Rituximab Instead of "Watch and Wait" in Asymptomatic Follicular Lymphoma

Zosia Chustecka

December 05, 2010

December 5, 2010 (Orlando, Florida) — Patients with asymptomatic nonbulky follicular lymphoma are generally followed with a "wait and watch" approach and then treated with chemotherapy as and when the cancer progresses. A new study suggests that administration of rituximab to these patients, even while they are asymptomatic, can significantly increase the time until they need chemotherapy — perhaps by several years.

Dr. Kirit Ardeshna

The watchful waiting approach defers chemotherapy, on average, for about 2.5 years. This time was significantly increased in the new study in patients on rituximab — the median time to initiation of chemotherapy was not reached at 4 years.

These results were reported today by lead author Kirit Ardeshna, MD, consultant hematologist at University College London Hospitals, in the United Kingdom, at a plenary session here at the American Society of Hematology (ASH) 52nd Annual Meeting.

These new data come from a "very high quality study" and show that there is a clear advantage to starting rituximab therapy early on, and not waiting until symptoms develop, American Society of Hematology Secretary Charles Abrams, MD, associate chief of the Division of Hematology/Oncology at the University of Pennsylvania in Philadelphia, commented in an interview with Medscape Medical News.

There was a clear improvement in progression-free survival, although not in overall survival, he added.

These new data will lead to changes in clinical practice.

"These new data will lead to changes in clinical practice, perhaps not so much in the United States as elsewhere in the world," Dr. Abrams predicted. He said that some US clinicians already use rituximab early on in asymptomatic patients with follicular lymphoma. However, other parts of the world, including Europe and Canada, are more conservative, he said, and added that watchful waiting is still the standard of care.

In the discussion period after the presentation at the plenary session, several US hematologists questioned aspects of the trial design and wondered about the cost of treating with rituximab, the effect it would have on quality of life, and the effect that early rituximab could have on subsequent therapies.

Session moderator J. Evan Sadler, MD, PhD, ASH president-elect, noted that some of these concerns are theoretical, but are valid nonetheless. In an interview with Medscape Medical News,he highlighted the lack of effect on overall survival, although he added that these patients can live for years with their disease, more than a decade or so, and so it will be difficult to show an impact on overall survival.

The results interesting, but are not practice changing. We need more data.

Dr. Sadler, who is professor of medicine in the hematology department at Washington University, in St. Louis, Missouri, said that "the results are interesting, but are not practice changing. We need more data." There are already some clinicians who are using rituximab early in this way, he said, but this is an individual decision to be made for each patient. [The decision] will need to take into account the extent of the tumor burden, the patient's psychological reaction to a 'watch and wait strategy,' their willingness to undergo rituximab treatment (which entails an intravenous infusion every 2 months), and how strongly they feel about delaying chemotherapy. It will be important to see what impact rituximab therapy will have on quality of life; these data are not available yet," he added.

Time Increased by Rituximab

The study involved 462 patients with asymptomatic stage 2, 3, or 4 follicular lymphoma. They were assigned either to watchful waiting or to treatment with rituximab, which was administered in 1 of 2 different schedules. Patients in both treatment groups received rituximab 375 mg/m2 weekly for 4 weeks, but 1 group also received rituximab maintenance every 2 months for 2 years.

Responses were assessed at months 7, 13, and 25, and patients underwent computed tomography at months 7 and 25. When patients progressed, they received a new therapy, which consisted of chemotherapy with or without rituximab in 88% and radiation in 10% of cases, and 1 patient underwent surgery, Dr. Ardeshna told the meeting.

The study began in September 2004, but by September 2007 it had become clear that the treatment group with maintenance rituximab therapy was superior to the other treatment group (in which patients received rituximab for only 4 weeks); hence, this treatment group was discontinued. The study then continued with only 2 groups until March 2010. At that time, the Data Monitoring Committee decreed that the data were mature and that a full analysis should be performed, even though 20 patients were still receiving rituximab maintenance therapy, Dr. Ardeshna explained. The median follow-up was 34 months.

The results show that time to initiation of new therapy was significantly increased by rituximab. At 3 years, 49% of patients in the watchful waiting group had not received any treatment compared with 80% in the group who took rituximab for 4 weeks and 91% who took rituximab for 4 weeks followed by rituximab maintenance therapy.

Progression-free survival was also significantly improved. After 3 years, 30% of patients in the watchful waiting group had not progressed compared with 60% of patients who took rituximab for 4 weeks and 81% of patients who took rituximab for 4 weeks and then received rituximab maintenance therapy.

However, there was no significant difference in overall survival among the 3 groups, and 96% of the patients are still alive in each group. Whether overall survival will be improved "is currently unclear," Dr. Ardeshna commented. At the press conference, he speculated that it may be, because the early treatment with rituximab would lead to shrinkage of the tumor and may reduce genetic mutations, which would in turn make resistance to treatment less likely later on, although he emphasized that this is just speculation.

May change the management of patients with newly diagnosed asymptomatic follicular lymphoma.

"Rituximab was very well tolerated," Dr. Ardeshna reported. There were 14 serious adverse events that may have been related to the drug, including 5 allergic reactions, 6 infections, and 3 episodes of neutropenia (grade 4).

Dr. Ardeshna concluded that rituximab significantly improved both the time to initiation of new therapy and progression-free survival, and he predicted that these results "may change the management of patients with newly diagnosed asymptomatic follicular lymphoma."

Change in Practice

The watchful waiting approach is favored by many clinicians, as it allows patients a good quality of life by avoiding chemotherapy, with its adverse effects, and also reduces hospital visits and blood tests, Dr. Ardeshna commented. However, it may cause anxiety among patients who feel that they are not being treated for a cancer that has been diagnosed.

Rituximab offers another option for these patients, and it is likely to prove popular with both patients and physicians as an alternative to watchful waiting, he predicted.

In an interview with Medscape Medical News, Dr. Ardeshna predicted that use of the watchful waiting approach will now decline. "Some physicians in the United States have already been using rituximab early on in these patients, and these new data now support that practice," he said.

However, he pointed out that some of these patients would never go on to develop full-blown disease, as their tumor remains indolent. A previous study from his team found that 19% of patients remained asymptomatic at 10 years. "But at the moment we can't identify these patients — we have no way of knowing who will progress and who won't," he said.

Research into this is now underway, he said, so that in the future it will be possible to identify those patients who are likely to progress, and hence who would benefit from early treatment, and those patients who are likely to remain asymptomatic, in whom treatment would be unnecessary. "That's our hope for the future," he said.

Questions About Trial Design

In the question period after the presentation, several US hematologists queried the design of the study. One remarked that the watchful waiting group was timed until first treatment, whereas in the rituximab groups the new treatment was a second treatment, and the time to a second treatment would be expected to be longer than time to a first treatment. Another wondered whether the watchful waiting group should have been offered rituximab alone as the first treatment, but Dr. Ardeshna countered with the response that at the time the patient progressed there was likely to be such a high tumor burden that rituximab alone would not be an appropriate therapy choice.

Others asked about the effect of rituximab on quality of life. Dr. Ardeshna said this was being evaluated, and that data on this effect should be available next year, but added that patients on rituximab maintenance therapy reported that they felt well.

Another issue raised was that of cost of rituximab maintenance therapy vs that of watchful waiting. In addition, several delegates highlighted the lack of effect on overall survival, although they acknowledged that these data would not be available for some time yet in this slowly progressing disease.

A further concern raised by several of the questioners was the effect that early rituximab could have on subsequent therapy and the possibility that patients could respond less well further down the line. Dr. Ardeshna replied that these patients would continue to be monitored, and their responses to subsequent lines of therapy would be documented.

This study was supported by Cancer Research UK, but Roche supplied rituximab free of charge. Dr. Ardeshna reported consultancy, honoraria, and research funding from Roche.

American Society of Hematology 52nd Annual Meeting: Abstract 6. Presented December 5, 2010.


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