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Edelira Longinotti

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Jul 17, 2024, 12:24:17 AM7/17/24

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Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of adults (18 to 69 years of age) with rapidly progressive scleroderma (systemic sclerosis) at risk of organ failure when either of the following is met:

Aetna considers hematopoietic cell transplantation (autologous or allogeneic) experimental and investigational for any of the following because the effectiveness of these approaches for these autoimmune diseases/conditions has not been established:

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Autoimmune diseases (ADs) include a heterogeneous group of immune-mediated disorders that are responsive to suppression or modulation of the immune system. Some common ADs are multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). The prevalence of ADs in the United States is estimated to be approximately 2 %. In particular, MS afflicts about 350,000 people in the United States, while RA and SLE affects 0.5 to 1.0 % and 0.05 % of Americans, respectively. These diseases are often characterized by chronic, painful and debilitating courses that warrant aggressive therapy. For some patients with severe, relapsing/refractory cases, conventional therapy may not be satisfactory.

High-dose chemotherapy (HDC) and bone marrow/peripheral stem cell transplantation (autologous or allogeneic) has been studied for the treatment of severe ADs. The notion of employing HDC and bone marrow/peripheral stem cell transplant to treat AD is based on encouraging results in experimental animals and from serendipitous reports of patients with both ADs and malignancies who were allotransplanted for the latter. High- dose chemotherapy and bone marrow/peripheral stem cell transplant has been tried for patients with ADs who are refractory to standard therapies and are at high-risk of subsequent morbidity and mortality. Multiple sclerosis, RA, SLE, and systemic sclerosis are the ADs that have been most commonly treated by this procedure. Although early findings are promising, the number of patients treated is limited, and only short-term follow-up is available. Furthermore, the mechanism of improvement or stabilization is unclear, and the procedure has the potential for life-threatening toxicity.

A review (Bingham et al, 2000) stated that autologous stem cell transplantation is starting to be examined as a potential therapy for severe, refractory ADs including neurological, rheumatological, and hematological diagnoses. Increasing numbers of cases are now reported in the scientific literature. Data from all transplanted patients are being collated in a centralized register by the European Group for Blood and Marrow Transplantation and the European League against Rheumatism to ensure effective assessment of the safety and effectiveness of this promising procedure. Thus far, results have been encouraging; however, they need to be confirmed by well-designed randomized, controlled studies in view of the well-known difficulty of judging objectively the effect of a treatment in patients with these diseases. Optimization of mobilization, conditioning regimen, as well as graft manipulation is needed to maximize effectiveness without increasing mortality and morbidity. The use of maintenance therapy after autologous stem cell transplantation to prevent relapse needs to be investigated. Furst (2000) noted that stem cell transplantation for the treatment of systemic sclerosis is showing some apparent effectiveness, but its use is only in the pilot stages.

Witkowska et al (2014) stated that autoimmune connective tissue diseases (ACTDs) are heterogeneous disorders associated with different manifestations, clinical course of disease and prognosis among patients. Although recent advances in understanding the pathogenesis have led to major progress in target-oriented therapy, they still remain incurable. Novel biological drugs, cellular therapy and HSCT are real hopes for treatment development in the future. The concept of both autologous and allogeneic HSCT in children with autoimmune diseases is developing energetically since 1996, when the first HSCT was performed. Nowadays, after 17 years of clinical experience, both types of HSCT remain attractive and powerful salvage methods of treatment. However, there are still many doubts and unclear issues, which need further investigation. These investigators provided an overview of the knowledge concerning actual data on HSCT in a pediatric group of patients with different ACTDs, focused on juvenile idiopathic arthritis (JIA), SLE and systemic sclerosis.

Cipriani et al (2015) stated that the presence of autoimmune diseases, including systemic sclerosis (SSc), suggest failure of the normal immune regulatory processes leading to activation and expansion of auto-reactive effector immune cells. Recently, stem cell transplantation emerged as a novel rescue therapy for a variety of refractory autoimmune diseases. The therapeutic strategy involves the ablation of the aberrant self-reactive immune cells by chemotherapy and the regeneration of a new self-tolerant immune system formed by the transplanted stem cells. In the last few years, thousands of patients worldwide have received HSCT, mostly autologous, as treatment for severe irreversible autoimmune diseases, with promising results. These investigators reviewed the results of published small series of SSc patients treated with allogeneic and autologous HSCT, as well as 3 randomized trials, exploring the safety and effectiveness of autologous HSCT in SSc. The authors concluded that although the results are encouraging, nonetheless, the correct application of stem cell transplantation remains an area of active investigation; results of larger randomized, double-blind clinical trials, will certainly improve the knowledge of the appropriate clinical use of stem cell therapy in SSc patients.

Host et al (2017) stated that autologous hematopoetic stem cell transplantation (AHSCT) has emerged as a therapeutic option for patients with refractory, severe autoimmune disease. This is a systematic review of the current literature on AHSCT in adult patients with systemic sclerosis (SSc). Original articles published between 2005 and 2016 that evaluated the use of AHSCT in patients with SSc were reviewed with respect to the primary outcomes of overall and transplant related mortality (TRM) rates, and secondary outcomes of changes in mRSS, FVC, progression-free survival (PFS)/EF) and quality of life (QOL) measures. These researchers also focused on patient characteristics, the AHSCT conditioning and mobilization regimens used, and their relationship to patient outcome in each study. Of the 155 articles found, only 9 articles were suitable for review. There were 2 randomized controlled trials (RCTs), ASTIS and ASSIST, and 7 observational and cohort studies. In general, patients undergoing AHSCT had diffuse SSc with mRSS greater than 14, and interstitial lung disease (ILD). The 2 RCTs showed a benefit in PFS/EFS (80 to 81 %), FVC and QOL measures in AHSCT compared to monthly cyclophosphamide. All the studies showed an improvement in mRSS; TRM rates varied among studies, from 0 to 23 %, with a trend to higher mortality rates in studies using higher doses of cyclophosphamide or myeloablative conditioning regimens. The authors concluded that AHSCT is beneficial in some patients with SSc and that patient selection and conditioning regimens are critical determinants of prognosis and mortality post-ASCT.

Del papa et al (2017) retrospectively evaluated the efficacy of AHSCT in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically- and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing mRSS, lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, TRM was 5.6 %. In this group, both mRSS and ESSG scores showed a significant reduction 1 year after AHSCT (p < 0.002); and these results were maintained until the end of follow-up. Conversely, DLCO values remained stable during the whole period of follow-up. Survival rate of AHSCT group was much higher than that observed in the whole control group (p = 0.0005). The probability that the ESSG score and mRSS would remain at a high level, and DLCO could decrease, was significantly higher in the control group as a whole and in the subgroup of control patients treated with cyclophosphamide than in the AHSCT group. The authors concluded that the findings of this study confirmed that the AHSCT was effective in prolonging survival, as well as in inducing a rapid reduction of skin involvement and disease activity, and preserving lung function in patients with rp-dcSSc.

The experts from the European League against Rheumatism (EULAR, 2017) recommended that hematopoietic stem cell transplantation (HSCT) should be considered for the treatment of selected patients with rapidly progressive SSc at risk of organ failure. To reduce the risk of treatment-related side effects, HSCT should be performed in selected centers with experience in this kind of treatment. Careful evaluation of the benefit to risk ratio in individual patients with SSc selected for HRCT should be done by experts. Further studies should help to identify subgroups of patients with SSc in whom HSCT would be most beneficial.

In a prospective, observational study, Nair and colleagues (2018) evaluated long-term outcomes in a cohort of patients with SSc treated with HSCT. A total of 4 SSc patients who underwent HSCT at a tertiary care center in India between 2008 to 2012 were included in this study. The selection criteria included young individuals with rapidly progressive disease and at least one major organ involvement. These researchers used granulocyte colony-stimulating factor for peripheral blood stem cell mobilization, pre-transplant conditioning with fludarabine, cyclophosphamide and rabbit anti-thymocyte globulin followed by re-infusion of autologous stem cells as per standard institute protocol. A total of 4 patients (1 male and 3 females) underwent autologous HSCT for SSc. Patients had heterogeneous disease manifestations including severe Raynaud's phenomenon with vasculopathic ulcers, gastro-intestinal (GI) problems and mild ILD. Patients were followed-up for a mean duration of 7 years. There was significant sustained improvement in skin score, vasculopathy and GI manifestations; ILD did not show any deterioration. The QOL indices showed remarkable improvement in all subjects. No complications related to transplant were noted. The authors concluded that in the absence of an effective pharmacotherapy for SSc, autologous HSCT has a huge potential in management of cutaneous and internal organ manifestations.