Mantle cell lymphoma is a pernicious, incurable disease. Front-line therapies for this disease are not currently standardized; however, novel therapies for relapsed or refractory mantle cell lymphoma can ideally be translated into beneficial treatments for newly diagnosed patients, as clearly demonstrated by the phase II study of lenalidomide (Revlimid) and rituximab (Rituxan) by Ruan and colleagues recently reported in The New England Journal of Medicine.1 As reviewed in this issue of The ASCO Post, Ruan and colleagues rapidly and effectively transferred the findings of a multi-institutional study of rituximab and lenalidomide for relapsed or refractory mantle cell lymphoma into the front-line setting and achieved a striking objective response rate of 92%—which is a major step forward in the fight against mantle cell lymphoma.
Recap of Lymhoma Studies
Lenalidomide was first approved by the U.S. Food and Drug Administration (FDA) for relapsed myeloma therapy in combination with dexamethasone.2 However, based on preclinical findings, lenalidomide was proposed to be a potentially effective treatment for lymphoma. With the preclinical work performed by Hernandez-Ilizaliturri et al3 and after approval of this agent by the FDA, Celgene initiated the lymphoma efforts.
Lenalidomide was first studied as a single agent in non-Hodgkin lymphoma by Wiernik and colleagues in 2008.4 In 49 patients, the objective response rate was 35%; however, in the 15 enrolled patients with mantle cell lymphoma, the objective response rate was 53%.
Based on these promising results, my colleague, Dr. Liang Zhang, and I conducted preclinical experiments to test the activity of lenalidomide and rituximab in mantle cell lymphoma cell lines, primary mantle cell lymphoma cells, and mantle cell lymphoma–bearing patient-derived xenograft mice. The combination was shown to be effective preclinically, which led us to propose our phase I/II clinical trial testing the combination in patients with relapsed or refractory mantle cell lymphoma.5
It is somewhat funny that I missed the initial deadline to submit a letter of intent to Celgene; however, I believed strongly in our preclinical data and predicted that this combination would exceed the efficacy of the currently approved bortezomib (Velcade), which had a response rate of 33% in relapsed/refractory mantle cell lymphoma.6 Although my letter of intent was past due, Celgene provided me with a moderate budget for my first investigator-initiated trial. In this trial, we enrolled 52 patients, and in the phase II portion, with 44 patients, an overall response rate of 57% was obtained.5 These promising results led the MD Anderson Cancer Center to expand the testing of this combination to follicular lymphoma or chronic lymphocytic leukemia.
Front-Line Setting
The trial by Ruan and colleagues quickly applied these findings in patients with relapsed or refractory mantle cell lymphoma to newly diagnosed patients with mantle cell lymphoma. They conducted a multicenter phase II trial with 38 patients with induction/maintenance phases, closely following the same dosing and scheduling previously published for relapsed or refractory mantle cell lymphoma with minor modifications.1
At the median follow-up of 30 months, the overall response rate was 92%, with a complete response rate of 64%, and no unexpected adverse events. Strikingly, the 2-year progression-free survival among the patients with mantle cell lymphoma who received this initial combination was 85%, which is in marked contrast to the median progression-free survival of 16 to 35 months witnessed in patients with mantle cell lymphoma who received initial therapy consisting of chemotherapy.7 Furthermore and encouragingly, the patients who progressed on this treatment responded favorably to subsequent therapeutic regimens. Nevertheless, in this trial, grade 3 toxicities were still numerous, including neutropenia (50%), rash (29%), thrombocytopenia (13%), and pneumonia (8%),1 suggesting that lenalidomide still causes severe adverse events in the front-line setting and may not be the miracle drug that we hoped.
Ibrutinib-Based Combinations
These results by Ruan and colleagues clearly demonstrate that treatment already shown to be effective in the relapsed/refractory setting should be tested in the front-line setting. We recently showed that the combination of ibrutinib (Imbruvica) and rituximab is efficacious in relapsed/refractory mantle cell lymphoma, with an overall response rate of 88% and a complete response rate of 40%.8
In support of this shift in the way mantle cell lymphoma is treated, we have opened two trials testing the combination of ibrutinib and rituximab in the front-line setting. First, we are testing the ibrutinib and rituximab combination as an initial treatment in older patients with mantle cell lymphoma (> 65 years of age) whose Ki67 levels are less than 50%; currently, 20 of 50 patients have been enrolled. Second, for younger patients (< 65 years of age), we designed the two-part Window protocol: ibrutinib and rituximab followed by R-hyper-CVAD (rituximab plus hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with the regimen of rituximab plus methotrexate and cytarabine for fewer cycles if the patient demonstrates a good response in part 1. To date, for the Window study, 30 of 50 patients have been enrolled. These trials testing novel front-line treatment combinations are creating a shift in the treatment of mantle cell lymphoma.
Starting with the auspicious efforts of Ruan and colleagues, multiple chemotherapy-free regimens for newly diagnosed patients with mantle cell lymphoma are on the verge of becoming standardized therapies. This is an exciting time in the treatment of mantle cell lymphoma—one in which we may be able to battle this disease successfully at the front line with multiple novel combinations of agents. ■
Disclosure: Dr. Wang reported no potential conflicts of interest.
References
1. Ruan J, et al: Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med 373:1835-1844, 2015.
2. Weber DM, et al: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133-2142, 2007.
3. Hernandez-Ilizaliturri FJ, et al: Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 11:5984-5992, 2005.
4. Wiernik PH, et al: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 26:4952-4957, 2008.
5. Wang M, et al: Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma. Lancet Oncol 13:716-723, 2012.
6. Fisher RI, et al: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-4874, 2006.
7. Howard OM, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma. J Clin Oncol 20:1288-1294, 2002.
8. Wang ML, et al: Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma. Lancet Oncol. November 27, 2015 (early release online).
Dr. Wang is Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, e University of Texas MD Anderson Cancer Center, Houston, Texas.
