CHICAGO—Temsirolimus (Torisel) prolongs progression-free survival in patients with relapsed and/or refractory mantle cell lymphoma when compared with commonly used conventional therapies, finds an international phase III trial.
“At the molecular level, mantle cell lymphoma is characterized by the translocation t(11;14) that results in the over-expression of cyclin D1, and the translation of cyclin D1 mRNA is regulated by the mTOR kinase,” Georg Hess, MD, PhD, said at ASCO 2008 (abstract 8513). Therefore, temsirolimus, an inhibitor of the mTOR kinase, may be efficacious in this disease.
Patients in the trial had relapsed and/or refractory mantle cell lymphoma and had received two to seven therapies for the disease, which may have included stem cell transplantation and must have included rituximab(Drug information on rituximab) (Rituxan), an anthracycline, and an alkylating agent, said Dr. Hess, a hematologist-oncologist at the Johannes-Gutenberg University, Mainz, Germany.
In the open-label trial, the patients were randomized to receive higher-dose temsirolimus (175 mg weekly for 3 weeks followed by 75 mg weekly); lower-dose temsirolimus (175 mg weekly for 3 weeks followed by 25 mg weekly); or the investigator’s choice of a single-agent conventional therapy, which was most commonly intravenous gemcitabine(Drug information on gemcitabine) (Gemzar) or intravenous or oral fludarabine.
Intention-to treat analyses were based on 54 patients in each arm.
Study Results
The objective response rate was significantly higher in the higher-dose temsirolimus group (22%) but not in the lower-dose group (6%), compared with the investigator’s choice group (2%), Dr. Hess reported.
Median progression-free survival was significantly longer with the higher dose (4.8 months, HR 0.44) and marginally so with the lower dose (3.4 months, HR 0.65) relative to the therapy of choice (1.9 months).
Median overall survival did not differ significantly (13.6, 10.0, and 9.7 months, respectively).
Adverse Events
 | “Further evaluation in combination or earlier-line treatment is warranted.” — Dr. Georg Hess |
Patients in the higher- and lower-dose temsirolimus groups had higher rates of grade 3-4 thrombocytopenia than those in the investigator’s choice group (63% and 52% vs 40%), but lower rates of grade 3-4 neutropenia (24% and 30% vs 45%). Epistaxis of any grade was much more common with temsirolimus (35% and 24% vs 6%), but there were no cases of grade 3-4 epistaxis, showing that this adverse effect is manageable, Dr. Hess commented.
Grade 3-4 infection was more common in the higher-dose temsirolimus group than in the investigator’s choice group (9% vs 4%).
In addition, rates of grade 3-4 asthenia and diarrhea were higher with temsirolimus of either dose.
An Attractive Therapeutic Alternative
“This first randomized phase III trial in mantle cell lymphoma established the concept of using this drug in this entity,” Dr. Hess commented. He observed that the results support the efficacy and safety of higher-dose temsirolimus in this patient population.
“We think that temsirolimus is an attractive therapeutic alternative for this disease, and with this data, further evaluation in combination or earlier-line treatment is warranted,” he concluded.
