Lymphoma Program, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania
Corresponding author: Stephen J. Schuster, MD, Perelman Center for Advanced Medicine, 2 West Pavilion, Room 2-393S, 3400 Civic Center Boulevard, Philadelphia, PA 19104; Fax: (215) 662-4064; firstname.lastname@example.org
The authors thank Frannie and Jim Maguire and Margarita Louis-Dreyfus for their support of the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania.
Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression. Furthermore, single-agent lenalidomide has therapeutic activity in relapsed/refractory B-cell lymphomas. These immunologic effects potentially may enhance the action of rituximab.
To test the efficacy of lenalidomide combined with rituximab, the authors conducted a phase 2 trial of lenalidomide, low-dose dexamethasone, and rituximab in patients who had rituximab-resistant, relapsed/refractory, indolent B-cell or mantle cell lymphomas. Patients received two 28-day treatment cycles of lenalidomide 10 mg daily and dexamethasone 8 mg once weekly (part I). During cycle 3, 4 weekly doses of rituximab 375 mg/m2 were administered with lenalidomide-dexamethasone (part II). After the part II response assessment, stable or responding patients continued to receive lenalidomide-dexamethasone.
Twenty-seven patients with follicular (n = 18), mantle cell (n = 5), small lymphocytic (n = 3), and marginal zone (n = 1) lymphomas started therapy; 3 of 27 patients discontinued therapy because of adverse events and were not evaluable for response. For 24 patients, the overall response rate after part I was 29% (4 patients had a complete response [CR] or CR unconfirmed, and 3 patients had a partial response), and the overall response rate after part II was 58% (8 patients had a CR, and 6 patients had a partial response). For 27 patients, at a median follow-up of 12.2 months, the median progression-free survival was 23.7 months.
The addition of rituximab to chemotherapy improves clinical outcomes for patients with low-grade B-cell lymphomas, and the inclusion of rituximab in treatment regimens is considered the standard of care for B-cell non-Hodgkin lymphomas.[1, 2] Unfortunately, many patients who receive rituximab-chemotherapy or rituximab monotherapy eventually relapse and develop resistance to rituximab or to rituximab-containing combination therapies. In our experience, the 5-year overall survival (OS) for patients with low-grade follicular lymphoma who fail to respond to or develop resistance to rituximab or a rituximab-containing treatment regimen is 58%, which is markedly decreased compared with the reported survival for all patients with follicular lymphoma. Thus, there is considerable incentive to overcome resistance to rituximab.
Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression.[5, 6] These immunologic effects could potentially enhance the action of rituximab. Furthermore, single-agent lenalidomide has demonstrated therapeutic activity in relapsed or refractory B-cell lymphomas,[7, 8] including follicular lymphoma and mantle cell lymphoma.[9, 10]
Preclinical studies have demonstrated the potential for synergy between lenalidomide and rituximab, both in vitro and in murine B-cell lymphoma models.[5, 11-13] In vitro, after pretreatment with lenalidomide, rituximab produced more growth inhibition and greater apoptosis compared with rituximab alone.[11, 12] This combination also demonstrably enhanced the natural killer cell, antibody-dependent cellular cytotoxicity of rituximab.[12, 13]
To test the efficacy of lenalidomide combined with rituximab, we conducted a phase 2 clinical trial in patients with indolent B-cell or mantle cell lymphomas who were previously resistant or refractory to rituximab or rituximab-based therapy. Low-dose, weekly dexamethasone was added to the regimen based on anecdotal clinical experience suggesting the amelioration of lenalidomide side effects, especially rash and tumor flare, as well as the known synergy between corticosteroids and immunomodulatory drugs.
MATERIALS AND METHODS
This was a single-center, prospective, open-label, phase 2 study examining the combination of lenalidomide, low-dose dexamethasone, and rituximab in patients with previously treated, rituximab-refractory or resistant, indolent B-cell or mantle cell lymphomas. The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of the University of Pennsylvania. All patients provided written informed consent before study entry. The clinical trial registration number was NCT00783367 (available at: clinicaltrials.gov) under the approved registry name “Combination Therapy Using Lenalidomide (Revlimid)–Low-Dose Dexamethasone and Rituximab for Treatment of Rituximab-Resistant, Nonaggressive B-Cell Lymphomas.”
Adults (aged ≥18 years) with histologically confirmed, CD20 antigen-expressing follicular (grades 1, 2, and 3a), marginal zone, small lymphocytic, lymphoplasmacytic, or mantle cell lymphomas were eligible. Tissue blocks were reviewed to confirm each diagnosis using the 2008 World Health Organization classification criteria. Patients were required to have progressive lymphoma requiring therapy, a life expectancy >3 months, and at least 1 measurable lesion (≥2 cm in greatest dimension). The criteria to initiate treatment on protocol required patients to have refractory or progressive lymphoma (defined as new lesions or enlargement ≥50% of existing lesions) within 6 months of rituximab monotherapy or a rituximab-chemotherapy combination. All images and response assessments were reviewed by the principal investigator and a board-certified radiologist. Patients were withdrawn from the study if they experienced relapse or disease progression after having received rituximab or at the discretion of the treating physician or patient.
In part I of protocol therapy, patients received oral lenalidomide 10 mg daily and oral dexamethasone 8 mg once weekly for two 28-day cycles. Response evaluation (computed tomography [CT] or positron emission tomography/CT imaging) was performed at the end of the second cycle (part I response). Patients then initiated part II of protocol therapy—cycles 3 through 5—regardless of their response status after part I. During cycle 3, in addition to continuous daily lenalidomide and weekly dexamethasone, patients received rituximab 375 mg/m2 once weekly for 4 weeks. Radiologic response was reassessed 2 months after completing rituximab at the end of cycle 5 (part II response). Patients who demonstrated either a response or stable disease were permitted to continue receiving lenalidomide with or without dexamethasone until they developed disease progression or withdrew, but patients were not permitted to receive additional rituximab while on study (Fig. 1). Patients who continued receiving lenalidomide had CT or PET/CT imaging at 12 months, 18 months, and 24 months after enrollment and then yearly for a maximum of 5 years from study entry. Lenalidomide was held for toxicity grade ≥3 based on version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events, and it was restarted at a lower dose (either 5 mg daily or every other day) upon the resolution of toxicity (≤ grade 2) within 28 days. At the discretion of the treating physician, the dose of oral lenalidomide could also be decreased to 5 mg daily or 5 mg every other day for lower grade symptoms possibly related to lenalidomide. All patients received either aspirin 81 mg daily or warfarin for antithrombotic prophylaxis. Contraceptive counseling was performed according to the RevAssist program (Celgene Corporation, Summit, NJ).
The primary study endpoint was the overall response rate (ORR) after cycle 5 (part II response) using international workshop response criteria for non-Hodgkin lymphoma. For 25 evaluable patients, using an α value of .05, we estimated 80% power to detect an ORR of at least 50%. Secondary clinical endpoints included progression-free survival (PFS), response duration (RD)/time to progression (TTP), OS, and a detailed toxicity assessment using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events. The Kaplan-Meier method was used to estimate PFS, RD/TTP, and OS. Statistical analyses were performed using STATA version 9.2 (Stata Corporation, College Station, Tex).
Twenty-seven patients were enrolled between July 2008 and May 2010. Prior to enrollment, 19 patients had disease progression after or during rituximab, 6 patients had stable disease after rituximab, and 2 patients relapsed within 6 months of responding to rituximab. The median time from diagnosis was 6.77 years (range, 0.89-26.12 years). Additional characteristics of the study cohort at enrollment are presented in Table 1.
Table 1. Patient Characteristics
No. of Patients/Total No. (%)
Abbreviations: CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; hyper CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and high-dose cytarabine; ECOG, Eastern Cooperative Oncology Group; ICE, ifosfamide, carboplatin, and etoposide; LDH, lactate dehydrogenase.
For any patient who received at least 1 dose of lenalidomide (N = 27), the ORR after part I was 26%, and the ORR after part II for all 27 patients who started protocol therapy, even if they did not receive rituximab, was 52%. There was no difference in the response rate between patients whose rituximab resistance-defining therapy was a rituximab-chemotherapy combination, rituximab monotherapy, or rituximab maintenance (P = .4).
Twenty-four of 27 patients received rituximab during cycle 3 and were evaluable for response to part I (2 cycles of lenalidomide and low-dose dexamethasone) and part 2 (lenalidomide and low-dose dexamethasone in cycles 3-5 with rituximab during cycle 3). After part I, the ORR for these 24 patients was 29% (complete response [CR]/CR unconfirmed [CRu] rate, 17%); the ORRs were 20% for follicular lymphoma (3 of 15 patients), 60% for mantle cell lymphoma (3 of 5 patients), 33% for small lymphocytic lymphoma (1 of 3 patients), and 0% for marginal zone lymphoma (0 of 1 patient). After part II, the ORR for these 24 patients was 58% (CR rate, 33%); the ORRs were 53% for follicular lymphoma (8 of 15 patients), 60% for mantle cell lymphoma (3 of 5 patients), 67% for small lymphocytic lymphoma (2 of 3 patients), and 100% for marginal zone lymphoma (1 of 1 patient). Nine of 24 patients (38%) demonstrated an improvement in protocol-defined response after receiving rituximab. Nineteen of 24 patients (75%) continued to receive lenalidomide and weekly dexamethasone after the completion of cycle 5. Of 14 patients who had stable disease or a partial response (PR) after completing 4 weekly doses of rituximab (part II response assessment), only 1 patient had a further improvement in response status during follow-up. As of November 10, 2012, the median follow-up was 12.2 months (range, 0.9-52.7 months), and the estimated median PFS and OS were 23.7 months and not reached, respectively (Fig. 2A). The RD/TTP for responding patients was 26.6 months (Fig. 2B). The percentage change in the sum of the products of the maximum perpendicular, cross-sectional dimensions of target lesions in individual patients after part I (lenalidomide-dexamethasone) and part II (lenalidomide-dexamethasone-rituximab) are illustrated shown in Figure 3A through C.
The most common adverse event attributed to lenalidomide was a mild change in bowel habits, usually increased frequency, which did not warrant discontinuation of therapy (grade 1). The reported grade 3 or 4 treatment-related adverse events were neutropenia (8 of 27 patients; 30%), leukopenia (4 of 27 patients; 15%), hypokalemia (4 of 27 patients; 15%), anemia (2 of 27 patients; 7%), hypophosphatemia (2 of 27 patients; 7%), thrombocytopenia (2 of 27 patients; 7%), transaminase elevation (1 of 27 patients; 4%), pneumonia (1 of 27 patients; 4%), diarrhea (1 of 27 patients; 4%), fatigue (1 of 27 patients; 4%), rash (1 of 27 patients; 4%), tumor flare (1 of 27 patients; 4%), pulmonary embolism (1 of 27 patients; 4%), and hyperuricemia (1 of 27 patients; 4%). Four patients (15%) had adverse events that led to discontinuation of therapy, including 3 who discontinued before part I response assessment (myocarditis, rash, thrombocytopenia) and 1 patient who discontinued after the part II response assessment (second malignancy). Four patients (15%) had treatment interruptions and dose reductions secondary to toxicity (thrombocytopenia, transaminase elevation, neutropenia, and tumor flare). One death from myocarditis occurred shortly after initiation of lenalidomide, low-dose dexamethasone.
In this study, patients with indolent B-cell or mantle cell lymphomas who were previously resistant to rituximab-based therapy received combined lenalidomide, low-dose dexamethasone, and rituximab. The ORR and the CR rate, as well as the TTP, were superior to the results reported for retreatment with single-agent rituximab in patients who were not selected for rituximab resistance.
Although the ORR increased from 29% after 2 cycles of lenalidomide plus low-dose dexamethasone to 58% after the addition of rituximab, based on the design of this single-arm trial, it was not possible to determine with certainty whether rituximab improved what would have been the response to further continuation of lenalidomide plus low-dose dexamethasone alone. However, of 20 patients who ultimately had reductions in tumor volume on this regimen, 7 patients initially had increases in their tumor volumes before the addition of rituximab (Fig. 3A). This suggests a response to rituximab in these patients. In addition, of the other 13 patients who ultimately had a reduction in tumor volume on this regimen, 12 had further reductions in tumor volume after receiving rituximab, which also suggests enhanced efficacy for the rituximab combination over lenalidomide plus low-dose dexamethasone alone (Fig. 3A). Although a few patients had CRs after receiving lenalidomide alone, both the timing and the magnitude of responses after the addition of rituximab in these previously rituximab-resistant patients suggest that the addition of rituximab to lenalidomide improved responses over lenalidomide plus low-dose dexamethasone alone.
To our, knowledge, this study is the first to describe the efficacy of combination lenalidomide, low-dose dexamethasone, and rituximab both in patients who were uniformly documented as resistant to rituximab and in patients with low-grade follicular lymphoma. Rituximab is a cornerstone of treatment for low-grade follicular lymphoma, and patients with rituximab-refractory, low-grade follicular lymphoma have poorer OS compared with all patients diagnosed with follicular lymphoma.[3, 4] Treatment with lenalidomide plus rituximab appears to be well tolerated and effective in patients with indolent B-cell and mantle cell lymphomas and may offer another therapeutic option for previously treated patients who have a poor prognosis. Lenalidomide also has the advantage of being an oral formulation. In addition, lenalidomide can be continued for years in the absence of cytopenias; the longest patient we report on has received lenalidomide for over 4 years. Moreover, in our experience, combination lenalidomide plus low-dose dexamethasone and rituximab did not interfere with the ability to administer subsequent chemotherapy.
The combination of lenalidomide and rituximab reportedly is effective in relapsed or refractory, aggressive B-cell lymphomas, including mantle cell lymphoma (ORR, 57%); relapsed or refractory diffuse large B-cell, follicular grade 3, and transformed lymphomas (ORR, 33%); and de novo diffuse large B-cell lymphoma (ORR, 35%). These trials differ from our study, in that they used a different dose and schedule of lenalidomide (oral lenalidomide 20 mg daily on days 1-21 of a 28-day cycle[19-21]) as well as different schedules for rituximab administration (rituximab weekly for cycle 1[19, 20] or rituximab every other week for 4 cycles); thus, those response rates are not directly comparable to our results.
In conclusion, we report the first clinical trial of combined lenalidomide, low-dose dexamethasone, and rituximab in patients with rituximab-resistant, indolent B-cell lymphoma or mantle cell lymphoma. Our data support other reports of efficacy for rituximab-lenalidomide in relapsed[19-23] and previously untreated, indolent B-cell lymphoma and, in part, are the basis for an ongoing multicenter, randomized trial comparing lenalidomide-rituximab with rituximab-chemotherapy as first-line therapy of follicular lymphoma (NCT01476787).
Tahamtan Ahmadi received a grant from the Leukemia and Lymphoma Society for the conduct of this study. Stephen J. Schuster and Nicole A. Aqui received research support from Celgene Corporation for this clinical trial.
CONFLICT OF INTEREST DISCLOSURES
Jakub Svoboda received a grant from Celgene Corporation for an investigator-initiated clinical trial. Anthony R. Mato has received compensation as a member of the Speakers Bureau of Celgene Corporation.