Standard of Care for Older Patients With Mantle Cell Lymphoma?

Roxanne Nelson

August 08, 2012

August 8, 2012 — For older patients with mantle cell lymphoma, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) induction therapy followed by maintenance therapy with rituximab is an effective treatment regimen, according to a study conducted as part of the European Mantle Cell Lymphoma Network.

The researchers found that a fludarabine-containing induction regimen was no more effective than R-CHOP, and was more toxic.

For patients who responded to R-CHOP induction therapy, maintenance therapy with rituximab, compared with interferon alfa, almost doubled the duration of remission.

Data from this study were originally presented at the 2011 Congress of the European Hematology Association, as reported at that time by Medscape Medical News. The updated results appear in the August 9 issue of the New England Journal of Medicine.

R-CHOP followed by maintenance therapy with 1 dose of rituximab every 2 months until progression should be the standard of care for older patients with mantle cell lymphoma, lead author Hanneke C. Kluin-Nelemans, MD, PhD, head of the Department of Hematology, University Medical Center Groningen, the Netherlands, told Medscape Medical News.

"The follow-up is long enough, and the data are solid and mature," she said. "They will not change with longer follow-up."

John Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College in New York City, who was not involved with the study, noted that this is "one of the few studies to demonstrate an overall survival benefit for a group of patients with mantle cell lymphoma."

"I suspect that many physicians will adopt maintenance rituximab after initial chemoimmunotherapy...possibly extrapolating to other regimens such as bendamustine plus rituximab, which is becoming commonly used off label in the United States in mantle cell lymphoma," Dr. Leonard told Medscape Medical News.

"The long duration of response in a substantial population of patients treated with induction and maintenance therapy, which is similar to what has been observed with more aggressive strategies in more favorable patients, suggests that maintenance approaches in mantle cell lymphoma have the potential to achieve results comparable to intensive treatments but with less acute toxicity," he said.

New Regimens Needed

Dr. Kluin-Nelemans and colleagues note that despite these promising data, a number of patients still died from their disease during the induction and maintenance phases. But the standard first-line therapy for younger patients — high doses of cytarabine followed by autologous stem-cell transplantation — is generally not a realistic option for older patients.

"The European Mantle Cell Lymphoma Network will launch a study of older patients in which 2 questions will be studied," said Dr. Kluin-Nelemans. Her team will be assessing the addition of high-doses of cytarabine in an alternating scheme to the R-CHOP induction regimen, as well as the addition of lenalidomide to the standard rituximab maintenance regimen.

Study Details

In mantle cell lymphoma, only a minority of patients experience a complete remission, and disease progression or relapse generally occurs within 2 to 3 years; overall survival is usually less than 5 years. In an effort to improve this prognosis, the researchers hoped to find a more effective induction therapy, which could result in a higher rate of complete remission. They also wanted to establish better postinduction strategies to prolong the duration of remission.

Previous research has shown that fludarabine-containing regimens are effective in the treatment of follicular lymphoma and relapsed mantle cell lymphoma. In addition, there was a trend toward a prolongation of progression-free survival in patients with mantle cell lymphoma treated with interferon alfa, which was considered standard therapy in a previous trial (Blood. 1996;88:453a), the researchers write. Previous research has also shown that maintenance therapy with rituximab significantly improved the duration of response in patients with relapsed follicular lymphoma or mantle cell lymphoma (Blood. 2006;108:4003-4008). Therefore, rituximab appears to be a promising alternative to interferon alfa.

On the basis of this information, Dr. Kluin-Nelemans and colleagues initiated a double-randomized intergroup trial to determine whether a fludarabine-containing induction regimen would improve the complete remission rate and whether maintenance therapy with rituximab would prolong remission.

A cohort of 560 patients 60 years or older with stage II to IV mantle cell lymphoma who were not eligible for high-dose therapy were randomized to 6 cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to 8 cycles of R-CHOP every 21 days. Those who experienced a response were then randomized to maintenance therapy with rituximab or interferon alfa until progression.

Of this group, 532 patients were included in the intention-to-treat analysis for response and 485 in the primary analysis for response. The median age was 70 years.

Results Show Shorter Survival

The researchers found that rates of complete remission were similar with R-FC and R-CHOP (40% and 34%, respectively; P =.10). However, progressive disease occurred more frequently in the R-FC group than in the R-CHOP group (14% vs 5%).

In addition, 4-year overall survival was significantly shorter with R-FC than with R-CHOP (47% vs 62%; P = .005). During the first remission, mortality was higher in the R-FC group (10% vs 4%).

For the 274 of 316 patients randomized to maintenance therapy, rituximab decreased the risk for disease progression or death by 45%. At 4 years, 58% (50 events) of the patients who received rituximab were still in remission, compared with 29% (71 events) of those who received interferon alfa (hazard ratio for progression or death, 0.55; P = .01).

Of those who responded to R-CHOP, maintenance therapy with rituximab significantly improved 4-year overall survival, compared with interferon alfa (87% vs 63%; P = .005).

Adverse Events

There were more hematologic toxic effects with R-FC than with R-CHOP. Grade 1 or 2 constipation and neuropathy were more common with R-CHOP, whereas the rate of grade 3 or 4 infection was similar in the 2 groups (17% vs 14%). There was a trend toward a higher frequency of febrile neutropenia with R-CHOP (17% vs 11%; P = .052). Grade 3 or 4 cardiac toxic effects were uncommon in both groups.

Because of the higher rates of hematologic toxic effects, treatment compliance was worse with R-FC.

During maintenance therapy, adverse events were "more pronounced" in those receiving interferon alfa. More patients in that group experienced leukocytopenia, thrombocytopenia, and fatigue, which was primarily grade 1 or 2. Rituximab therapy was associated with more grade 1 or 2 infections.

The study was funded by grants from the European Commission the Lymphoma Research Foundation, Roche Pharmaceuticals, Bayer Schering Pharma, and Schering-Plough.

N Engl J Med. 2012;367:520-531. Abstract

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