Serious Infections From Unapproved Stem-Cell Treatments Identified in Multiple States

Ricki Lewis, PhD

December 20, 2018

Twelve patients in three states contracted bloodstream, joint, and other infections from the use of non–FDA-approved umbilical cord blood-derived stem cells, according to a report published online today in Morbidity and Mortality Weekly Report.

Kiran M. Perkins, MD, from the Centers for Disease Control and Prevention, and colleagues tracked reports of infection from the cells, which were processed by Genetech, Inc in San Diego, California and distributed by Liveyon LLC, a biotechnology company based in Yorba Linda, California.

The first notification, from the Texas Department of State Health Services, came on September 17. It reported Enterobacter cloacae and Citrobacter freundii bloodstream infections in three patients who had received injections or infusions of the cells. Isolates of E cloacae from the patients yielded identical pulsed-field gel electrophoresis patterns, indicating a shared source.

Five days later, the Florida Department of Health reported Escherichia coli, Enterococcus faecalis, and Proteus mirabilis infections of the joints in four patients who had received injections of the same stem-cell products at an orthopedic clinic between February 15 and August 30, also for unapproved treatments. Analysis of the contents of unopened cultures at the Florida clinic revealed contamination with E coli and E faecalis.

Liveyon ceased buying the suspect cells and issued a voluntary recall of the product on September 28.

On October 4, the CDC issued a nationwide request for reports of infections in patients who had received the Liveyon product. Cultures confirmed the infections and identified the bacteria.

By last Friday, the agency had confirmed 12 cases: seven from Texas, four from Florida, and one from Arizona. All injections had been intra-articular, with seven intended to alleviate pain. In addition to the bloodstream and joint infections, there were infections of the knee and shoulder and epidural abscesses.

The FDA today sent a warning letter to Genetech over marketing "dangerous" unapproved stem-cell products and for "significant" deviations from current good tissue practice (CGTP) and current good manufacturing practice (CGMP) requirements. The agency has requested a response from Genetech within 15 working days of receipt of the letter.

Eleven of the patients were known to not have the conditions for which FDA approves use of the stem cells. (The only stem-cell products that FDA approves for therapeutic use are derived from umbilical cord blood and their only approved use is in hematopoietic and immunologic reconstitution.) All patients were hospitalized and all survived.

Further investigation found that six unopened vials from the Texas site came from the same donor and contained E cloacae. Five of those vials also had C freundii. The four vials from Florida were from different donors and had processing dates different than those from Texas. One of two vials from different donors yielded E coli and E faecalis, while one of two vials from the same donor had E coli.

Initial findings suggest that the bacterial contamination happened before the stem cells were distributed. This is possible, the authors discuss, because of the lack of validated processes to sterilize cord blood after collection, risking contamination of derived products. Registration of the two companies with the FDA isn't equivalent to approval of their products.

The authors warn that unapproved stem cell treatments continue to be offered at outpatient clinics, purportedly to treat various orthopedic, neurologic, and rheumatologic conditions, without FDA approval. The agency urges patients to sign up for stem cell-based treatments only as part of a controlled clinical trial under an investigational new drug application.

"Regardless of when contamination occurred, this investigation highlights the serious potential risks to patients of stem cell therapies administered for unapproved and unproven uses other than hematopoietic or immunologic reconstitution," the researchers conclude.

The investigation continues. In the meantime, healthcare providers should report adverse events stemming from the Genetech/Liveyon products, or other problems with unapproved stem-cell therapies, to FDA's MedWatch Safety Information and Adverse Event Reporting Program (https://www.fda.gov/Safety/MedWatch/).

The researchers have disclosed no relevant financial relationships.

MMWR. 2018;67:1397-1398. Full text

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