Temsirolimus Offers Short-Lived Responses in Relapsed/Refractory CNS Lymphoma

Single-agent therapy with the mammalian target of rapamycin (mTOR) inhibitor temsirolimus produced some responses in patients with relapsed or refractory primary central nervous system lymphoma (PCNSL), but the responses tended to be short-lived, according to a new phase II study.

“There is preclinical and clinical evidence that the mTOR pathway is important in tumor biology of aggressive lymphoma,” wrote study authors led by Agnieszka Korfel, MD, of Charité University Medicine Berlin in Germany. Previous work in PCNSL has shown the prognosis to be uniformly poor, and a variety of chemotherapy and immunotherapy agents have been tested without substantial success.

This study included 37 patients with a median age of 70 years; all were immunocompetent and had failed prior treatments. The first six patients received 25-mg temsirolimus administered intravenously once per week, and the remaining patients received a dose of 75 mg. The results were published in the Journal of Clinical Oncology.

Five patients (13.5%) achieved a complete response with temsirolimus; another 3 (8%) had an unconfirmed complete response and 12 patients (32.4%) had a partial response. Overall, this yielded a response rate of 54%. Seven patients (18.9%) had stable disease. Six patients had been pretreated with whole-brain radiotherapy; one had a complete response while none of the other five achieved a response. Of seven other patients pretreated with high-dose chemotherapy with an autologous stem cell transplant, two had a complete response and one had an unconfirmed complete response.

The median progression-free survival (PFS) in the study was 2.1 months; the 1-year PFS rate was 5.4%. Overall survival was also poor, with a median of 3.7 months, and 1-year and 2-year rates of 19% and 16.2%, respectively.

The most common grade 3 or 4 adverse events included hyperglycemia in 29.7% of patients (notably, 6 patients were taking steroids), infection in 19%, and thrombocytopenia in 21.6%. Ten patients died within 4 weeks of the final study therapy, five of them due to toxicity and five due to tumor progression.

“Response rate in the present trial is in the upper range of responses in other studies on refractory/relapsed PCNSL, which is remarkable considering the accumulation of negative prognostic factors” in these patients, the authors wrote. “The short life span of the responses indicates that temsirolimus is active in PCNSL, but its activity is often transient, probably due to development of tumor cell resistance.” Because of that transience, the authors noted that incorporating the agent into earlier treatment lines or combining it with other agents may be worth investigation.