Unlike children with single lineage autoimmune cytopenias, children with autoimmune destruction of multiple cell lineages often have chronic therapy-refractory disease. Many patients develop significant morbidity from long-term corticosteroids, and novel therapeutic approaches are needed. We previously demonstrated that treatment with sirolimus (rapamycin) led to complete responses (CRs) in a small cohort of children (5 of 5) with autoimmune lymphoproliferative syndrome (ALPS) in a retrospective case series. We opened a prospective IRB-approved clinical trial treating children with treatment-refractory ALPS with sirolimus. Based on an early efficacy signal, we broadened the inclusion criteria to any children with autoimmune cytopenias who failed or were intolerant to standard immunosuppressive therapy. We have now treated 27 children on the trial.

Twelve of the children have ALPS (aged 18 mo. to 18 yrs). Of these, 10 had a durable CR, which was rigorously defined as resolution of autoimmune cytopenias (normal CBC), lymphoproliferation, and other autoimmune manifestations. One child had a near-CR (NCR) with resolution of autoimmunity but mild breakthrough adenopathy with viral illness. One child had a partial response (PR) with improvement in autoimmune disease. This child had only been on therapy for 2 months. Double negative T cells, the biologic hallmark of ALPS, are no longer detectable in 8 of 12 children, suggesting sirolimus targets the pathogenic cell population. In addition to the 12 children on the trial, we have advised clinicians treating an additional 28 children with ALPS at our own institution and at other centers in the USA and from 13 different countries. By report, the majority of these patients (24 of 28) have had complete and durable responses with sirolimus. These additional anecdotal cases support our finding of a >80% CR rate on our prospective trial. Many of these children have successfully tolerated sirolimus for over 5 years. Correlative studies in murine models in our laboratory demonstrate mTOR signaling is dysregulated in ALPS, suggesting sirolimus is targeted therapy.

Two children with common variable immunodeficiency (CVID) and two with systemic lupus erythematosus (SLE) with refractory multi-lineage autoimmune cytopenias were treated on the trial, and 3 of 4 had a CR. One had NCR with resolution of autoimmune destruction of 2 cell lineages but persistent immune thrombocytopenia (ITP; mean platelet count pre-treatment <20,000/mm3; post-treatment > 50,000/mm3). Six children with Evans syndrome (ES) have been treated on the trial with 3 CR, 1 PR, and 2 non-responders (NRs). We have treated 5 children with refractory single lineage autoimmune cytopenias (4 ITP, 1 autoimmune hemolytic anemia) with 1 CR, 1 PR, and 3 NR.

Overall CR rates for the trial are 83% (10 of 12) for ALPS, 60% for non-ALPS multi-lineage autoimmune cytopenias (6 of 10), 20% for single lineage disease (1 of 5), and 63% for the entire cohort (17 of 27). The CR + PR rate for children with multi-lineage autoimmune cytopenias is 91% (20 of 22). Of responding patients, all were steroid-refractory or intolerant and most had failed multiple agents (avg: 3; range 2-6).

Side effects were mild and included grade (gr) 1-2 mucositis (10 children; resolved after 1 month in most without therapy modification), gr1 diarrhea (1 child), gr2 acne (2), gr1-2 headache (3), and gr2 hyperlipidemia requiring therapy (2 with fish oil and 1 with statin; all responded). One child had such a rapid reduction in splenomegaly that she developed a splenic infarct potentially attributable to the sirolimus.

Studies of immune function were performed on a subset of patients. Remarkably, ALPS patients treated with sirolimus had improvement in immune function and developed normal B and T cell numbers and function. In contrast, patients with non-ALPS immune cytopenias developed mild B and T cell immune suppression, as expected. No child developed any documented serious or opportunistic infection.

In summary, sirolimus led to complete and durable responses in a majority of children with multi-lineage autoimmune cytopenias. The responses in ALPS were profound, and these results suggest sirolimus should be considered as first-line for these children based on its efficacy and lack of significant toxicity or immunosuppression. More studies are needed for children with ES, CVID, and SLE; however, initial results of this trial are encouraging.


Off Label Use: Sirolimus for autoimmune cytopenias. Smith-Whitley:GlycoMimetics, Inc: Research Funding. Lambert:GSK: Research Funding; Nestle: Consultancy; Amgen: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.