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Drug Trial Shows "Profound" Success Treating Rare Blood Disorders

Published on November 3, 2015 · Last Updated 4 years 3 months ago


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When the immune system inappropriately destroys blood cells, in a relatively rare group of diseases called autoimmune cytopenias, children may suffer for years with anemia, uncontrolled bleeding, and vulnerability to infections, while their parents struggle to find a diagnosis.

Once diagnosed, even the standard treatment does not necessarily bring patients’ struggles to an end. Some patients cannot tolerate the standard corticosteroid drugs that are used to suppress the immune system, and some develop resistance. Over the long term, corticosteroids also increase the risk of osteoporosis and vulnerability to infection.

Findings from a new multicenter research study may offer hope to these patients. The study, led by hematology researchers at The Children’s Hospital of Philadelphia and published in the journal Blood, demonstrates success that the researchers called “profound” in a treating a small group of children and young adults with cytopenias, and particularly the condition autoimmune lymphoproliferative syndrome (ALPS). All the patients in the trial with ALPS showed a durable, complete response, with normal blood cell counts and rapid improvements.

“Patients with ALPS and similar autoimmune disorders have had few long-term treatment options for managing their disease,” said study leader David T. Teachey, MD, a physician-researcher in hematology and oncology at CHOP. “The immunosuppressive drug we used, sirolimus, is effective and well-tolerated, with very few side effects.”

The current study builds on preliminary results published by Teachey and colleagues in 2009, showing sirolimus successfully treated a small cohort of five children with ALPS. Most were treated at CHOP, which has one of the world’s largest clinical programs for ALPS patients.

“These patients undergo multiple trials of other treatments, some with many side effects, and often without resolution of their symptoms,” said Karen Bride, MD, PhD, a fellow in hematology and oncology at CHOP and first author of the new study. “Sirolimus led to a complete remission in all of the patients with ALPS, which is extraordinary and a real boon for these patients and families.”

In the current study, the first prospective multicenter trial of sirolimus in patients with refractory autoimmune cytopenias, there were 30 participants, ranging in age from 5 to 19 years old. Twelve patients had ALPS, six had other autoimmune cytopenias, and 12 others had secondary cytopenias caused by other underlying autoimmune diseases. All were intolerant of or resistant to corticosteroids.

Of the 12 children with ALPS, 11 had complete responses — normal blood cell counts — from one to three months after receiving sirolimus, with the 12th patient having a complete response after 18 months. Patients also had improvements in spleen and lymph node abnormalities. All 12 patients were able to discontinue steroids and other drugs within one to three months after receiving sirolimus. Over a median follow-up of two years, there were few adverse side effects, primarily mucositis — an inflammation of the mucous membranes.

The majority of the patients with non-ALPS, secondary autoimmune cytopenias (eight out of 12), also had complete responses, although later than for ALPS patients. The six patients with other autoimmune cytopenias had less robust results — one complete response and two partial responses.

“More research remains to be done, but this treatment has produced profound, dramatic results for children, and has improved their quality of life,” s Dr. Teachey said.

Sirolimus, an immunosuppressant also known as rapamycin, has long been used to prevent rejection after a solid organ transplant. Based on the new findings, the study team recommended that doctors should consider using sirolimus early in the management of patients with autoimmune blood disorders that require ongoing treatment. In addition, Dr. Teachey said, further studies should investigate whether sirolimus can be discontinued after patients achieve a complete response.

He added that because many ALPS cases result from underlying gene mutations, future studies also could test whether sirolimus can treat other ALPS-like disorders with mutations in similar genes.

“This type of genomic profiling will hopefully increase our understanding of the underlying pathogenesis of autoimmune cytopenias, which we believe will naturally lead to precision-medicine approaches to this rare set of disorders, and more improved outcomes,” Dr. Bride said.

Collaborators from 15 medical centers contributed to the research; Dr. Teachey and Dr. Bride had study co-authors from four institutions. Funding for this study came from Cures Within Reach, the Partnership for Cures Patient Impact Initiative, as well as from the United States Immunodeficiency Network, through the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Other funders were the Goldman Philanthropic Partnerships, the Rockefeller Brothers Fund, the Barbara Brodsky Foundation and a Foerderer-Murray Award. In addition to his CHOP position, Dr. Teachey is an assistant professor at the Perelman School of Medicine at the University of Pennsylvania.