Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma.
OBJECTIVE
Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL.


METHODS
Patients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance.


RESULTS
Thirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week.


CONCLUSIONS
Single-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.
Witzig
Thomas E
TE
Mayo Clinic College of Medicine, Stabile 628, 200 First St SW, Rochester, MN 55905, USA. witzig@mayo.edu
Geyer
Susan M
SM
Ghobrial
Irene
I
Inwards
David J
DJ
Fonseca
Rafael
R
Kurtin
Paul
P
Ansell
Stephen M
SM
Luyun
Ronnie
R
Flynn
Patrick J
PJ
Morton
Roscoe F
RF
Dakhil
Shaker R
SR
Gross
Howard
H
Kaufmann
Scott H
SH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019938:Cyclin D1 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D016879:Salvage Therapy; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D019938:Cyclin D1; C401859:temsirolimus; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus