In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
On June 5, 2013, lenalidomide (Revlimid) was approved for treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (Velcade).1,2
Approval was based on overall response rate and duration of response in a single-arm, multicenter trial in 134 patients with mantle cell lymphoma who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab (Rituxan), and bortezomib, alone or in combination. Patients had to have an absolute neutrophil count ≥ 1,500/µL, platelet count ≥ 60,000/µL, serum AST or ALT ≤ 3 × upper limit of normal unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin ≤ 1.5 × upper limit of normal except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance > 30 mL/min.
Patients with creatinine clearance > 60 mL/min received lenalidomide at 25 mg once daily for 21 days every 28 days, and those with creatinine clearance ≥ 30 mL/min and < 60 mL/min received 10 mg once daily for 21 days every 28 days. Patients had a median age of 67 years, 96% were Caucasian, 81% were male, and 86% had an ECOG performance status of 0 or 1. Furthermore, 61% had mantle cell lymphoma for at least 3 years, 72% had stage IV disease, 67% had a high or intermediate mantle cell lymphoma Prognostic Index Score, 57% had high tumor burden, 33% had bulky disease, 75% had extranodal disease. Approximately 53% had at least four prior systemic therapies, 29% had prior autologous bone marrow or stem cell transplantation, and 60% were demonstrated to be bortezomib-refractory.
In the 133 patients evaluable for efficacy, overall response rate was 26%, including complete response or complete response–unconfirmed in 9 patients (7%) and partial response in 25 (19%). The median duration of response among the 34 patients with a response was 16.6 months.
How It Works
Lenalidomide is a thalidomide (Thalomid) analog with immunomodulatory, antiangiogenic, and antineoplastic properties. It inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells, mantle cell lymphoma, multiple myeloma, and del(5q) myelodysplastic syndromes in vitro. Immunomodulatory properties of the agent include activation of T cells and natural killer cells, increased numbers of natural killer T cells, and inhibition of proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin-6) by monocytes.
How It Is Given
The recommended starting dose of lenalidomide is 25 mg/d orally on days 1 to 21 of repeated 28-day cycles. Starting doses should be 10 mg once daily for moderate renal impairment, 15 mg every 48 hours for severe impairment, and 5 mg once daily following dialysis in patients requiring dialysis. Lenalidomide should be taken at about the same time each day, either with or without food. Treatment should be continued until disease progression or unacceptable toxicity.
Treatment should be interrupted in patients developing thrombocytopenia or neutropenia, and complete blood counts should be followed weekly. Upon recovery, the lenalidomide dose should be reduced by 5 mg to no lower than 5 mg/d. Treatment should be discontinued in patients with a suspected allergic reaction to lenalidomide.
Periodic monitoring of digoxin plasma levels is recommended in patients receiving lenalidomide, since digoxin exposure is increased with concomitant treatment. Patients taking such agents as erythropoietin-stimulating agents or estrogen-containing therapies may be at increased risk of venous thromboembolism.
To avoid embryo-fetal exposure, lenalidomide is available only through a restricted distribution program, the Revlimid REMSTM program, formerly known as the “RevAssist®” program (information available at www.celgeneriskmanagement.com or 1-888-423-5436).
Safety Profile
The median duration of lenalidomide therapy in the mantle cell lymphoma trial was 95 days (range, 1–1,002), and 58% of patients received three or more cycles. The most common nonhematologic adverse events of any grade were fatigue (34%), diarrhea (31%), nausea (30%), and cough (28%); the most common grade 3 or 4 adverse events were pneumonia (9%), fatigue (7%), diarrhea (6%), and dyspnea (6%).
Hematologic toxicities of any grade included neutropenia in 49%, thrombocytopenia in 36%, anemia in 31%, and leukopenia in 15%, with toxicity being grade 3 or 4 in 43%, 28%, 11%, and 7%, respectively. Grade 3 or 4 febrile neutropenia occurred in 6%. Adverse events caused dose interruption in 57% of patients, dose reduction in 38%, and treatment discontinuation in 19%.
Lenalidomide carries boxed warnings for embryo-fetal toxicity, hematologic toxicity, and venous thromboembolism. It also carries warnings/precautions for allergic reactions (hypersensitivity, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatalities; tumor lysis syndrome, including fatalities; tumor flare reaction (observed during investigational use in chronic lymphocytic leukemia and lymphoma); hepatotoxicity (eg, hepatic failure, including fatalities); and second primary malignancies (observed in trials in multiple myeloma). Liver function must be monitored regularly during lenalidomide treatment, and patients with high tumor burden must be monitored for potential tumor lysis syndrome.
Lenalidomide is contraindicated in pregnancy and in patients with demonstrated hypersensitivity to the agent. ■
References
1. U.S. Food and Drug Administration: Lenalidomide. Avalable at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm355438.htm. Accessed July 1, 2013.
2. REVLIMID® (lenalidomide) capsules prescribing information, Celgene Corporation, June 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021880s034lbl.pdf. Accessed July 1, 2013.
