Person Spectrum Disorder (SPSD):

SPSD HSCT candidate features: In a 23‑subject pilot, 74% responded and 47% had sustained remission (mean 3.5 years); responders were more likely to have episodic spasms, normal reflexes, positive CSF anti‑GAD, and absence of agonist/antagonist co‑contraction; pre‑HSCT SSRI/SNRI use was associated with relapse/non‑response.

Single‑center, Class IV evidence; selection criteria critical.

Potentially appropriate indications (based on published series/trials)

Indications reported in case series, trials, or registries that may be considered in highly selected patients:

Indications with supporting evidence: Reported uses with supportive case‑series or trial data include SPSD, CIDP, NMOSD, refractory myasthenia gravis, and other immune‑mediated neurologic diseases; evidence is heterogeneous and often limited to case series or phase II trials.

Consider only after failure of standard therapies and with specialized center expertise.

Mesenchymal stem cell therapies

Systematic-review level findings on MSC transplantation:

MSC transplantation evidence: Systematic reviews and meta‑analyses report some positive effects of MSCs across autoimmune diseases (RA, SLE, IBD, AS) with no major safety signals in included RCTs, but call for more high‑quality RCTs before routine coverage.

Insufficient high‑strength evidence for routine coverage across indications.

Retinal organoid–based therapies

Status of pluripotent stem cell‑derived retinal organoid therapies:

Retinal organoid therapy status: Preclinical and translational work support potential for retinal organoids, but further preclinical refinement and clinical trials are needed before clinical application; these approaches remain investigational.

Not ready for routine clinical use pending clinical efficacy and safety data.

Exclusion criteria for autologous hematopoietic cell transplantation in systemic sclerosis mirror the trial safety thresholds and transplant contraindications. Absolute exclusions include creatinine clearance < 40 ml/min, DLCO < 40% predicted, FVC < 45% predicted, presence of pulmonary arterial hypertension, and a left ventricular ejection fraction < 50%. Other trial-based exclusions cited include active gastric antral vascular ectasia and prior extensive cyclophosphamide exposure (> 6 months in the trial context).

The policy lists multiple autoimmune diseases and miscellaneous conditions for which hematopoietic cell transplantation (autologous or allogeneic) is considered experimental and investigational because effectiveness has not been established. Representative conditions include: anti-phospholipid syndrome; autoimmune cytopenias (autoimmune hemolytic anemia, Evans syndrome, idiopathic thrombocytopenic purpura); autoimmune-disease–induced cirrhosis; celiac disease; chronic inflammatory demyelinating polyradiculopathy; Cogan syndrome; Crohn’s disease; dermatomyositis; type I diabetes mellitus; lupus nephritis; multiple sclerosis; myasthenia gravis; neuromyelitis optica spectrum disorder; pemphigus; rheumatoid arthritis; stiff-person spectrum disorder; systemic lupus erythematosus; systemic vasculitis; ulcerative colitis; and miscellaneous conditions such as age-related macular degeneration, amyotrophic lateral sclerosis, essential thrombocythemia, polycythemia vera, recessive dystrophic epidermolysis bullosa, retinitis pigmentosa, and thrombotic thrombocytopenic purpura.

In the systemic sclerosis transplant trials, patients were excluded for conditions that increased peri-transplant risk or indicated irreversible organ dysfunction. Trial exclusion conditions specifically included active gastric antral vascular ectasia, DLCO < 40% predicted, FVC < 45% predicted, LVEF < 50%, creatinine clearance < 40 ml/min, pulmonary arterial hypertension, or prior cyclophosphamide treatment exceeding the trial limit (more than 6 months).

Across autoimmune indications, the policy emphasizes that there are currently no well-designed, large randomized controlled trials definitively demonstrating long-term clinical benefit for stem cell transplantation in most autoimmune diseases; as a result, many applications remain investigational and require further RCT evidence before routine coverage is supported.

Use of autologous HCT for progressive forms of multiple sclerosis without evidence of active inflammatory disease is not supported by the current evidence base. Editorial and observational analyses note that autologous HSCT has not demonstrated clear benefit in established progressive MS and, absent new data, is not recommended outside research settings for progressive MS without inflammatory activity.

UpToDate reviews cited in the policy do not mention transplantation as a therapeutic option for certain conditions, which the policy interprets as lack of support for transplant in those indications. Examples provided include thrombotic thrombocytopenic purpura–hemolytic uremic syndromes and severe ulcerative colitis, where UpToDate treatment reviews do not list transplantation as a management strategy.

UpToDate reviews and the cited literature do not support stem cell transplantation or umbilical cord blood as standard therapy for conditions such as lupus nephritis and multiple system atrophy; these sources classify such approaches as investigational and do not list them as routine management options in current practice.

An UpToDate review of Cogan syndrome is noted to omit autologous stem cell transplantation as a management option, indicating an absence of evidence to support HSCT for Cogan syndrome in current clinical reviews.

This Clinical Policy Bulletin is intended to assist in administering plan benefits and provides a general description of coverage considerations; it does not constitute a contract or guarantee of coverage, and participating providers remain responsible for clinical care decisions.

The policy explicitly identifies a broad set of indications and techniques as experimental and investigational (and therefore excluded from routine coverage) when effectiveness has not been established, including mesenchymal stem cell transplantation for autoimmune diseases, intra-arterial/intrathecal/intravenous MSC administration for multiple system atrophy, autologous umbilical cord blood for autism, and pluripotent stem cell–based retinal organoids for restoration of vision.

A randomized trial of autologous HSCT in Crohn’s disease (Hawkey et al, 2015) did not demonstrate a statistically significant improvement in sustained disease remission at 1 year (2 of 23 HSCT patients versus 1 of 22 controls), and HSCT was associated with substantially more serious adverse events (76 vs 38) and one treatment-related death; the authors concluded these results do not support widespread use of HSCT for refractory Crohn’s disease.

The policy states that, in the absence of robust randomized trial evidence, stem cell transplantation is not established as standard care for most autoimmune diseases and should be considered investigational or reserved for clinical trials or very selected cases where evidence supports benefit.

For multiple sclerosis, the policy highlights that autologous HSCT demonstrates benefit primarily in inflammatory, relapsing–remitting phenotypes; for patients with progressive MS without active inflammation, current data do not support routine use of AHSCT and it is not routinely indicated outside research.

A randomized, placebo-controlled trial of umbilical cord blood (UCB) infusion in children with autism (Dawson et al, 2020; n=180) found the single IV infusion to be safe but showed no evidence of improvement in the primary socialization outcome or secondary autism symptom measures for the overall trial population; subgroup signals warrant further study but do not support routine clinical use.

Pluripotent stem cell–derived retinal organoid therapies are described as a promising regenerative approach based on preclinical proof-of-concept and early translational work, but further preclinical refinement and clinical trials are required before these therapies can be considered established or covered for restoration of vision.

Candidate Selection and Eligibility

Candidate criteria for HSCT in systemic sclerosis

Candidate selection requirements for autologous HCT in systemic sclerosis:

Candidate requirements: Adult with rapidly progressive systemic sclerosis at risk of organ failure; active interstitial lung disease with FVC or DLCO <70% OR prior scleroderma‑related renal disease; meets transplant center selection criteria and does not meet listed exclusion thresholds (see pulmonary/renal/cardiac thresholds).See pulmonary/renal thresholds (FVC/DLCO <70% inclusion; DLCO <40% or FVC <45% exclusion; creatinine clearance <40 mL/min; LVEF <50% exclusion)

From medical necessity section and trial inclusion/exclusion criteria.

Candidate populations described

Populations described as candidates or studied in the literature:

Crohn's disease candidates: Adults 18–50 years with refractory Crohn's disease not amenable to surgery who have failed ≥3 immunosuppressive or biologic agents were the population studied in the randomized HSCT trial; registry series included patients with many prior lines of therapy and prior surgery.

Contraindications and High-Risk Findings

Absolute contraindications and exclusions for transplantation in the systemic sclerosis trial and in the policy include: creatinine clearance < 40 ml/min; DLCO < 40% predicted or FVC < 45% predicted; pulmonary arterial hypertension; and left ventricular ejection fraction < 50%. These thresholds are used to identify patients at prohibitive risk for transplant-related morbidity and mortality.

The policy reiterates the same absolute exclusion thresholds for systemic sclerosis transplant candidacy: creatinine clearance < 40 ml/min; severe pulmonary dysfunction defined as DLCO < 40% predicted or FVC < 45% predicted; pulmonary arterial hypertension; and cardiac dysfunction with LVEF < 50%.

These exclusion criteria are presented in the policy as absolute trial-based thresholds: patients with DLCO < 40% predicted, FVC < 45% predicted, creatinine clearance < 40 ml/min, pulmonary arterial hypertension, or LVEF < 50% would have been ineligible for the cited systemic sclerosis transplant trial and are considered contraindications in the policy context.

The policy consistently identifies poor renal, pulmonary, or cardiac function as absolute exclusions to autologous HCT for systemic sclerosis, using the trial thresholds of creatinine clearance < 40 ml/min, DLCO < 40% predicted, FVC < 45% predicted, pulmonary arterial hypertension, and LVEF < 50% to denote prohibitively high peri-transplant risk.

The policy's list of absolute exclusions is reiterated across sections and includes the same organ‑function thresholds: creatinine clearance < 40 ml/min, DLCO < 40% predicted, FVC < 45% predicted, pulmonary arterial hypertension, and LVEF < 50%.

Pre-Transplant Evaluation and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization required for hematopoietic cell transplantation (HCT) and related services. Providers must obtain prior authorization (pre-approval) for HCT (autologous or allogeneic) and associated services before scheduling or performing transplantation.

Prior authorization recommended/required for transplant or cell therapy (allogeneic and autologous HCT).
Prior authorization: document severity of disease and prior therapies attempted (including dates, doses, and responses).
Prior authorization: include evidence of eligibility and prior therapy (clinical notes, specialist evaluations, imaging, labs, and prior treatment failure documentation).
Prior authorization note: lack of prior authorization may result in claim denial or reduced reimbursement.

Documentation Required

Clinical Eligibility and Required Baseline Testing

Clinical eligibility confirmation and documentation. Before authorization, confirm the patient meets disease-specific clinical eligibility (diagnosis confirmation, disease severity, functional status, and organ-specific assessments). Include provider specialty evaluation and rationale for HCT as the selected therapy.

Prior Authorization, Documentation, and Step Therapy

Prior Authorization

Prior authorization required for HCT and related services (use listed CPT/HCPCS codes)

Obtain prior authorization for hematopoietic cell transplantation and related harvesting/transplantation services when submitting codes listed in the policy (e.g., 38204–38241, 86813–86822, 86920–86923, S2150).

Include the relevant CPT/HCPCS codes from the policy in the authorization request.
Authorization should cover harvesting, transplantation, and associated global services as encompassed by S2150.

Prior Authorization

Prior authorization strongly recommended due to significant toxicity and variable efficacy

Obtain prior authorization because HSCT carries significant toxicity and variable efficacy across indications; the policy advises authorization given the risks documented in trials (e.g., Crohn's trial with increased serious adverse events).

Provide justification of medical necessity and risk/benefit given the significant toxicity reported in randomized and registry studies.

Billing Codes and Clinical Thresholds

CPT/HCPCS codes related to transplantation and servicesmixed

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
38207-38215	Bone marrow or stem cell services/procedures
38230-38232	Bone marrow harvesting for transplantation; allogeneic or autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	Autologous transplantation
86813	HLA typing; A, B or C, multiple antigens
86817	DR/DQ, multiple antigens
86821	Lymphocyte culture, mixed (MLC)

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ICD-10 codes (covered and not covered lists)ICD-10

M34.0 - M34.9	Systemic sclerosis [scleroderma]
D45	Polycythemia vera
D47.3	Essential (hemorrhagic) thrombocythemia
D59.0 - D59.1	Autoimmune hemolytic anemia
D68.61	Antiphospholipid syndrome
D69.3	Immune thrombocytopenic purpura
D69.41	Evan's syndrome
E08.00 - E13.9	Diabetes mellitus
F84.0 - F84.9	Pervasive developmental disorders
G12.21	Amyotrophic lateral sclerosis

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Pulmonary function thresholds for scleroderma eligibility/exclusion

Inclusion threshold (pulmonary)Inclusion example: FVC or DLCO < 70% predicted when active interstitial lung disease is present.

Absolute exclusion — DLCODLCO < 40% predicted is an exclusion criterion in the cited systemic sclerosis trial.

Absolute exclusion — FVCFVC < 45% predicted is an exclusion criterion in the cited systemic sclerosis trial.

Renal and cardiac function thresholds (exclusion values)

Renal exclusion thresholdCreatinine clearance < 40 mL/min is an exclusion criterion.

Cardiac exclusion threshold

Post-Transplant Services and Follow-Up

Comprehensive transplant‑related services under S2150 (HCPCS)

HCPCS S2150 scopeS2150 describes bone marrow or blood‑derived stem cells (peripheral or umbilical), harvesting, transplantation, and related complications including pheresis, cell preparation/storage, marrow ablative therapy, drugs, supplies, hospitalization, and outpatient follow‑up.

Comprehensive services impliedPre‑ and post‑transplant care and related services are encompassed in the global description of S2150 as listed in the policy coding section.

Coding contextS2150 is listed among CPT/HCPCS codes related to transplantation and services in the policy coding table.

Longitudinal follow‑up: infection surveillance and complication management

Infection surveillance necessitySignificant post‑transplant monitoring is required due to high rates of serious adverse events and infectious complications (example: CMV disease reported after HSCT).

Provider and Center Qualifications

Prior Authorization

Perform HSCT at experienced transplant centers (EULAR recommendation)

HSCT should be performed in selected, experienced HSCT centers to reduce treatment‑related side effects; the policy and guideline references imply center expertise is required for candidate selection and follow‑up.

Document that the procedure will be performed at an experienced transplant center and include center reports or accreditation where available.

Background and Definitions

Background: Autoimmune diseases are a heterogeneous group of immune‑mediated disorders that may respond to immune suppression or modulation; some severe, refractory cases have been treated with high‑dose chemotherapy and hematopoietic stem cell transplantation (autologous or allogeneic). The policy notes that evidence is limited but growing—particularly for systemic sclerosis where randomized trials have shown benefits but with increased treatment‑related toxicity—and that HSCT carries potential for life‑threatening toxicity requiring careful patient selection and experienced centers.

High‑dose chemotherapy (HDC) and HSCT definition

HDC + HSCT definitionHigh‑dose chemotherapy (HDC) with hematopoietic stem cell transplantation involves intensive chemotherapy to ablate autoreactive immune cells followed by infusion of autologous or allogeneic hematopoietic stem cells to regenerate the immune system.

Conditioning intensityConditioning regimens vary in intensity (myeloablative, lympho‑ablative, intermediate, non‑myeloablative) and may include agents such as cyclophosphamide, busulfan, BEAM, and anti‑thymocyte globulin.

Clinical contextUsed experimentally for severe, refractory autoimmune diseases where conventional therapies have failed; trials report both efficacy and significant toxicity risks.

Policy History and Administrative Notes

Administrative note: the Clinical Policy Bulletin is developed to assist in administering plan benefits and contains only a partial, general description of plan or program benefits; it does not constitute a contract or offer of coverage and is subject to updates. Participating providers remain responsible for clinical advice and treatment decisions.

Navigation and legal caveat: additional information pages and policy history are provided for reference, and the Clinical Policy Bulletin reiterates that the bulletin does not guarantee coverage and does not replace contractual plan documents; providers should consult plan contracts and the policy history for details and updates.

Policy Summary

PayerAetna

PolicyHematopoietic Cell Transplantation for Autoimmune Diseases and Miscellaneous Indications

Policy CodePolicy 0606

Change TypeNo material change noted

Effective DateApr 23, 2002

Next Review DateJun 27, 2024

Key ActionObtain prior authorization and document disease severity, prior therapies, and required organ-function testing when requesting hematopoietic cell transplantation.

SourceLink

On This Page

Trial population described in Hawkey et al and EBMT registry analyses.

Systemic sclerosis candidates: Patients with systemic sclerosis and pulmonary involvement defined as active ILD plus FVC or DLCO <70% predicted were included in cited myeloablative autologous HCT trials, which applied cardiac, renal, and pulmonary exclusion thresholds.FVC/DLCO <70% inclusion; DLCO <40% or FVC <45% exclusion

Derived from Sullivan et al. trial inclusion/exclusion.

Very early onset IBD with IL‑10/IL‑10R deficiency: Patients with confirmed IL‑10 or IL‑10R deficiency and refractory infantile IBD have been treated with allo‑HSCT with sustained remission in small series.

Candidate context described in IBD/primary immunodeficiency literature.

Candidate indications from cited studies

Clinical populations in which AHSCT has been studied and may be considered:

Multiple sclerosis (relapsing‑remitting): RRMS refractory to DMTs has shown improvements in disability, relapse rates, and MRI lesion burden after AHSCT in cohort studies and phase II trials; greatest benefit seen in inflammatory‑active disease early in course.

Burt et al. 2009, 2015; Mancardi 2015; Atkins/HALT‑MS.

Type 1 diabetes mellitus: Small trials report periods of insulin independence and improvements in C‑peptide and HbA1c after high‑dose immunosuppression with autologous HSCs, particularly when applied early after diagnosis; evidence is limited and heterogeneous.

Voltarelli 2007; El‑Badawy 2016.

Crohn's disease: Retrospective series report clinical and endoscopic remission in subsets of refractory Crohn's patients after AHSCT, but randomized trial showed no significant sustained remission at 1 year and higher serious AEs in some reports.

Hawkey et al. randomized trial and EBMT registry data.

AHSCT candidate features

Candidate selection elements commonly used in MS trials and series:

Candidate selection: Adults (trial ages varied, commonly 18–50/69) with aggressive, treatment‑refractory RRMS; EDSS typically 3.0–6.0 in major trials; documented MRI activity or relapses despite high‑efficacy DMTs; younger age and lower baseline disability predict better outcomes.EDSS ~3.0–6.0 in trials

Supported across multiple trials and cohort studies (HALT‑MS, Burt, Atkins).

Candidate selection for MS

Selection factors associated with better outcomes in MS candidates for AHSCT:

Selection factors for better MS outcomes: Younger age, relapsing‑remitting phenotype, lower baseline EDSS score, and shorter disease duration are associated with more favorable outcomes after AHSCT.

Derived from observational studies, meta‑analyses, and registry data.

SPSD candidate selection

SPSD candidate features reported in the literature:

Candidate features for benefit in SPSD: Episodic/intermittent muscle spasms, normal tendon reflexes, positive CSF anti‑GAD serology, absence of simultaneous agonist/antagonist co‑contraction, and not taking SSRI/SNRI antidepressants were associated with response to HSCT in the pilot cohort.

Derived from Burt et al 2021 pilot study (n=23).

Selection observations for SPSD

Observational selection insights for SPSD:

SPSD candidate observations: Responders in reported series were more likely to have intermittent spasms, normal reflexes, and positive CSF anti‑GAD; EMG‑documented simultaneous agonist/antagonist contraction and pre‑HSCT SSRI/SNRI use were associated with non‑response or relapse.

Single‑center data; selection critical to observed outcomes.

Neurologic autoimmune disease candidate criteria

Neurologic autoimmune disease candidate contexts summarized:

Neurologic autoimmune indications: Reported use of HSCT in CIDP, SPS/SPSD, NMOSD, and refractory myasthenia gravis with variable rates of remission or relapse‑free survival across series; consideration is reserved for refractory/severe cases after standard therapies fail.

Evidence derives from case series, a phase II trial, and systematic reviews; larger prospective studies recommended.

Rapidly progressive systemic sclerosis in the policy context refers to patients at high risk of organ failure who were the population enrolled in pivotal trials: adults aged 18 to 69 years with disease duration typically ≤ 5 years and pulmonary or renal involvement (examples include active interstitial lung disease by chest CT/broncho‑alveolar assessment and prior scleroderma-related renal disease). Trial inclusion criteria required either active ILD plus an FVC or DLCO < 70% predicted, or prior scleroderma-related renal disease, reflecting clinical features that define the rapidly progressive phenotype.

Inclusion/exclusion thresholds (systemic sclerosis trial example)

Inclusion (example from systemic sclerosis trial)Active interstitial lung disease plus either FVC or DLCO < 70% of predicted.

Age range for medically necessary AHSCT in sclerodermaAdults 18 to 69 years of age.

Key exclusion thresholds (pulmonary)DLCO < 40% predicted or FVC < 45% predicted (trial exclusions).

Key exclusion thresholds (renal/cardiac)Creatinine clearance < 40 mL/min; left ventricular ejection fraction (LVEF) < 50%.

Autologous hematopoietic stem cell transplantation (AHSCT) definition

DefinitionAutologous hematopoietic stem cell transplantation (AHSCT) is high‑dose immunosuppression with autologous hematopoietic stem cell mobilization, collection, and reinfusion after conditioning to 'reset' the immune system.

Typical componentsMobilization (cyclophosphamide ± G‑CSF), stem cell collection by leukapheresis, conditioning (myeloablative or non‑myeloablative regimens), and reinfusion of autologous cells.

PurposeUsed to ablate autoreactive immune cells and regenerate immune tolerance in severe, refractory autoimmune diseases.

NEDA (No evidence of disease activity)

NEDA definitionNo evidence of disease activity (NEDA): composite of no clinical relapses, no new MRI lesions (including Gd‑enhancing or new T2 lesions), and no disability progression.

Reported pooled ratePooled proportion of NEDA patients at 2 years reported as 83% (range 70%–92%).

ContextDerived from meta-analysis of AHSCT studies in MS (pooled analysis of multiple studies).

Event‑free survival / progression endpoint definitions

Event-free survival (EFS) definitionSurvival without death or disease activity, where disease activity includes disability progression, clinical relapse, or new MRI lesions.

Use in trialsPrimary outcome in several MS trials (e.g., HALT‑MS defined EFS as survival without death or disease activity including EDSS progression, relapse, or new MRI lesions).

Reported EFS ratesExamples: HALT‑MS reported EFS ~69% at 3 years; other trials report 3–5 year event‑free/relapse‑free outcomes of 69–91% across studies.

6‑month confirmed disability progression (CDP) definition

6‑month confirmed disability progression (CDP) definitionAn increase in EDSS score (commonly ≥1.0 point) that is confirmed on an evaluation repeated 6 months later.

Use in randomized trialsUsed as primary or secondary endpoint to assess sustained disability worsening (example: Burt 2019 defined progression as EDSS increase confirmed at 6 months).

Reported effect with AHSCTPropensity‑matched analysis reported longer time to first 6‑month CDP with AHSCT (HR 0.50) and higher proportion free from CDP at 5 years in transplanted patients (e.g., 61.7% free from CDP at 5 years in one analysis).

In the diabetes stem cell literature summarized in the policy, patients with a history of diabetic ketoacidosis were identified as poor responders to some stem cell approaches and were excluded from certain trials; prior diabetic ketoacidosis may therefore be considered a relative contraindication or a predictor of poor response in this context.

The policy restates the same absolute exclusion thresholds across multiple sections: creatinine clearance < 40 ml/min, DLCO < 40% predicted or FVC < 45% predicted, pulmonary arterial hypertension, and LVEF < 50% are key contraindications to consideration of HCT in the systemic sclerosis trial framework.

Safety signals identified in MSC infusion and implantation studies include procedure‑related ischemic lesions after intra‑arterial MSC infusion and dose‑limiting painful implantation responses with intrathecal MSCs at higher doses; such high‑risk findings inform contraindication considerations and underscore investigational status for some MSC administration routes.

The document repeats the key absolute exclusions used to screen candidates for autologous transplantation in systemic sclerosis trials: creatinine clearance < 40 ml/min, DLCO < 40% predicted, FVC < 45% predicted, pulmonary arterial hypertension, and LVEF < 50%.

Clinical eligibility confirmation: documented diagnosis with appropriate diagnostic testing (e.g., autoantibody tests, genetic testing when indicated such as LRBA suspicion, MRI for neurologic diseases, pulmonary function tests for ILD/systemic sclerosis).
Required clinical baseline testing: organ-specific baseline studies (cardiac evaluation with LVEF, pulmonary function tests including FVC and DLCO, renal function and creatinine clearance, liver tests), infectious disease screening, and relevant neurologic or immunologic testing.
Required clinical documentation: baseline test results, specialist consultation notes, explicit statement of transplant intent, and risk/benefit assessment.

Step Therapy

Prior Therapy and Step-Therapy Context

Severity, prior therapy, and step-therapy expectations. Authorization reviewers expect documentation of disease severity, prior standard therapies used, duration and outcomes, and that HCT is being considered after inadequate response to appropriate standard treatments unless HCT is clearly indicated as first-line per evidence.

Step therapy note: when applicable, show trials of standard therapies and documented failure or intolerance before HCT (for example, refractory multiple sclerosis after disease-modifying therapy (DMT) failure).
Step therapy expectation: for autoimmune neurologic conditions (MS, NMOSD), document prior DMTs and objective evidence of continued disease activity or progression despite therapy.
Prior DMT failure considerations: specify agents tried, duration, objective response measures (EDSS, MRI activity), and reasons for intolerance or contraindication if fewer than standard therapies were used.
HCT as rescue therapy: document if HCT is proposed as rescue after failure of standard treatments.

Denial Risk

Denial Risk and Evidence Gaps

Denial risk and evidence sufficiency. Cases not meeting documentation or evidence requirements are at risk for denial. Transplants for indications without supportive evidence or insufficient documentation of severity/prior therapy are likely to be declined.

Denial risk for non-conforming indications: HCT requests outside established indications or without required documentation may be denied.
Risk of denial for non-refractory cases: requests for HCT for patients who have not failed standard therapy where step therapy is expected may be denied.
Evidence insufficiency: absence of supportive trial or case-series evidence for the indication, or missing baseline testing, increases denial risk.
Cogan syndrome and similar rare diagnoses: if no HSCT indication is cited in the evidence base, authorization is unlikely without strong supportive data.

Billing Rule

Administrative, Coding, and Submission Notes

Coding, administrative, and submission guidance. Ensure claims and authorization requests include accurate codes, complete clinical documentation, and any required forms to prevent administrative denial or delays.

Coding and documentation: submit relevant ICD-10 diagnosis codes, CPT/HCPCS procedure codes for HCT and related services, and supporting clinical records.
This section contains administrative/legislative notes: follow payer-specific prior authorization pathways and use designated portals or forms.
No denial criteria provided in these addenda: specific numeric denial thresholds beyond documentation requirements are not provided here; follow general policy rules and prior authorization decisions.
Provider action: if required documentation is not present in the submission, the request may be held or denied pending completion.

Documentation Required

Organ-Specific Risk and Eligibility

Cardiac and organ-specific risk considerations. Cardiac function and other organ-specific risk factors may affect eligibility; poor baseline organ function increases transplant risk and may render a patient ineligible.

Cardiac risk may affect eligibility: documented LVEF required (common exclusion if LVEF <50% in trials) and cardiology assessment when indicated.
Required baseline thresholds (examples from trials): FVC, DLCO, and creatinine clearance limits should be documented when relevant to the disease indication (e.g., systemic sclerosis exclusion thresholds such as DLCO <40% or FVC <45%).
Provider action: include comorbidity assessment and peri-transplant risk mitigation plans.

Note

Evidence and Justification for Authorization

Evidence submission and justification. Provide trial, case-series, registry, or published evidence that supports HCT for the specific indication, and relate the patient’s clinical course to that evidence in the authorization package.

Provide trial and case-series evidence supporting the indication (e.g., MS, systemic sclerosis, selected neurologic or immunologic diseases) as part of the prior authorization documentation.
This section contains administrative and clinical guidance: relate published outcomes, inclusion/exclusion criteria, and trial baseline thresholds to the patient’s profile.
Provider action: when evidence is limited for a rare indication, include detailed rationale and consulting specialist opinions to support medical necessity.

Prior Authorization

Include documentation of disease severity and prior therapy failures with authorization request

When requesting authorization, include documentation of disease severity and prior therapies: trial-level evidence evaluated HSCT in severe or treatment‑refractory populations and prior therapy failure history is required to justify transplant.

Submit records showing failure of conventional therapies and objective measures of disease activity (e.g., MRI lesions, EDSS, CDAI).

Prior Authorization

Confirm clinical eligibility (MS-specific) in authorization

Confirm clinical eligibility for HSCT in MS by documenting relapsing‑remitting phenotype with documented relapses and EDSS in trial ranges (commonly EDSS ~2.0–6.0) and failure of conventional DMTs as part of prior authorization.

Provide EDSS score and relapse history (e.g., ≥2 relapses while on DMT in prior year per Burt RCT).
Include MRI evidence of activity where applicable (gadolinium‑enhancing lesions).

Prior Authorization

Prior authorization for AHSCT in MS requires specialty center evaluation and prior DMT failure documentation

For AHSCT consideration in MS, include specialty center evaluation and documentation of prior DMT failure and ongoing disease activity; the policy frames AHSCT as an emerging option requiring careful selection.

Provide center evaluation notes showing multidisciplinary assessment and transplant center candidacy determination.
Document why AHSCT is preferred over alternate high‑efficacy DMTs given patient‑specific factors.

Prior Authorization

Prior authorization must demonstrate disease severity/refractoriness and include indication‑specific testing

For any transplant or experimental cell therapy, prior authorization must show disease is severe/refractory to standard therapies and include relevant diagnostic testing and prior treatment history specific to the indication.

For SLE/APS: document refractory status to standard immunosuppression and SLEDAI or anticoagulation status.
For cirrhosis/MSCT: include MELD, liver function tests, and prior interventions.

Prior Authorization

Provide trial/registry evidence and prior therapy history with authorization

Include indication‑specific evidence (trial or registry data), documentation of prior therapy failures, and patient characteristics associated with response in authorization requests, especially for neurologic indications referenced in case series and trials.

Attach relevant publications or registry reports that support the proposed indication and patient phenotype.
Summarize prior treatments tried, response durations, and why HSCT is being pursued.

Note

Consult policy history/Clinical Policy Bulletin for guidance (no extra procedural triggers in these sections)

Note in submissions that the policy is periodically reviewed and consult the Clinical Policy Bulletin for coverage guidance; the document does not provide additional explicit administrative authorization procedures in these chunks.

Clinical Policy Bulletin pages referenced for history and definitions; include policy number (0606) and last review date if helpful.

Note

No additional prior authorization codes or procedures specified in this section

The policy text does not specify additional or alternate prior authorization codes or procedural steps beyond listing CPT/HCPCS codes; do not assume extra administrative codes are required from these pages.

If your plan requires a separate prior authorization form or portal, follow payer‑specific administrative processes in addition to citing policy codes.

Step Therapy

No explicit step‑therapy algorithm specified (comparators used in trials only)

Evidence cited used active comparators but the policy does not define a formal step‑therapy algorithm; do not assume a mandated step‑therapy sequence from the policy text alone.

Clinical trials compared HSCT to agents like cyclophosphamide or mitoxantrone, but no explicit step‑therapy rules are given in the policy excerpts.

Step Therapy

Document failure of standard therapies (HCT studied as late/rescue therapy in Crohn's)

In indications such as Crohn's disease, HSCT was studied as a rescue therapy after failure of multiple immunosuppressive/biologic agents (≥3); authorization requests should document that standard therapies were tried and failed.

Provide complete treatment history including number and classes of biologic/immunosuppressive agents and reasons for failure or intolerance.

Step Therapy

Require documentation of standard therapy trial and failure before HSCT

Prior authorization requests should demonstrate that standard therapies were tried and were ineffective or not tolerated before HSCT is considered; the policy suggests requiring failure or unsuitability for standard DMTs.

For MS, list prior DMTs and dates; for other conditions, list standard immunosuppressive and biologic agents attempted.

Step Therapy

Specify prior DMT failures (number and agents) in authorization materials

Provide details of prior disease‑modifying therapy failures when applicable; trials generally enrolled patients who had failed prior DMTs and authorization should reflect that context.

State how many and which DMTs failed and include objective measures of failure (e.g., ongoing relapses, MRI activity).

Step Therapy

In MS, show failure of DMTs and ongoing inflammatory activity before authorization

For MS patients, document attempts with disease‑modifying therapies and show ongoing inflammatory activity despite therapy; policy places AHSCT mainly in highly active, refractory MS after DMT trials.

Include EDSS, relapse history, and MRI activity to show refractory, inflammatory disease state.

Step Therapy

Attempt and document standard immunosuppressive/biologic therapies first

Before considering HSCT or experimental cell therapies, conservative/standard immunosuppressive therapies and biologics should generally have been attempted and documented as ineffective or not tolerated.

Document trials of standard agents, durations, responses, and reasons for discontinuation or intolerance.

Step Therapy

For NMOSD, require trial of standard therapies before HSCT consideration

For NMOSD, document use of conventional immunotherapies and approved monoclonal agents; AHSCT is an alternative for severe or refractory cases after standard options have been considered.

Include prior monoclonal agent trials (e.g., rituximab, eculizumab) and clinical rationale why AHSCT is being pursued.

Note

No formal step‑therapy mandates in policy excerpts — verify payer administrative rules

The policy excerpts do not establish formal step‑therapy requirements; administrative processes may vary by plan and should be confirmed with the payer's authorization guidelines.

If the plan has specific step‑therapy rules, follow those in addition to the policy's clinical expectations.

Note

No additional step‑therapy rules present in these sections

The policy does not include additional step‑therapy constraints in the cited pages; absence of explicit rules means clinical justification and documentation will guide authorization decisions.

Provide robust evidence of refractory disease and rationale for HSCT in the authorization packet.

Billing Rule

Include policy-listed diagnosis and procedure codes in authorization/claims

Include diagnosis and procedure codes from the policy's coding tables with authorization and claims: document the applicable ICD‑10 diagnosis and CPT/HCPCS procedure codes (e.g., 38204–38241, 86813–86822, 86920–86923, S2150) in submissions.

Ensure claims and authorization requests reference the codes listed in the policy's CPT/HCPCS and ICD‑10 sections.
Use S2150 where applicable to reflect the global transplant-related service description.

Documentation Required

Submit required baseline clinical tests (PFTs, chest CT, LVEF, creatinine clearance)

Provide baseline clinical testing required by the policy in authorization packets: pulmonary function tests (FVC and DLCO), chest CT for ILD, echocardiogram/MUGA for LVEF, and creatinine clearance for renal function.

Report numeric results and % predicted values for FVC and DLCO.
Report creatinine clearance and LVEF values to confirm exclusion thresholds are not met.

Documentation Required

Include transplant center reports and prior treatment history as supporting documentation

Suggested supporting documentation for authorization includes prior treatment failure records, transplant center evaluation reports, and relevant trial or registry outcome summaries when applicable.

Attach transplant center consultation notes, prior therapy timelines, and outcome data from pertinent trials/registries supporting the indication.

Documentation Required

Provide baseline disease subtype, EDSS, prior therapies, and planned regimen intensity

For neurologic indications and MS, include clinical baseline documentation items listed in policy: baseline disease subtype, EDSS score, prior DMTs and their outcomes, and conditioning regimen intensity planned.

Provide EDSS at baseline, MRI findings, list of prior DMTs with dates, and proposed conditioning regimen (myeloablative vs non‑myeloablative).

Documentation Required

Provide outcome metrics (EDSS, 6‑month CDP, survival, infections) in authorization/supporting docs

When reporting outcomes or selection rationale, include EDSS scores, time to 6‑month confirmed disability progression (6‑month CDP), survival and infection outcomes as these metrics were used in trials and registries.

Provide follow‑up plans to capture EDSS and MRI monitoring intervals used in studies.
Include anticipated infection surveillance and management plans.

Documentation Required

Provide genetic diagnosis (LRBA) when requesting allo‑HSCT authorization

For allo‑HSCT consideration in LRBA deficiency, include genetic diagnostic confirmation (LRBA mutation status) in the authorization record as this was used to select candidates in the cited case report.

Attach targeted sequencing results and the genetic report demonstrating LRBA mutations prior to allo‑HSCT authorization.

Prior Authorization

Provide trial and case‑series evidence with authorization requests for non‑standard indications

Attach relevant trial publications, registry analyses, or case‑series evidence to authorization requests to support indications lacking high‑level RCT evidence; the policy expects inclusion of trial/case‑series evidence for many indications.

Include key citations (e.g., Burt et al 2021, Jaime‑Perez 2022) and brief summaries tying the patient to populations studied.

Note

Administrative note — Clinical Policy Bulletin is guidance, not a guarantee of coverage

Use administrative/navigation links and Clinical Policy Bulletin notes as references but recognize the bulletin does not itself guarantee coverage; follow payer procedures and include required clinical documentation.

Clinical Policy Bulletin pages and policy number may be referenced, but include full clinical documentation per earlier items.

Note

Administrative/legal notices — follow clinical requirements in policy for authorization

Administrative/legal notices in the Additional Information section do not specify extra provider authorization requirements; follow the clinical documentation and coding requirements outlined elsewhere in the policy.

Ensure clinical justification and required test results accompany any authorization despite lack of extra administrative rules in this section.

Denial Risk

Denial risk if request does not meet scleroderma medical necessity criteria or is for investigational indications

Requests for HCT that do not meet the policy's medical necessity criteria for autologous HCT in rapidly progressive systemic sclerosis or that are for conditions listed as experimental/investigational are at risk for denial.

Cite applicable medical necessity criteria and demonstrate how the patient meets them to reduce denial risk.

Denial Risk

Denial risk when trial exclusion thresholds (pulmonary/cardiac/renal) are met

Patients with extreme pulmonary or cardiac dysfunction (e.g., DLCO <40% predicted, FVC <45% predicted, LVEF <50%), creatinine clearance <40 mL/min, pulmonary arterial hypertension, or other listed exclusion criteria used in the scleroderma trial pose denial risk for coverage.

Verify and report numeric values; meeting any exclusion threshold cited in the trial context may render the patient ineligible per policy.

Denial Risk

Denial risk for indications lacking RCT evidence

Insufficient randomized controlled trial evidence across many autoimmune indications may justify denial or requirement for enrollment in a clinical trial when evidence of benefit is lacking.

For investigational indications, provide compelling case‑series/registry evidence or consider trial enrollment to support coverage.

Denial Risk

Denial or careful review risk when high‑risk prognostic factors are present

Higher baseline EDSS, older age, progressive MS phenotype, and multiple prior DMTs were associated with worse outcomes and higher transplant‑related mortality; these factors may prompt denial or careful review.

Include patient age, EDSS, disease subtype, and number of prior DMTs to allow risk assessment in authorization review.

Denial Risk

Cardiac dysfunction increases denial risk and must be documented

Significant cardiac dysfunction may increase risk of cardiac toxicity and could preclude transplantation; document cardiac evaluation and rationale if abnormalities are present.

Provide detailed cardiology assessment and any measures taken to mitigate cardiac risk if considering HSCT in patients with cardiac findings.

Denial Risk

Denial risk for non‑refractory cases lacking documented therapy failures

Requests for HSCT in non‑refractory cases (i.e., without documented failure of standard therapies) face higher risk of denial given high adverse event rates and limited evidence supporting routine use outside refractory populations.

Demonstrate failure/intolerance of standard therapies to justify HSCT in such cases.

Denial Risk

Denial risk for indications without evidence (example: Cogan syndrome)

Absence of evidence for HSCT in Cogan syndrome (UpToDate review does not mention HSCT) may prompt denial for that indication without compelling supporting data.

For uncommon indications without literature support, include rationale and any case reports or series if available; otherwise expect denial risk.

Note

Administrative note — rely on policy medical necessity/exclusion language for denial assessment

Policy references and history are provided for context but do not list additional denial criteria in the Additional Information pages; rely on medical necessity criteria and exclusions for coverage determinations.

Follow the explicit medical necessity and exclusion language in the policy when preparing authorization requests.

Note

No additional denial criteria provided in supplementary pages

The policy's supplemental pages do not provide extra denial criteria beyond those already stated; absent new criteria, apply the documented exclusions and medical necessity requirements.

Ensure documentation addresses the policy's explicit exclusions and required clinical criteria.

Left ventricular ejection fraction (LVEF) < 50% is an exclusion criterion.

Additional cardiac/pulmonary exclusionsPulmonary arterial hypertension listed as exclusion in trial context.

Management scopeLongitudinal follow‑up should address infectious complications, graft‑related complications, and management of transplant‑related adverse events as reported in registry and trial data.

Registry/trial evidenceEBMT registry and randomized trial reports document serious adverse events and infectious deaths, supporting need for intensive post‑transplant surveillance.

Clinical outcome and MRI surveillance post‑AHSCT

Clinical outcome surveillancePost‑AHSCT follow‑up typically includes EDSS assessments, MRI surveillance for new or enhancing lesions, and clinical relapse monitoring.

Follow‑up durations reportedStudies reported follow‑up ranging from months to years (examples: median follow‑up 2 years; mean follow‑up 2.5 years; HALT‑MS median 62 months).

Imaging outcomesMRI lesion counts and new Gd‑enhancing lesions were routinely monitored post‑transplant to assess disease activity and durability of response.

Longitudinal EDSS and MRI monitoring

EDSS monitoringLongitudinal EDSS scoring is required to detect sustained improvement or confirmed disability progression (e.g., 6‑month CDP endpoints).

MRI monitoringSerial brain MRI scans for new/enhancing T2 lesions and gadolinium‑enhancing lesions are used to evaluate ongoing inflammatory activity after AHSCT.

DurationLong‑term follow‑up (years) is necessary to assess durability of response and late adverse events; some trials report up to 13 years imaging follow‑up.

Long‑term follow‑up per transplant center protocols

Follow‑up per center protocolsPost‑transplant monitoring should follow transplant center protocols and include infection surveillance, graft function/chimerism where applicable, and disease‑specific outcome measures (e.g., EDSS for MS, SLEDAI for SLE).

Experienced center requirementLong‑term follow‑up and monitoring are typically conducted at specialized transplant centers with experience in HSCT as reported in multicenter studies and registries.

Registry reportingEBMT and multicenter study data inform recommended monitoring practices and durations; individual centers may extend surveillance based on local protocols and study findings.

Clinical and laboratory surveillance post‑infusion (liver function, MELD, adverse events)

Liver function monitoringPost‑infusion monitoring for liver function tests and MELD scores was performed in the MSC cirrhosis study with follow‑up at 6 months, 1 and 2 years.

Adverse event monitoringNo serious adverse events observed during or within 24 hours of MSC infusion in the cited 26‑patient study; routine AE surveillance recommended.

Laboratory surveillanceOngoing laboratory monitoring (LFTs, coagulation, bilirubin, albumin) should be part of post‑infusion follow‑up per study timelines.

Longitudinal outcome assessment examples (follow‑up durations reported)

Reported follow‑up durationsSPSD pilot trial: responders had sustained remission for a mean of 3.5 years; 47% remained in remission at mean 3.5 years.

Example outcome periodsMS studies reported median follow‑up 2 years (mean 2.5 years) or longer; CD registry median follow‑up 41 months; other cohorts report up to 13 years of surveillance.

Use for planning surveillancePublished follow‑up durations can inform expected monitoring intervals and duration of post‑transplant outcome assessments.

Rapidly progressive systemic sclerosis (scleroderma) definition

Rapidly progressive systemic sclerosis (definition)Systemic sclerosis with features placing the patient at risk of organ failure, including active interstitial lung disease or previous scleroderma‑related renal disease and meeting specific pulmonary, renal, and cardiac function thresholds used in trials.

Trial contextCited randomized myeloablative trial enrolled adults 18–69 years with scleroderma ≤5 years and pulmonary or renal involvement at high risk of organ failure.

Clinical implicationsRapid progression implies need for specialized transplant center evaluation and strict application of inclusion/exclusion thresholds to minimize treatment‑related mortality.

Inclusion/exclusion thresholds example (systemic sclerosis trial)

Inclusion exampleActive interstitial lung disease plus FVC or DLCO < 70% predicted was required for inclusion in the cited scleroderma trial.

Pulmonary exclusion valuesDLCO < 40% predicted or FVC < 45% predicted excluded patients in the trial context.

Other exclusionsAdditional exclusions included LVEF < 50%, creatinine clearance < 40 mL/min, pulmonary arterial hypertension, active gastric antral vascular ectasia, or >6 months prior cyclophosphamide.

AHSCT purpose (resetting the immune system)

AHSCT roleAHSCT aims to 'reset' the immune system by using high‑dose immunosuppression followed by reinfusion of autologous hematopoietic stem cells to regenerate immune tolerance.

Typical regimen elementsMobilization (cyclophosphamide ± filgrastim), collection by leukapheresis, conditioning (cyclophosphamide with ATG or alemtuzumab for non‑myeloablative regimens), then reinfusion of unmanipulated peripheral blood stem cells.

Indication contextUsed in select severe or refractory autoimmune diseases with evidence of inflammatory activity where trials have shown clinical benefit (e.g., scleroderma, RRMS).

NEDA definition and reported rate

NEDA definitionNo evidence of disease activity (NEDA): absence of relapses, new MRI lesions, and disability progression.

Reported ratePooled NEDA rate at 2 years reported as 83% in meta‑analysis of AHSCT studies in MS.

RelevanceNEDA used as a composite outcome to indicate complete control of clinical and radiologic disease activity after AHSCT.

Event‑free survival endpoint definition

Event‑free survival (EFS)Defined as survival without death or disease activity (disability progression, relapse, or new MRI lesions); used as a primary endpoint in multiple trials (e.g., HALT‑MS).

Example reported EFSHALT‑MS reported MS activity‑free survival at 3 years of ~69.6%; other trials report event‑free/relapse‑free outcomes of 69–91% over 3–5 years in selected cohorts.

Use for durability assessmentEFS/EFS‑type endpoints assess both survival and freedom from clinical or imaging evidence of disease activity post‑transplant.

AHSCT / HSCT shorthand definition

AHSCT / HSCT shorthandAHSCT refers to autologous hematopoietic stem cell transplantation; HSCT is used generically for hematopoietic stem cell transplantation (autologous or allogeneic).

Conditioning intensity noteHSCT conditioning regimens vary (myeloablative, lympho‑ablative, intermediate, non‑myeloablative) and are referenced throughout the literature on AHSCT for autoimmune diseases.

Context of useTerms used interchangeably in policy background when describing trial populations and outcomes across autoimmune indications.

6‑month confirmed disability progression (CDP) definition

6‑month CDP definitionAn increase in EDSS score confirmed on a subsequent evaluation 6 months later (commonly ≥1.0 point) indicating sustained disability progression.

Use in trialsUsed as an endpoint for disease progression in randomized and observational MS studies (e.g., Burt 2019; propensity‑matched SPMS analysis reporting time to 6‑month CDP).

Reported outcomesAHSCT associated with longer time to first 6‑month CDP in some analyses (e.g., HR 0.50 in propensity‑matched SPMS cohort).

APS definition and HSCT findings

APS definitionAnti‑phospholipid syndrome (APS) is a prothrombotic autoimmune disorder that can be associated with SLE; pooled HSCT series reported some patients achieved aPL negativization and many could discontinue anticoagulation.

HSCT findings in APSIn pooled SLE/APS reports, 32 of 44 (73%) APS patients were able to discontinue anticoagulation after HSCT; infections and AEs were common (30.8% infection rate).

Coverage implicationDue to heterogeneous evidence and infection risk, HSCT for APS is considered for selected refractory cases only in cited literature.

SPSD definition and HSCT findings

SPSD definitionStiff‑Person Spectrum Disorder (SPSD) is a rare autoimmune neurologic disorder characterized in responsive cohorts by episodic muscle spasms, often positive CSF anti‑GAD serology, and specific electromyographic features.

HSCT findingsPilot autologous non‑myeloablative HSCT produced a 74% response rate in a 23‑subject cohort with 47% remaining in remission (mean 3.5 years) among responders.

Candidate phenotypeResponders more likely to have intermittent spasms, normal reflexes, positive CSF anti‑GAD, and absence of agonist/antagonist co‑contraction.

Autologous non‑myeloablative HSCT definition

Autologous non‑myeloablative HSCT definitionA transplant approach using the patient's own hematopoietic stem cells after non‑myeloablative (less intensive) conditioning, often mobilization with cyclophosphamide + G‑CSF and conditioning with lower‑intensity cyclophosphamide + ATG or alemtuzumab.

Typical regimen componentsMobilization (cyclophosphamide 2.0 g/m2 + filgrastim), conditioning (high‑dose cyclophosphamide 200 mg/kg and rabbit ATG in many protocols), then reinfusion of unselected peripheral blood stem cells.

Clinical useUsed in MS, SPSD, and other autoimmune indications in studies reporting disability improvement and relapse control with variable toxicity profiles.

Retinal organoids (hPSC‑derived) definition

Retinal organoids definitionThree‑dimensional retinal tissue generated from human pluripotent stem cells (hPSC) that contains retinal cell types and can be used for trophic support or potential cell replacement in retinal degenerative diseases.

AdvantageshPSC‑derived organoids provide a replenishable source of human retinal cells without ethical issues of fetal tissue and may support early neurotrophic or later cell‑replacement approaches.

Developmental statusProof‑of‑concept and preclinical evidence exist, but further preclinical refinement and clinical trials are needed before clinical application and coverage.