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Sirolimus shows promise for pediatric ALPS
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Treatment with sirolimus led to durable complete responses in children with refractory multi-lineage autoimmune cytopenias, according to the results of a prospective multi-institutional trial.
As such, sirolimus should be considered a first-line, non-steroidal treatment for patients with autoimmune lymphoproliferative syndrome (ALPS) who require chronic treatment, according to the researchers.
“Treatment of patients with ALPS varies significantly, with no consensus on the management,” David T. Teachey, MD, attending physician at Children’s Hospital of Philadelphia and assistant professor of pediatrics at University of Pennsylvania’s Perelman School of Medicine, and colleagues wrote. “We have previously demonstrated that treatment with the mTOR inhibitor sirolimus led to a complete response (CR) in a small retrospective cohort of 5 children with corticosteroid refractory ALPS.”
Based on the results of their initial study, Teachey and colleagues conducted a prospective, multi-institutional clinical trial to determine the efficacy of sirolimus in children with treatment-refractory ALPS.
The study included data from 30 patients aged 12 months to 39 years with autoimmune cytopenias, including 12 children with ALPS. The median age at diagnosis was 5 years (range, 5 months-19 years) and the median age at start of treatment with sirolimus was 11 years (range, 1.8-21).
Patients received 2 to 2.5 mg/m2 sirolimus per day. The anticipated length of treatment was 6 months, with responding patients given the option to continue treatment with monitored follow-up.
All 12 patients with ALPS achieved a durable CR, including rapid improvement in autoimmune disease, lymphadenopathy and splenomegaly within 1 to 3 months of treatment initiation.
The researchers noted that double-negative T cells disappeared in most patients, whereas other lymphocyte populations remained, suggesting a targeted effect of sirolimus.
Further, among 12 additional patients with multi-lineage cytopenias secondary to common variable immune deficiency, Evans syndrome or systemic lupus erythematosus, a majority (n = 8) achieved CR. However, the time to CR was delayed in these patients compared with those with ALPS.
Among six children with single lineage autoimmune cytopenias, only two patients responded.
The researchers observed favorable toxicity profiles with sirolimus. Grade 1 to grade 2 mucositis was the most commonly reported adverse event (n = 10).
All responding patients have remained on therapy for longer than 1 year (median, 2 years; range, 1-4.5).
“The responses in patients with ALPS were profound, and these results suggest sirolimus should be considered early in the management of patients who need chronic treatment,” Teachey and colleagues wrote. “Sirolimus is an effective, well-tolerated medication that has yielded durable and dramatic responses, and should be considered for refractory patients.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
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