Bortezomib/Lenalidomide Combination Therapy Evaluated in Relapsed/Refractory Mantle Cell Lymphoma
Although the majority of patients with mantle cell lymphoma respond to initial therapy, the duration of remission is typically short (1.5 to 3 years). Although bortezomib (Velcade) and lenalidomide (Revlimid) as single agents have been associated with response rates as high as 53% in patients with relapsed/refractory disease, Morrison et al reported an overall response rate of almost 40% with combination bortezomib/lenalidomide therapy in an article published in Leukemia & Lymphoma.
The incidence of mantle cell lymphoma has increased dramatically over the past several decades. The median overall survival is 3 to 6 years with standard chemotherapy approaches, and fewer than 15% of patients are long-term survivors.
Therefore, researchers continue to investigate newer therapeutic options for these patients. One such approach was the combination of bortezomib and lenalidomide, particularly in patients who experienced relapse from or were refractory to previous treatments. In the phase II CALGB 50501 trial, a team of investigators from the University of Minnesota, Duke University, Dana-Farber Cancer Institute, Ohio State University, Washington University, and Georgetown University attempted to evaluate the feasibility of combination treatment with bortezomib and lenalidomide in patients with relapsed or refractory mantle cell lymphoma.
Study Details
In total, 53 patients received lenalidomide (days 1–14) plus bortezomib (days 1, 4, 8, and 11), every 21 days for eight cycles. Complete and partial responders received maintenance lenalidomide (days 1–14) and bortezomib (days 1 and 8) every 21 days. The dosage of bortezomib was 1.3 mg/m2 intravenously, and the dosage of lenalidomide was 20 mg orally. The primary endpoint was overall response rate.
At the time of treatment, the median age of study patients was 67 years (range, 39–83 years), and 83% were male. The study was conducted from November 2007 to July 2011.
Fifty-two patients received prior chemotherapy; of these, 31 patients (60%) received one prior regimen, 13 (25%) received two prior regimens, 6 (12%) received three prior regimens, and 1 each (2%) received four and five regimens. Fifty patients (94%) received prior immunotherapy, primarily rituximab (Rituxan), 14 (26%) received prior radiotherapy, and 21 (40%) had undergone a prior autologous stem cell transplant.
Patients were administered a median four cycles of treatment (range, 1–93). Twenty-two patients (41.5%) discontinued protocol therapy due to disease progression or nonresponse to treatment.
Study Results
Patients treated with combination bortezomib/lenalidomide therapy had an overall response rate of 39.6% (90% confidence interval [CI] = 34%–68%). Complete response was reported in 15.1% of patients, and partial response was reported in 24.5% of patients. Two patients in complete remission discontinued bortezomib/lenalidomide therapy after cycles 4 and 7 due to adverse events. Only 6 of 21 responders underwent prolonged maintenance therapy (18–82 total cycles, including the 8 induction cycles), and 2 of these patients remained in remission.
In regard to safety and tolerability 36% of patients experienced grade 2 sensory neuropathy, and 8% experienced grade 3/4 sensory neuropathy. Although 21% of patients had grade 3/4 neutropenia, infections were not common. One patient had febrile neutropenia.
Closing Thoughts
The investigators acknowledged that the nearly 40% overall response rate was “disappointing,” especially considering the single-agent response rates documented in previous clinical trials. They noted that the lower-than-anticipated response rate may have been related to inadequate lenalidomide dosing, initial simultaneous dose reductions in both agents to account for toxicity, and the limited amount of bortezomib/lenalidomide therapy administered in 37% of patients related to disease progression and tolerability issues.
“Unfortunately, due to small numbers, we could not assess the impact of maintenance therapy in our trial. However, this sort of maintenance therapy may not be deliverable, and case-by-case decisions with regard to the option of maintenance may need to include its impact on quality of life,” said the investigators. They added that the combination would not be pursued further in this setting.
Vicki A. Morrison, MD, of the University of Minnesota Medical School, Minneapolis, is the corresponding author of the article in Leukemia & Lymphoma.
The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology and to the Alliance Statistics and Data Center. For full disclosures of the study authors, visit www.informahealthcare.com/lal.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
