Becky McCall

June 13, 2011

June 13, 2011 (London, United Kingdom) — The duration of remission doubled in elderly patients with mantle cell lymphoma (MCL) who received rituximab as maintenance therapy after responding to induction therapy. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care.

Hanneke Kluin-Nelemans, MD, from the University Medical Center Groningen, the Netherlands, presented these results here at the 16th Congress of the European Hematology Association.

At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). "This means we doubled remission duration, which is a very impressive improvement," Dr. Kluin-Nelemans told Medscape Medical News.

The results come from a randomized controlled trial, which the researchers conducted jointly with the European Mantle Cell Lymphoma Network. According to Dr. Kluin-Nelemans, the treatment used in patients younger than 60 years of age, which involves high-dose cytarabine and autologous stem cell transplantation, is not feasible for older patients. "Without this intensive therapy, only a minority of patients obtain a complete remission upon standard induction therapy; afterward, all patients relapse, resulting in an overall survival usually between 3 and 5 years," she said.

The researchers designed this study to determine whether maintenance therapy with rituximab after 2 different induction regimens would improve remission duration and overall survival in elderly patients with MCL.

The study involved 560 patients with MCL, drawn from 8 different European countries, and was carried out from 2004 to 2010. Median age was 70 years and patients had extensive disease.

The median follow-up time to date is about 37 months; for those recruited at the start, it is more than 3 years. Of the initial 560 patients, only the 310 patients in partial or complete remission underwent the second randomization. Dr. Kluin-Nelemans explained.

"It's an elderly cohort, so not everyone was willing to undergo second randomization. We'll continue to follow these patients lifelong," she said.

Originally, patients received 1 of 2 different induction schemes of 6 to 8 cycles: either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); or rituximab, fludarabin, and cyclophosphamide (R-FC). If they showed a good response after 5 months (78% to 87% of patients had any response after induction therapy), patients underwent a second randomization, to either low-dose interferon or to rituximab (experimental group), 1 infusion every 2 months.

"Usually maintenance is given for around 2 years, but we decided to continue until progression of the disease," explained Dr. Kluin-Nelemans.

In addition to observing the doubling of remission duration in patients receiving rituximab maintenance, the researchers observed improved overall survival, from 62% to 77%, at 4 years.

"Patients pretreated with R-CHOP benefited most from rituximab maintenance, compared with those pretreated with R-FC. These particular patients [pretreated with R-CHOP] reached a 4-year overall survival of around 87%" said Dr. Kluin-Nelemans.

In terms of toxicity, the rate of hematologic adverse effects was higher with interferon than with rituximab (36% vs 17% for leukocytopenia and 16% vs 7% for thrombocytopenia). Serious infections were the same in both groups, at 7%. Dr. Kluin-Nelemans was concerned about infections related to the action of rituximab against B-cells and lymphocytes. "The less than 10% infection rate with rituximab is important because this is an elderly cohort," she said.

With respect to induction therapy, Dr. Kluin-Nelemans suggested that R-CHOP is preferable to R-FC; after that, responders should receive rituximab once every 2 months. "This gives a maximum benefit, according to our study," she noted.

This is having a major impact; it should become the standard.

Dr. Kluin-Nelemans suggested that every elderly patient who responds to induction chemotherapy for MCL should be offered rituximab once every 2 months. "This is having a major impact; it should become the standard and be covered by insurance companies. However, this is still not a cure because even on rituximab maintenance, patients relapse."

She added that any future trial should compare rituximab maintenance as the new standard with rituximab plus an additional drug to further improve the results.

Dr. Kluin-Nelemans also suggested that rituximab maintenance might benefit younger patients. "Although their survival curves are much better, the majority of these patients ultimately relapse after autologous stem cell transplantation. We are now discussing whether these patients should also receive rituximab maintenance."

It should become the standard of care.

Approached for comment, Srdan Verstovsek, MD, associate professor from the Department of Leukemia, University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News that this study substantiates the use of rituximab in the maintenance phase, and agreed with Dr. Kluin-Nelemans that it should now become the standard of care.

"It was very instructive that maintenance with the targeted-agent approach [rituximab] in MCL prolongs the remission duration. Initial attempts to add rituximab to CHOP during induction worked very well, and this is now the standard frontline approach. Also, it clearly shows that overall survival is prolonged in patients who received rituximab for a couple of years. This is a relatively benign therapy, not chemotherapy, so the toxicity profile is excellent and it should become the standard of care, he said.

"This shows a significant prolongation of event-free survival; hopefully, this will translate into overall survival for the whole group as it did for the subgroup," added Dr. Verstovsek.

However, during the discussion after the presentation, Elly Lugtenburg, MD, from the Erasmus MC University Medical Center, Rotterdam, the Netherlands, questioned the use of the comparator in this study. "You say that rituximab maintenance should become the new standard of care, but in this trial it was compared with interferon maintenance; it was not compared with placebo."

Dr. Kluin-Nelemans responded by explaining that 87 patients who responded to induction therapy but who were not randomized to the maintenance phase (for various reasons, such as refusal, preference for rituximab, and persisting hematologic toxicity after the induction) effectively illustrated the placebo effect. "We did an unadjusted analysis and used this as a control cohort, although obviously not in a randomized setting of course, and we observed that the patients who did not receive any maintenance had the worst survival."

Dr. Kluin-Nelemans, Dr. Verstovsek, and Dr. Lugtenburg have disclosed no relevant financial relationships.

16th Congress of the European Hematology Association (EHA). Presented June 11, 2011.

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