A study comparing two induction therapies for older patients with mantle-cell lymphoma (MCL) is published today in the New England Journal of Medicine, finding that R-CHOP was less toxic than a fludarabine-based regimen, and that rituximab(Drug information on rituximab) maintenance added to R-CHOP induction is an effective treatment for older patients with the disease.
Dr. Hanneke C. Kluin-Nelemans, of the department of hematology at the University of Groningen in the Netherlands and colleagues addressed whether a fludarabine-based regimen could achieve better complete remission rates than the current standard of care, the R-CHOP regimen, and whether rituximab (Rituxan) maintenance therapy helped to prolong remission in this patient population.
Intermediate magnification micrograph of mantle-cell lymphoma of the terminal ileum. Endoscopic biopsy. Cyclin D1 immunostain; source: Nephron, Wikimedia CommonsThe study randomized 532 intent-to-treat MCL patients to either six cycles of rituximab, fludarabine, and cyclophosphamide(Drug information on cyclophosphamide) (R-FC) or to eight cycles of rituximab, cyclophosphamide, doxorubicin(Drug information on doxorubicin), vincristine, and prednisone(Drug information on prednisone) (R-CHOP). Patients had stage II to stage IV disease, a median age of 70, and were not eligible for high-dose therapy with rituximab. Patients who responded to therapy were subsequently given maintenance therapy with rituximab or interferon alfa until disease progression.
The Results
Patients given the R-CHOP regimen had a lower frequency of progressive disease—5% compared to 14% of patients on the R-FC regimen. However, complete remission rates were similar for both treatment courses, 40% for R-FC and 34% for R-CHOP (P = .10). The 4-year overall survival rate was 47% with R-FC compared to 62% with R-CHOP (P = .005). More patient deaths were seen in the first remission with the R-FC regimen (10% for R-FC compared to 4% with R-CHOP regimen).
Those patients receiving rituximab as maintenance therapy did better than those who received interferon alfa. A total of 274 patients were included in the maintenance therapy analysis. Rituximab reduced the risk of disease progression or death by 45%. After 4 years, 58% of the patients in the rituximab arm were in remission compared to 29% of those in the interferon-alfa arm (P = .01).
Additionally, the overall survival rate was better among patients taking rituximab as maintenance therapy—87% 4-year survival rate compared to 63% for those patients taking interferon alfa as maintenance (P = .005). But, the overall survival did not differ depending on the type of maintenance therapy received. Survival rates were 79% in the rituximab group compared to 67% in the interferon alfa group after 4 years (P = .13).
“The outcome of the fludarabine-containing regimen was disappointing, given the high expectations in the early 2000s,” state the authors.
“The excellent results with rituximab administered as maintenance therapy are important. Maintenance therapy with rituximab showed not only a progression-free survival benefit but also a significant survival advantage among patients who were successfully pretreated with R-CHOP,” highlight the authors.
Both patient groups had similar rates of high-grade infections but hematological adverse events were higher for patients in the R-FC group.
While this study was initiated in 2004, the regimens and results are still very pertinent today. R-CHOP is still commonly used to treat older MCL patients who are not candidates for more intense regiments or for high-dose chemotherapy and stem cell support.
“This is an important study, showing you can do randomized trial in MCL, even with an age-limited study population,” said Mitchell R. Smith, MD, PhD, director of the lymphoma program at Fox Chase Cancer Center in Philadelphia.
“Rituximab maintenance has already changed the treatment landscape,” added Smith. The data published here was first presented at the American Society for Hematology at the end of 2011. Previously, rituximab was not widely used as maintenance therapy. Smith noted that the R-FC and fludarabine-based regimens in general are not commonly used for MCL treatment, particularly in the United States. Smith said that he was not surprised that the treatment was less effective and more toxic in this older patient population.
Rituximab is an anti-CD20 antibody, targeting cancerous B cells. The antibody is approved by the US Food and Drug Administration for untreated CD-20 positive Non-Hodgkin lymphoma (NHL) in combination with chemotherapy and as a monotherapy maintenance treatment. It is also approved for chronic lymphocytic leukemia and rheumatoid arthritis.
Smith stated that the maintenance benefit with rituximab for patients who received the R-CHOP induction regimen was larger than he expected. But the caveat to the results is that only responders were randomized to maintenance, therefore selecting for a favorable subgroup. There is a concern that rituximab maintenance will not work following all induction regimens, as demonstrated in this study with the R-FC group, said Smith.
Mantle-Cell Lymphoma
While lymphoma is the most common type of blood cancer, MCL is rare, accounting for about 6% of all NHL—about 3,000 new cases every year in the United States. MCL is typically an aggressive form of B-cell lymphoma that predominantly affects men over the age of 60 and is diagnosed at late stage of disease. The overall survival is usually less than 5 years. The median age of patients is 65 and most have disease that already involves multiple lymph nodes, the bone marrow, and the gastrointestinal tract, at the time of diagnosis. The name comes from the fact that mantle-cell tumor cells arise.
Smith highlighted evidence that bortezomib(Drug information on bortezomib) (Velcade) has been approved for relapsed MCL as well as evidence that lenalidomide (Revlimid) is active in MCL and may be synergistic with rituximab. A recently opened phase II US Eastern Cooperative Oncology Group Trial E1411 will test various induction combinations of rituximab plus either bortezomib or lenalidomide followed by rituximab maintenance therapy. The trial will address whether adding bortezomib to induction therapy helps remission rates and whether lenalidomide added to rituximab as maintenance therapy is better than rituximab alone.
Earlier this year at the annual meeting of the American Society of Clinical Oncology, Mathias Rummel, MD, PhD et al presented findings that bendamustine (Treanda) plus rituximab is more effective and less toxic than R-CHOP and should be considered as the preferred first-line treatment for elderly patients with mantle-cell lymphoma.
Recent advances have facilitated long responses and survival for MCL patients, with new therapies including biologics that target B-cell receptors in development. “Survival in all recent trials is better than reported not that long ago, so we are making progress,” said Smith.
