Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial.
BACKGROUND
The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL.


METHODS
Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632.


RESULTS
52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response.


CONCLUSIONS
Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL.


BACKGROUND
Celgene.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. miwang@mdanderson.org
Michael
M
Wang
Luis
L
Fayad
Nicolaus
N
Wagner-Bartak
Liang
L
Zhang
Fredrick
F
Hagemeister
Sattva S
SS
Neelapu
Felipe
F
Samaniego
Peter
P
McLaughlin
Michelle
M
Fanale
Anas
A
Younes
Fernando
F
Cabanillas
Nathan
N
Fowler
Kate J
KJ
Newberry
Luhong
L
Sun
Ken H
KH
Young
Richard
R
Champlin
Larry
L
Kwak
Lei
L
Feng
Maria
M
Badillo
Maria
M
Bejarano
Kimberly
K
Hartig
Wendy
W
Chen
Yiming
Y
Chen
Catriona
C
Byrne
Neda
N
Bell
Jerome
J
Zeldis
Jorge
J
Romaguera
D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012008:Recurrence; D000069283:Rituximab; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D013792:Thalidomide; D000077269:Lenalidomide