Not Clear: Best Use of Rituximab in Follicular Lymphoma

Nick Mulcahy

April 16, 2014

The best initial treatment strategy for asymptomatic, advanced-stage nonbulky follicular lymphoma is "not clear," according to an editorial published in the April edition of Lancet Oncology.

The opinion piece, from Stephen Ansell, MD, from the Mayo Clinic in Rochester, Minnesota, accompanies the published final results of a phase 3 trial that compared 2 different regimens of rituximab (Rituxan, MabThera, Roche) and a third approach, watch-and-wait.

Watch-and-wait is the "widely practiced strategy" in this setting, acknowledge the study authors led by Kirit Ardeshna, MD, consultant hematologist at University College London Hospitals, in the United Kingdom.

However, they believe that rituximab "should be considered as a treatment option" in these asymptomatic patients.

The investigators make that assertion based on the final results of their multinational trial, in which asymptomatic adult patients with low-tumor-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned to 3 arms: watchful waiting; rituximab 375 mg/m2 weekly for 4 weeks (induction); or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance).

They found that, with a follow-up of 50 months, maintenance strategy deferred the need for more treatment with chemotherapy and radiotherapy (a primary endpoint) — but only compared with watchful waiting (not induction).

The maintenance strategy also did not significantly improve overall survival (compared with the 2 other arms) or reduce the rate of disease transformation to a more aggressive lymphoma (compared with induction).

However, with the maintenance strategy there was a benefit in terms of quality of life, which was another primary endpoint.

Compared with the watchful-waiting group, patients in the maintenance rituximab group had significant improvements in a number of mental health measures between baseline and month 7.

In his editorial, Dr. Ansell says that prescribing rituximab for "anxious" patients who are not psychologically comfortable with watching and waiting is a "reasonable consideration."

However, he also says that it is "much less clear" whether long-term (2 years) "maintenance" rituximab "should be the standard treatment approach for all patients with follicular lymphoma who have a low burden of disease."

It may be best to simply use a short-term (4 weeks) "induction" rituximab, Dr. Ansell says.

Ongoing and future research will help address the "optimum schedule" of rituximab in this setting, Dr. Ardeshna and his coinvestigators comment.

Not all hematologists agree that rituximab should be used early on.

"In my view, the standard of care for non-bulky asymptomatic patients remains observation," said Jeremy Abramson, MD, of the lymphoma program at Massachusetts General Hospital in Boston, in a Reuters story on the trial.

Another expert quoted in the story also expressed reservations.

"I do not generally use maintenance rituximab in this population because of the lack of survival benefit (and) the likelihood that there will be some low-grade toxicity," said Sonali Smith, MD, of the lymphoma program at the University of Chicago in Illinois.

Trial Details

Notably, recruitment into the induction group was closed after news of a benefit of the maintenance strategy (compared with watchful waiting) caused decreased overall recruitment in the trial.

In the end, 192 patients were randomized to maintenance, 187 to watchful waiting, and 84 patients were enrolled in the induction arm.

For time to start of new treatment (generally chemotherapy and radiation), 88% in the maintenance rituximab group did not need treatment at 3 years compared with 46% of patients in the watchful-waiting group (P < .0001). And 78% of patients in the rituximab induction group did not need treatment at 3 years, which was also significantly more than in the watchful-waiting group (P < .0001), but no different compared with the maintenance rituximab group (P = .33).

There was also other evidence that maintenance was not better than induction.

There was no difference between the two rituximab treatment groups in overall survival (P = .82) or in the likelihood of transformation to a more aggressive lymphoma (P = .82).

However, the progression-free survival at 3 years for patients receiving maintenance rituximab was significantly better than for patients who received induction rituximab alone (P = .011).

For quality of life at month 7, the rituximab maintenance strategy was more outstanding in its effectiveness.

Compared with the watchful-waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (P = .0004) and Illness Coping Style score (P = .0012) between baseline and month 7.

Patients in the rituximab induction group did not show improvements in their quality-of-life scores compared with the watchful-waiting group, the authors report.

"Clearly, the findings from this study show that quality of life of patients receiving treatment with rituximab is better than those who undergo watchful waiting," editorialist Dr. Ansell comments.

However, the maintenance strategy was more toxic.

There were 18 serious adverse events reported in the rituximab groups (4 in the rituximab induction group and 14 in the maintenance rituximab group). Twelve of these were grade 3 or 4 (5 infections, 3 allergic reactions, and 4 neutropenias), but all fully resolved, say the authors.

The study was supported with funding from the Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.  Dr. Ardeshna has received funding from Roche for being an advisory board member, speaker, and data manager, and for travel and accommodation at international conferences. Other authors also have ties to Roche and other companies. Dr. Ansell has disclosed no relevant financial relationships.

Lancet Oncol. 2014;15:424-435 and 368-369.

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