Temsirolimus demonstrates short-lived activity in primary CNS lymphoma

Temsirolimus monotherapy exhibited clinical activity in patients with relapsed and refractory primary central nervous system lymphoma, although most responses were short lived, according to results of a phase 2 trial.

Researchers also noted temsirolimus increased risk for hematotoxicity and infections that require primary antibiotic prophylaxis.

“Approximately one-quarter of patients with primary central nervous system lymphoma (PCNSL) do not respond to first-line therapy and more than one-half relapse,” Agnieszka Korfel, MD, of the department of hematology and oncology at Charité University in Berlin, and colleagues wrote. “The prognosis of patients with relapsed/refractory PCNSL is poor, and therapeutic options remain limited.”

Salvage chemotherapy is a common treatment option for patients with relapsed and refractory PCNSL who have previously responded well to chemotherapy, according to study background.

However, prior studies have suggested that the mammalian target of rapamycin (mTOR) pathway is crucial to the tumor biology of aggressive lymphoma, and that agents targeting the mTOR pathway may be effective.

Thus, Korfel and colleagues sought to evaluate the efficacy of temsirolimus (Torisel, Pfizer) —an mTOR inhibitor that also has the ability to penetrate brain tumor tissue — in patients with relapsed and refractory PCNSL. All patients had progressed after high-dose methotrexate chemotherapy and were not eligible for — or had previously progressed with — high-dose chemotherapy with autologous stem cell transplantation.

The analysis included data from 37 patients (median age, 70 years; median, 22-83; 51% women). An initial cohort of 6 patients received 25-mg IV temsirolimus once weekly. Two of these six patients experienced a grade 3 toxicity and one achieved a partial response. The study was permitted to continue and all other patients received 75-mg IV doses weekly.

The median time from last treatment was 3.9 months (range, 0.1-14.6).

Five patients (13.5%) achieved a complete response, three (8%) achieved an unconfirmed complete response and 12 (32.4%) achieved a partial response. The overall response rate was 54% (95% CI, 37-71).

Median PFS was 2.1 months (95% CI, 1.1-3) and median OS was 3.7 months.

“Unfortunately, the relatively high response rate in the current study did not translate into a longer PFS ... A possible explanation could be that the effects of targeted agents in PCNSL, which are currently almost unknown, are different from those seen with classical chemotherapy,” the researchers 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 tumor cell resistance. Thus, incorporation of temsirolimus into earlier treatment lines ... seems worth consideration.”

The most frequently reported grade 3 or higher adverse events included hyperglycemia (n = 11), thrombocytopenia (n = 8), infection (n = 7), anemia (n = 4) and rash (n = 3).

Twenty-one patients experienced severe adverse events, including infection (n = 14), hospitalization due to clinical worsening of progressive disease (n = 4), deep vein thrombosis (n = 2), hyperglycemia (n = 2), seizure (n = 1), thrombocytopenia (n = 1), hyponatremia (n = 1), renal insufficiency (n = 1) and atrial fibrillation (n = 1).

Ten patients died within 4 weeks of their last temsirolimus administration. These occurred due to toxicity (n = 5) or tumor progression (n = 5).

“Given the toxicity observed in this study, [further study] should be done in younger patients who are fitter for treatment and using primary antibiotic prophylaxis,” the researchers wrote.

The researchers collected 14 blood and cerebrospinal fluid pairs from nine patients (25 mg cohort: 10 pairs, five patients; 75 mg cohort: four pairs, four patients).

The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25 mg cohort. For the 75 mg cohort, the mean maximum blood concentrations were 484 ng/mL for temsirolimus and 91.1 ng/mL for sirolimus.

One patient from the 75 mg cohort had temsirolimus concentration in their cerebrospinal fluid (2 ng/mL); no other patients had detectable agents in their cerebrospinal fluid.

“There is an obvious discrepancy between temsirolimus activity and lack of detectable concentration of the drug and its main metabolite in the cerebrospinal fluid,” the researchers wrote. “High drug concentrations in the tumor tissue and the adjacent brain, with no or barely measureable cerebrospinal fluid concentrations, have been reported for sever cytostatic agents ... However, the limited data available suggest that drug concentrations in the brain tissue usually drop with increasing distance from the tumor, to levels that are frequently too low to eradicate infiltrating tumor cells.” – by Cameron Kelsall

Disclosure: Korfel reports honoraria, research funding and travel expenses from, as well as consultant roles with Mundipharma, Pfizer, Piqur, RIEMSER and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.