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Sirolimus Monotherapy Found to Be Safe, Effective in Treating Children with Relapsed/Refractory Autoimmune Cytopenias

December 30, 2021

Children with multi-lineage autoimmune cytopenias often have chronic disease that is refractory to the few available treatments and require chronic immunosuppression.

Autoimmune lymphoproliferative syndrome (ALPS) is one rare disorder that can lead to the development of multi-lineage cytopenias, along with chronic nonmalignant lymphadenopathy, splenomegaly, and lymphoma. Treatment of ALPS varies, and there is no overall consensus on management of the disease. According to a recent study published in Blood, monotherapy with the mTOR inhibitor sirolimus is a safe and effective option for patients with relapsed/refractory autoimmune cytopenias, suggesting that it can be used as a first-line, steroid-sparing option earlier in treatment – particularly in patients with ALPS.

The current study expands on a previous small trial conducted by Karen L. Bride, MD, PhD, from the division of oncology at the Children's Hospital of Philadelphia in Pennsylvania, and colleagues, that found that treatment with sirolimus led to complete responses (CR) in children with ALPS. To further characterize the safety and efficacy of sirolimus in this patient population, Dr. Bride and colleagues conducted a multicenter, prospective, open-label clinical trial in 30 patients (12 months to 40 years old) with a diagnosis of autoimmune cytopenias (either autoimmune neutropenia, autoimmune thrombocytopenia, or autoimmune hemolytic anemia) requiring medication.

Following a maximum initial dose of sirolimus (4 mg/m2 per day), the drug was administered at a dose of 2 mg/m2 to 2.5 mg/m2 per day in either liquid or tablet form. The intended treatment length was six months, though patients with a good response were allowed to continue treatment with follow-up to monitor toxicities.

Of the 30 patients, 12 were diagnosed with ALPS: eight had Evans syndrome (ES), two had common variable immunodeficiency (CVID), and two had systemic lupus erythematosus (SLE). The median patient age was five years (range, 5-19 years), and the median age at the start of sirolimus treatment was 11 years (range = 1.8-21 years).

All of the 12 ALPS patients were previously treated with corticosteroids; although nine of these patients did respond to steroids, they were unable to be weaned off of the medication. The remaining three patients had either no or poor response to steroids.

After the start of sirolimus, drug trough levels were monitored twice weekly until they reached a steady state. To assess response, Dr. Bride and researchers evaluated blood counts every two weeks until the goal trough sirolimus levels (4.6-20.0 ng/mL) were attained, then spaced them out to every three months. Efficacy was also measured by immune cell assays and immune function, including:

T-cell subsets (CD4+, CD8+, and double negative T cells)

Quantitative immunoglobulin G

Mitogen assays (phytohemagglutinin A, concanavalin A, and poke weed mitogen)

Of the patients with ALPS, 11 experienced a hematologic CR within three months of starting sirolimus; the remaining patient achieved a partial response during the first year and reached CR by 18 months. Notably, all ALPS patients were able to wean off of steroids, and all but one were able to wean off of all other immunosuppressants within one week to one month (the remaining patient was weaned off by three months). Of the patients with multilineage autoimmune cytopenias, three patients with ES, two patients with CVID, and one patient with SLE reached CR by three months after starting sirolimus treatment.

Over a median follow-up of two years (range, 0-8 years), the authors observed durable responses in the ALPS patients, with patients remaining on treatment for a median of 3.5 years (range = 1.5-8 years). The drug was also well tolerated; grade 1 or 2 mucositis was the most common adverse event, occurring in 10 of 30 patients.

"Our data re-emphasize the safety and efficacy of steroid-sparing oral immune suppressants," David Teachey, MD, corresponding author on the study, told ASH Clinical News, noting that corticosteroids are associated with long-term morbidity. “Sirolimus is safe to treat patients for years and effective in many patients with refractory multi-lineage autoimmune cytopenias, including patients with ALPS, lupus, and common variable immune deficiency."

"In addition, our data suggest single-agent sirolimus, while effective, does not affect B- or T-cell function in most patients. Accordingly, the risk of infection is very low," Dr. Teachey added.

The current study is small – only a 30-patient cohort – so these results will need to be confirmed in larger populations. Additionally, one patient with ES who had reached CR for more than one year experienced a life-threatening relapse two months later; further studies are necessary to determine whether discontinuation of sirolimus is possible.


Bride KL, Vincent T, Smith-Whitley K, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2015 October 26. [Epub ahead of print]


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