Treatment with cyclosporin in auto-immune cytopenias in children: The experience from the French cohort OBS'CEREVANCE

To the Editor: Auto-immune cytopenias are rare and heterogeneous in children. Auto-immune hemolytic anemia (AIHA) is associated with primary immunodeficiency or autoimmune disease in 25% of cases.1 About 30% evolve toward Evans syndrome (ES). These diseases are associated with significant morbidity–mortality: the risk of death is about 10% in AIHA and 7% to 35% in ES. First-line treatment with prolonged corticosteroid is well codified but there is no consensus about second-line treatment in case of resistance or dependence to steroids. The use of cyclosporin in auto-immune cytopenias was reported in the late 1980s, with inconsistent efficacy, treatment schedules, and doses. This drug is cheap, licensed in immunologic diseases, adaptable with blood levels, and does not expose to major infections. This study reports the use of cyclosporin for the patients included in the French National prospective cohort OBS'CEREVANCE, of the French National Reference Center for the study and monitoring of pediatric auto-immune cytopenias (Bordeaux, France). The study analyzes the medical records of 34 patients: 15 AIHA and 12 ES, 7 immune thrombopenias (ITP) treated with cyclosporin between 1993 and 2013. We excluded patients with inherited cytopenia and cytopenia occurring after transplant. Usual complete remission (CR) criteria were used.2 Median age at diagnosis was 4 years [0.2–16]. Among the 15 patient treated for AIHA, 7 had a suspected or identified immunodeficiency (human leucocyte antigen class II), 1 had lupus antibodies. Three patients with ES had immunodeficiency (two auto-immune lymphoproliferative syndromes (ALPS), one LRBA mutation) and three had auto-immune disease (two lupus antibodies and one uncharacterized disease). Cyclosporin was initiated in median delay after diagnosis of 7 months [0.3–79] for AIHA and ITP, and 56 months for ES [2–130]. Thirteen patients had received other second-line treatment before. Median initial dose was 4 mg/kg/day [1.4–7]. Median duration of treatment was 8.6 months [4–51] in AIHA, 3 months in ITP and 25 months [5–52] in ES. The best response was a CR for 7/15 AIHA (6/8 patients without immunodeficiency) and 6/12 ES (including 2 with ALPS). The treatment allowed steroid decrease in 9/15 cases of AIHA and 9/12 ES. We didn't observe any efficacy in ITP. Cyclosporin was stopped because of sustained CR for four patients with AIHA and two with ES, and for failure or adverse events for the others. Median duration of response was 8.6 months in AIHA [4–51], 25 months in ES [3–52] (Figure 1). Twelve patients with AIHA and the 12 with ES needed subsequent treatments. Two died because of toxicity of other treatments, one died of acute AIHA. Evolution of patients At least one adverse event was reported for 15 patients. Hypertension was reported in 5, simultaneously treated with corticosteroids. Transient doubling of creatinine was reported for 3. Other reported side effects were hypertrichosis (N = 3), gingival hypertrophy (N = 3), elevated liver enzymes (N = 2), digestive disorders (N = 3), alopecia (N = 1). Adverse effects were the primary cause of discontinuation for five patients. This study is the largest series of cases treated with cyclosporin for childhood severe auto-immune cytopenia. It appears that cyclosporin is particularly interesting for patients treated for AIHA without immunodeficiency. In ES, steroids could be decreased in 9 of the 12 patients, and a complete or partial response was achieved in 7, with a median duration of 2 years. This work is observational. Doses and targeted residual levels were heterogeneous since there is no current recommendation in this context. A hundred of heterogenous cases of autoimmune cytopenias treated with cyclosporin with variable doses, residual levels, associated drugs, duration of treatment, efficacy criteria, also suggest benefit. Cyclosporin selectively blocks the activation of CD4+ T-lymphocytes.3 It is licensed as first-line treatment in immunologic aplastic anemia. However, many mechanisms may be involved in autoimmune cytopenia, involving dysregulation of humoral and cellular immunity. Particularly in ES, recent studies underscored the potential efficacy of sirolimus, supporting the hypothesis that it could be a form of ALPS. In this work, the underlying context seems to be an important factor of response, especially in AIHA: almost none of the patients with immunodeficiency responded to cyclosporin, while nearly all the patients with autoimmunity or isolated AIHA achieved CR. This could suggest multiple mechanisms in these diseases, depending on the underlying pathology. In ES, all the CR were transient: cyclosporin seems only suspensory, as rituximab.4 Howbeit, these patients often experiment poor prognosis, with multiple relapses despite numerous treatments: CR of few months or corticosteroid-sparing were considered as clinically significant. The median initial dose was 4 mg/kg/day. We couldn't establish a correlation between residual level, efficacy, and tolerance. It has been described that lower residual levels could have an interesting immunomodulating effect in aplastic anemia. Some cases of AIHA and ES controlled with low-dose and low blood levels have been reported.5 Indeed, low-dose cyclosporin promotes the regulatory T-cells differentiation. It was also described that initial response is observed after 21 to 28 days, maximum efficacy after 30 to 180 days6: prolonged treatment could permit more responses. The observed toxicity was acceptable and comparable with previous reports. Renal function should be monitored closely. The dose of cyclosporin is directly correlated with the severity of adverse events. Close monitoring of blood levels should help to reduce toxicity and enhance evaluation of efficacy. Cyclosporin is an interesting drug in the management of autoimmune cytopenias, with a potential immunomodulatory effect at low doses in patients treated for AIHA without underlying immune deficiency or in ES. It is mandatory to monitor blood levels to establish a correlation with the response and the tolerance. The inclusion of patients in observational databases allows to share and increase knowledge in those rare diseases. Nothing to report.