A new approach that avoids chemotherapy and instead uses a combination of lenalidomide (Revlimid, Celgene Corporation) plus rituximab (Rituxan, Genentech, Inc/Biogen Idec Limited) was effective and safe when used as a first-line therapy for mantle cell lymphoma.
Although there is no set standard for first-line therapy in mantle cell lymphoma, it usually includes cytotoxic chemotherapy. However, many patients with the disease are older and are often unable to undergo intensive regimens.
The new lower-intensity approach was highly active, with durable responses observed in most patients, according to new data published November 5 in the New England Journal of Medicine.
In this multicenter, phase 2 study, 38 patients (median age, 65 years) were treated with lenalidomide and rituximab for both induction and maintenance phases.
At 30 months, the overall response rate for evaluable patients was 92% (36 patients), and the complete response rate was 64% (95% confidence interval [CI], 46 - 79).
Median progression-free and overall survival had not been reached. The 2-year progression-free survival is estimated to be 85% (95% CI, 67 - 94), and the 2-year overall survival, 97% (95% CI, 79 - 99).
"For patients, their quality of life was preserved or improved, and that's a huge step up from regular chemotherapy," said lead author Jia Ruan, MD, an associate professor of clinical medicine at Weill Cornell Medicine, New York City. "We feel that further study of this approach in larger trials will allow a better assessment of its value relative to other mantle cell leukemia regimens.
"Given that the approach to mantle cell lymphoma treatment is highly variable and decisions are made with consideration of balancing efficacy and toxicity, the lenalidomide plus rituximab regimen represents a useful option to consider for some patients, particularly those who wish to avoid or cannot tolerate more intensive chemotherapy-based treatment," he told Medscape Medical News.
Not Ready for Routine Use
Lenalidomide, a second-generation immunomodulatory compound, and rituximab, an anti-CD20 antibody, are both active in patients with recurrent mantle cell lymphoma.
First-line treatment of mantle cell lymphoma varies, but it generally involves intensive approaches, including high-dose chemotherapy and hematopoietic-cell transplant, note the authors. Treatment selection is influenced by age, patient preferences, and the presence of coexisting conditions. Treatment remains a clinical challenge for patients who are not appropriate candidates for highly intensive regimens.
"What is novel about this study is that lenalidomide is being used as a frontline treatment strategy," said Brad Kahl, MD, a professor of medicine at Washington University School of Medicine, in St. Louis, Missouri, who was approached for comment. "Most patients receive some type of chemotherapy regimen first line."
Lenalidomide is approved for use in recurrent mantle cell lymphoma, he explained, and there are good data that suggest that lenalidomide combined with rituximab is more effective than the agent used alone.
"The intensity of the regimen will depend on the patient's age, comorbidities, and the philosophies of the particular center," said Dr Kahl, who is also a spokesman for the American Society of Hematology. "A rule of thumb is that patients younger than 65 in the US will most likely receive more intensive regimens and stem cell transplantation, and those that are older, less intensive chemotherapy."
But he does not think that on the basis of this study, the regimen is going to supplant the usual frontline therapies. "One of the main points is that this is a small study with only 38 patients, and they are only followed for 30 months," he told Medscape Medical News. "I think it will be important to follow these patients over a longer period of time to see how durable the responses are."
Relapses in mantle cell lymphoma generally occur in the range of 3 to 4 years, Dr Kahl pointed out. "So another 12 to 24 months of follow-up will really be very informative about this regimen," he said. "The results are very promising and intriguing, but it does need more maturation."
Dr Kahl did note that there is not one standard of care for frontline treatment of mantle cell lymphoma, so it is possible that some physicians may be interested in trying this regimen for certain patients. "But generally speaking, we do need further study on this, with a larger population and a longer follow-up."
Because mantle cell lymphoma is generally considered incurable, the major therapeutic goals are to extend survival and improve quality of life. Dr Ruan and colleagues hypothesized that first- line therapy with biologic agents might offer patients a treatment option that is effective and that has a more favorable side-effect profile compared with some of the chemotherapy approaches.
From July 2011 through April 2014, 38 untreated patients were enrolled at four centers (Weill Cornell Medical College and New York–Presbyterian Hospital, the Moffit Cancer Center, the University of Pennsylvania Abramson Cancer Center, and the University of Chicago Medical Center).
The median age was 65 years (range, 42 to 86 years); 100% of patients had stage III or IV disease. On the basis of Mantle Cell Lymphoma International Prognostic Index scores, 34% had low-risk disease, 34% had intermediate-risk disease, and 32% had high-risk disease.
During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles, with dose escalation to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle. It was then reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression.
The study's primary endpoint was overall response rate; secondary endpoints included outcomes related to safety, survival, and quality of life.
Of the 36 evaluable patients, 28 (78%) were in remission without disease progression, including 26 who had completed induction therapy and were receiving maintenance therapy, one who had almost completed induction therapy, and one who was treated for 3 years and had ended treatment.
Eight evaluable patients experienced disease progression, three with primary refractory disease and five whose lymphoma progressed after initial responses.
The authors note that treatment-related side effects were expected. The most common grade 3 or 4 adverse events were neutropenia (50% of patients), rash (29%), thrombocytopenia (13%), an inflammatory syndrome ("tumor flare") (11%), anemia (11%), serum sickness (8%), and fatigue (8%).
Health-related quality of life was measured with use of the Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) scale. Scores on this scale remained stable or improved during both the induction and maintenance phases. Trends toward improvement from baseline were noted in the mean FACT-Lym total scores among those who completed the assessment both at month 12 and at baseline (139.1 ± 19.1 at month 12 vs 133.6 ± 22.8 at baseline, P = .04) and for patients who completed the assessment both at month 21 and at baseline (139.3 ± 24.1 vs 133.7 ± 24.6, P = .06).
The study was supported in part by the Celgene Corporation and by a Weill Cornell Medical College Clinical Translational Science Center grant (to Dr Christos). Several of the coauthors have disclosed relationships with industry, including Celgene, as noted in the original article.
N Engl J Med. 2015;373:1835-1844.