A US national drug shortage has been linked to a higher rate of relapse among children, teenagers and young adults with Hodgkin lymphoma, according to a new study.

Estimated two-year cancer-free survival for patients enrolled in the study, which was led by St Jude Children's Research Hospital, fell from 88% to 75% after the drug cyclophosphamide was substituted for mechlorethamine for treatment of patients with intermediate- or high-risk Hodgkin lymphoma. The study was launched before the US drug shortages began, and the change occurred after a mechlorethamine shortage that began in 2009; the drug has only recently become available again.

No study patients have died, but those who relapsed received additional intensive therapy that is associated with higher odds for infertility and other health problems later, say the researchers, reporting their findings in the New England Journal of Medicine (NEJM).

The study provides the first evidence of a drug shortage adversely impacting treatment outcomes in specific patients, they add.

Cyclophosphamide has been widely used in treatment of both adults and children with Hodgkin lymphoma. Based on earlier studies, it was considered a safe and effective alternative to mechlorethamine.

However, the new study's findings are "a devastating example of how drug shortages affect patients and why these shortages must be prevented," said Dr Monika Metzger, an associate member of the St Jude Department of Oncology and the study's principal investigator. "Our results demonstrate that, for many chemotherapy drugs, there are no adequate substitute drugs available," she added.

Past drug shortages have been resolved in a variety of ways and always before a substitution became necessary, added Michael Link, a professor of paediatric hematology-oncology and the report's senior author.

"This puts a face on the problem of drug shortages and shows that the problem is real, not theoretical. This is about a curative therapy that we were unable to administer because the drug we needed was not available," he said.

"Despite heroic efforts by the drug shortage office of the Food and Drug Administration [FDA] to solve the shortages of a number of medically-necessary drugs, it is clear that patients are still suffering from the unavailability of life-saving drugs. A more systematic solution to the problem is needed," added Prof Link, who is the immediate past-president of the American Society of Clinical Oncology (ASCO).

Hodgkin lymphoma, a cancer of the lymph system, accounts for about 6% of childhood cancers. In the US, about 90% of patients will become long-term survivors.

When the researchers assessed the impact of substituting cyclophosphamide for the unavailable mechlorethamine, they found that estimated disease-free survival was 88% for the 181 patients whose treatment included mechlorethamine but was 75% for the 40 patients who received cyclophosphamide instead. The difference led the researchers to stop enrolling new patients in the trials.

"We can think of no credible explanation for this dramatic different in event-free survival other than the drug substitution," they report.

Patients who relapsed received additional therapy. It is too soon to know if these patients will have the same long-term survival rates as those who did not relapse, say the researchers. The additional treatment included intensive chemotherapy followed by a stem cell transplant using the patient's own blood-producing stem cells.