Revlimid Receives a New Indication for the Treatment of Patients with Relapsed or Progressing Mantle-Cell Lymphoma
Mantle-cell lymphoma (MCL), which accounts for approximately 6% of new non–Hodgkin lymphoma diagnoses, is a rare and often aggressive cancer.1,2 MCL is most often diagnosed in older white adults (typically patients are in their mid-60s) and is usually in advanced stages.1,2 Splenomegaly and lymph node enlargement are typically present, in addition to bone marrow, liver, and gastrointestinal tract involvement.2
Although genetic abnormalities (ie, translocations of chromosomes 11 and 14) and the overexpression of cyclin D1 are characteristic of MCL, their clinical and prognostic implications remain unclear.1,3 A recent analysis of 62 cases of MCL demonstrated that other disease features, particularly blastoid (vs classical) morphology and the presence of TP53 gene mutations, are significantly correlated with poor clinical outcomes.3
MCL is an uncommon diagnosis in the United States. A study using Surveillance, Epidemiology and End Results (SEER) registry data collected between 1992 and 2001 documented an incidence rate of 0.51 per 100,000 person-years.4 In this analysis, patients diagnosed with MCL were more likely to be white and male.4 An 8% annual increase in the incidence of MCL was noted during the 10-year time frame over which data were collected, but researchers hypothesized that changes in diagnostic practices explained this trend.4
The clinical course of MCL can be indolent or moderately aggressive at diagnosis. Over time, however, the disease invariably becomes clinically aggressive and refractory to cytotoxic chemotherapy.5 Data reported in 1995 suggest that patients with MCL have the worst long-term survival among patients with all B-cell lymphoma subtypes, with a median survival of approximately 3 years.6 In a more recent series of patients with MCL, this estimate has increased to approximately 5 years, possibly as a result of the use of anthracycline-containing treatment regimens, stem-cell transplantation, advances in supportive care, and the general improvement of life span.7
Although assessments of the cost burden associated with MCL are few, the results of a recent cost-effectiveness analysis that was conducted using US payer data showed that total per-patient costs for patients with MCL exceeded $100,000.8 This study, which compared the combination of bendamustine and rituximab (BR) with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in treatment-naïve patients with MCL, calculated average per-patient costs of $115,191 and $100,261 for BR and R-CHOP, respectively.8
Until recently, bortezomib (Velcade) was the only drug approved by the US Food and Drug Administration (FDA) for the treatment of patients with MCL, specifically those who have received at least 1 previous therapy.9 In clinical practice, combinations of chemotherapy with anti-CD20 monoclonal antibody therapy, high-dose chemotherapy followed by stem-cell transplant, and radioimmunotherapy are viable options for the treatment of patients with MCL.5
Novel options that are being investigated in MCL clinical trials include cytotoxic agents (bendamustine, cladribine); monoclonal antibodies (rituxumab); mTOR inhibitors (temsirolimus, which is approved in Europe for MCL); cyclin-dependent kinase inhibitors (flavopiridol); histone deacetylase inhibitors; B-cell leukemia/lymphoma-2 inhibitors; Bruton’s tyrosine kinase inhibitors; and immunotoxins.10
Revlimid a New Treatment Option for Patients with MCL
In June 2013, the FDA approved the immunomodulatory agent lenalidomide (Revlimid, Celgene Corporation) for the treatment of patients with MCL whose disease has relapsed or progressed after 2 previous therapies, one of which included bortezomib.11
The approval of lenalidomide for MCL was based on the demonstration of efficacy (overall response rate [ORR] and duration of response) in a phase 2 multicenter clinical trial of 134 heavily pretreated patients with MCL.11 Data from this trial, known as the MCL-001 EMERGE study, were presented at the annual meeting of the American Society of Hematology in December 2012 and were published in September 2013.12,13
In a recent interview regarding his experience in this phase 2 trial of lenalidomide in patients with MCL, Andre Goy, MD, MS, Chairman and Director, and Chief of Lymphoma, John Theurer Cancer Center, Hackensack, NJ, stated, “What was very important was the duration of response….Here, the median duration of response was more than 16 months…regardless of the number of prior therapies; bulky, high tumor load; [and] prior high-dose chemotherapy refractory to the last therapy or refractory to bortezomib.”14
Lenalidomide is also approved for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least 1 previous therapy, and in patients with transfusion-dependent anemia resulting from low- or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.15
Mechanism of Action
As an analog of thalidomide, lenalidomide has immunomodulatory, antiangiogenic, and antineoplastic properties. In vitro, the drug inhibits cell proliferation and induces programmed cell death of specific hematopoietic tumor cells, including MM, MCL, and MDS associated with a deletion 5q abnormality. Lenalidomide also has immunomodulatory properties: it activates T-cells and natural killer cells, increases the number of natural killer T-cells, and inhibits proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, by monocytes.15
Phase 2 Clinical Trial: MCL-001 EMERGE
In the phase 2 multicenter MCL-001 EMERGE trial, Goy and colleagues enrolled 134 patients with MCL who had been treated with multiple therapies, including rituximab, cyclophosphamide, and anthracycline.13 All patients had MCL that had relapsed or had progressed within 12 months of therapy with bortezomib or whose disease was refractory to bortezomib. Lenalidomide was given as a single agent at a dose of 25 mg daily administered on days 1 to 21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal.13 The lenalidomide dose was 10 mg once daily for 21 days every 28 days for patients with a creatinine clearance between 30 mL/min and 59 mL/min.15
The primary end points of the MCL-001 EMERGE study were ORR and duration of response.13 Duration of response was defined as the time from initial response to documented disease progression.15 Secondary end points included complete response (CR), progression-free survival, time to progression, overall survival, and safety.13 The efficacy parameters were assessed by investigators, as well as by an independent central review committee.13
The median age of patients enrolled in the phase 2 study of lenalidomide was 67 years.13 The majority of patients in this trial were male (81%) and white (96%), with advanced (stage III/IV) MCL (93%).13,15 Of these patients, 78% had received 3 or more previous treatments (median, 4; range, 2-10).13
The phase 2 study demonstrated that lenalidomide monotherapy is active and safe in patients with MCL whose disease has relapsed or progressed after bortezomib therapy or whose disease was refractory to bortezomib. According to independent central review, the ORR was 28% (7.5% CR) and the median duration of response was 16.6 months. According to investigators, the ORR was 32% (16% CR) and the median duration of response was 18.5 months. Table 1 includes these data, as well as secondary end point data, from the phase 2 study of lenalidomide.13
More than half of the patients (58%) received 3 or more cycles of lenalidomide in this trial.13 The median duration of therapy was 95 days (range, 1-1002 days) and the average dose of lenalidomide was 20 mg daily.13 Of the patients with MCL, 38% required a dose reduction of lenalidomide.13
The most common grade 3 or 4 adverse events reported in the study were neutropenia (43%), thrombocytopenia (27%), anemia (11%), pneumonia (8%), and fatigue (7%).13 Other adverse events of any grade included tumor flare reaction (10%), deep-vein thrombosis (4%), pulmonary embolism (2%), and invasive second primary malignancies (2%).13,15 A total of 19% of the patients in this study discontinued lenalidomide therapy because of adverse events.13
Dosing and Administration
For patients with MCL whose disease relapsed or progressed after bortezomib therapy or was refractory to bortezomib, the recommended dose and schedule for lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles.15 Lenalidomide should be taken at approximately the same time each day, either with or without food.15 The FDA approval of lenalidomide for the treatment of patients with MCL also included an approval of a new 20-mg capsule strength of this agent.15
Table 2 summarizes lenalidomide dose modification guidelines for patients with grade 3 or 4 neutropenia or thrombocytopenia, or with other grade 3 or 4 toxicities that are believed to be drug-related.15
Because lenalidomide is primarily excreted unchanged by the kidneys, patients with moderate or severe renal impairment, including patients on dialysis, should receive lower initial starting doses.15 Specific dose recommendations for lenalidomide in patients with MCL and renal insufficiency are provided in Table 3.15
Warnings and Precautions
Lenalidomide, a thalidomide analog, should not be used during pregnancy. Thalidomide causes human birth defects and embryo-fetal death. Pregnancy must be excluded before the start of lenalidomide treatment and must be prevented during treatment by the use of 2 reliable contraception methods. Because the blood may be given to a pregnant female patient whose fetus must not be exposed to lenalidomide, patients taking lenalidomide must not donate blood during treatment and for 1 month after discontinuation of the drug. Given this embryo-fetal risk, access to lenalidomide is restricted under a Risk Evaluation and Mitigation Strategy (REMS) program, known as the Revlimid REMS program.15
In the phase 2 trial of lenalidomide in MCL, grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia were reported in 43% and 28% of patients, respectively.13 Patients with MCL who take lenalidomide should have their complete blood count (CBC) monitored.15 CBC tests are recommended weekly for the first cycle (28 days), every 2 weeks during cycles 2 to 4, and then monthly while receiving lenalidomide therapy.15
Some patients with MCL who received lenalidomide experienced venous thromboembolic events, typically deep venous thrombosis and pulmonary embolism.15 It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with lenalidomide can minimize the risk of venous thromboembolism.15
Lenalidomide has been associated with angioedema and serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Such reactions can be fatal. Physicians should consider interruption or discontinuation of lenalidomide for grade 2 to 3 skin reactions. Lenalidomide must be permanently discontinued if angioedema, grade 4 rash, exfoliative or bullous rash occur, or if Stevens-Johnson syndrome occurs or toxic epidermal necrolysis is suspected. Lenalidomide should not be given to any patient who experienced a grade 4 rash while receiving thalidomide.15
Tumor Lysis Syndrome
Fatalities secondary to tumor lysis syndrome have been documented in patients taking lenalidomide. Because patients with high tumor burden before treatment are at risk for tumor lysis syndrome, healthcare professionals should monitor these patients closely and take appropriate precautions.15
Tumor Flare Reaction
Patients with MCL taking lenalidomide should be monitored for tumor flare reaction, which is characterized by lymph node swelling, low-grade fever, pain, and rash.15 Of patients in the MCL trial, 10% experienced grade 1 or grade 2 tumor flare reaction in the first cycle of lenalidomide treatment.13 One of these patients developed tumor flare reaction again in cycle 11.13 If grades 1 and 2 tumor flare reaction occur, lenalidomide can be continued without interruption or modification, at the physician’s discretion.15 Corticosteroids, nonsteroidal anti-inflammatory drugs, and/or narcotic analgesics can be used for symptom management.15 Patients who experience more severe tumor flare reaction (grade 3 or 4) should not receive lenalidomide treatment until the TFR resolves to grade 1 or less.15
Second Primary Malignancies
Patients taking lenalidomide should be monitored for the development of second malignancies.15 In the MCL trial, 3 patients (2%) developed invasive second primary malignancies.13
Lenalidomide, the first oral drug approved for the treatment of patients with MCL, has demonstrated efficacy with manageable toxicities in heavily pretreated patients whose disease has relapsed or progressed after bortezomib or is refractory to bortezomib. Lenalidomide joins bortezomib as the only 2 FDA-approved agents currently available for this rare and often aggressive form of B-cell lymphoma. Because it is not cytotoxic, lenalidomide may offer clinical value when combined with other treatments for MCL. Current clinical trials are evaluating the use of lenalidomide in combination with rituximab, bendamustine, and/or bortezomib in patients with MCL for use as first- or second-line treatment.16
- Leukemia and Lymphoma Society. Mantle cell lymphoma facts. Revised July 2012. www.lls.org/content/nationalcontent/resourcecenter/freeeduca tionmaterials/lymphoma/pdf/mantlecelllymphoma.pdf. Accessed July 30, 2013.
- National Cancer Institute. Mantle cell lymphoma: disease information. 2010 Hematopoietic and Lymphoid Database. Updated February 5, 2013. http://seer.cancer.gov/seertools/hemelymph/2010/. Accessed July 30, 2013.
- Slotta-Huspenina J, Koch I, de Leval L, et al. The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index. Haematologica. 2012;97:1422-1430.
- Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276.
- Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114:1469-1476.
- Zucca E, Roggero E, Pinotti G, et al. Patterns of survival in mantle cell lymphoma. Ann Oncol. 1995;6:257-262.
- Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-518.
- Su W, Quon P, Whalen J, et al. Cost-effectiveness analysis of bendamustine plus rituximab versus CHOP-R in treatment-naive patients with mantle cell (MCL) and indolent lymphomas (IL). J Clin Oncol. 2012;30(suppl). Abstract 6553.
- US Food and Drug Administration. FDA approves bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. Updated May 21, 2009. www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm094929.htm. Accessed September 17, 2013.
- Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol. 2011;80:69-86.
- US Food and Drug Administration. Drugs: lenalidomide. Updated June 5, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm355438.htm. Accessed September 18, 2013.
- Goy A, Sinha R, Williams ME, et al. Phase II multicenter study of single-agent lenalidomide in subjects with mantle cell lymphoma who relapsed or progressed after or were refractory to bortezomib: the MCL-001 “EMERGE” study. Presented at the American Society of Hematology annual meeting; December 8-11, 2012; Atlanta, GA.
- Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013 Sep 3. Epub ahead of print.
- OncLiveTV. Dr. Goy on lenalidomide for mantle cell lymphoma. YouTube. June 10, 2013. www.youtube.com/watch?v=l-oV-Y6OvBE. Accessed July 30, 2013.
- Revlimid (lenalidomide) capsules [prescribing information]. Summit, NJ: Celgene Corporation; June 2013.
ClinicalTrials.gov. Lenalidomide mantle cell lymphoma. Search results. http://clinicaltrials.gov/ct2/results?term=lenalidomide+mantle+cell+lymphoma&Search=Search. Accessed September 18, 2013.