ORLANDO, FL—For patients with newly diagnosed follicular lymphoma, a course of rituximab followed by rituximab maintenance approximately doubled the number of patients not requiring chemotherapy or radiotherapy at three years, compared with the standard of watchful waiting.
The data are from a preliminary analysis of an Intergroup randomized trial comparing rituximab with a watch-and-wait strategy in patients with Stage II, III, IV asymptomatic, non-bulky follicular lymphoma, Grades 1, 2 and 3a, presented here during the plenary session of the American Society of Hematology Annual Meeting.
At three years, 48% of the patients in the watch-and-wait arm had not required further treatment (chemotherapy or radiotherapy), versus 80% in the rituximab-induction arm and 91% among patients receiving rituximab for induction followed by rituximab maintenance.
“The aim of early rituximab treatment is to defer chemotherapy and avoid its side effects, while extending the period of time when the patient feels well,” said lead author Kirit M Ardeshna, MD, hematology consultant at University College London Hospitals.
The trial (Abstract 6) was sponsored by Cancer Research UK.
Dr. Ardeshna noted that previous studies had shown no benefit for early treatment after diagnosis in asymptomatic, advanced follicular lymphoma patients, compared with watchful waiting until symptoms develop. He said the time to initial treatment under watch-and-wait is typically two and a half years.
After presenting this new data, he predicted that rituximab treatment immediately after diagnosis along with rituximab maintenance would become popular with hematologists and oncologists.
“Provided quality of life is not worse with the administration of rituximab, I believe it will become a popular option for doctors for their patients with asymptomatic follicular lymphoma, and is likely to become the standard of care,” Dr. Ardeshna said, during a news conference highlighting studies deemed newsworthy by the ASH program committee.
In the plenary presentation, Dr. Ardeshna reported that with a medium follow-up of 32 months, data at three years showed that 48% of the watch-and-wait group had not required further treatment (chemotherapy or radiotherapy).
This compared with 80% in the rituximab-induction arm and 91% in rituximab-maintenance arm.
(When other recent studies showed a benefit to rituximab maintenance, and because accrual in this trial was going slowly, the rituximab-alone arm was closed, Dr. Ardeshna said.)
But in overall survival there was no difference at three years, with 95% of patients still alive, he said. “These data indicate that initial treatment with rituximab significantly delays the need for new therapy. This finding may change the management of patients with newly diagnosed asymptomatic follicular lymphoma.”
Favorable Safety Profile
Dr. Ardeshna said the side effects profile of rituximab was limited and particularly favorable, “probably because patients have not had chemotherapy yet.” He said he did not expect that rituximab maintenance would reduce the impact of rituximab as treatment after relapse.
The moderator of the news conference, Ginna G. Laport, MD, Associate Professor of Medicine at Stanford University Medical Center, noted that the widespread standard of care in the United States for asymptomatic follicular lymphoma patients is watch-and-wait, and currently there is little use of rituximab as maintenance.
Dr. Ardeshna responded that watch-and-wait “is not dead” and would still be appropriate in some patients, but he said he sees rituximab maintenance becoming the more common prescription for asymptomatic follicular lymphoma patients.
Adult patients with asymptomatic Stage 2, 3 or 4 follicular lymphoma (Grades 1, 2, and 3a) and adequate bone marrow reserve were randomly assigned with a ratio to watchful waiting (Arm A), or rituximab at 375 mg/m2 weekly for four weeks (Arm B), or rituximab at 375 mg/m2 weekly for four weeks followed by rituximab maintenance every two months for two years starting at month three until month 25 (Arm C).
The primary endpoints were time to initiation of new therapy (chemotherapy or radiotherapy) and the effect on quality of life.
In September 2007, a decision was made to discontinue Arm B as evidence of the efficacy of maintenance rituximab became clear.
Between September 2004 and May 2009, a total of 462 patients were randomly assigned to watch-and-wait in arm A (186 patients), rituximab in Arm B (84), and Arm C (192); 98% entered the study within four months of diagnostic biopsy.
The patients' median age was 60, 54% were female, and 42% had bone marrow involvement. Stage 2 disease was diagnosed in 21% of patients, Stage 3 in 40%, and Stage 4 in 39%. FLIPI scores were 9% at 0; 26% at 1; 41% at 2; 22% at 3; and 2% at 4.
Dr. Ardeshna reported that 45 significant adverse events had been reported at the time of his presentation: 14 in Arm A; six in Arm B; and 25 in Arm C. Among those, 14 (4 in Arm B; 10 in Arm C) were considered possibly, probably, or definitely related to the study drug.
Among the adverse events were five allergic reactions (two Grade 3), six infections, and three episodes of Grade 4 neutropenia.
Remissions were assessed at Months 7, 13, and 25. An interim analysis performed in February 2010 showed that at Month 7, the watch-and-wait Arm A had 3% of patients in spontaneous remission, partial remissions in 6%, 74% with no change, and progressive disease in 17%.
In rituximab Arm B, 45% of patients were in complete remission or unconfirmed complete remission, 33% had a partial remission, 19% showed no change, and 3% had progressive disease.
And in the rituximab-maintenance Arm C, 49% had complete remission or unconfirmed complete remission, 36% had a partial remission, 11% had no change, and 3% had progressive disease. At the time of the interim analysis 93 (20%) patients had initiated new treatment.
Dr. Ardeshna noted that the estimated median time to initiation of new therapy in Arm A was 33 months, similar to a previous report from his group, published in 2003 in TheLancet, adding that only 84 of the 142 patients reported to have clinically progressed disease had initiated new therapy.
The time to initiation of new therapy was significantly longer in both rituximab arms, and the median time was not reached at four years. There were again significant differences in progression-free survival between the observation and rituximab arms, but importantly, there was no difference in overall survival between the three arms.
Some members of the audience took issue with the trial's design, conclusions, and implications.
Ariela Noy, MD, associate member and attending physician in the Lymphoma Service of Memorial Sloan-Kettering Cancer Center, noted that there was no crossover from watch-and-wait to rituximab. “Would watch-and-wait patients have had different outcomes if they had crossed over to rituximab?,” she asked.
Dr. Ardeshna replied that that question would require a different trial. He said this study's protocol defined initial treatment as chemotherapy or radiotherapy, and investigators were asked not to give single-agent rituximab to patients when they progressed.
Also in the audience, Joseph M. Tuscano, MD, Associate Professor of Hematology Oncology at the University of California Davis Cancer Center, questioned Dr. Ardeshna's prediction that if quality-of-life data turn out to be the same for both study arms, then rituximab would be considered a reasonable alternative to watchful waiting in asymptomatic follicular lymphoma.
“But if overall survival is the same and quality of life is the same, what would be the rationale to start therapy early?,” Dr. Tuscano asked.
Dr. Ardeshna clarified his statement, saying that what he said was that if there was no decrement to quality of life with rituximab, it would then be a reasonable option for newly diagnosed patients.
“Of course, each case would be considered individually,” he added.
Another member of the audience objected to the definition of “initial treatment,” and also to the selection of primary endpoint.
He said that giving rituximab before the first chemotherapy is in itself the initial treatment, and one would expect rituximab patients to have longer time to chemotherapy versus patients who went through the watch-and-wait period before initiating chemotherapy.
Dr. Ardeshna said the aim was to defer chemotherapy by using rituximab, which has a more favorable toxicity profile.
“Well, most of us are hoping to defer any treatment,” the audience member said. A more appropriate endpoint in this study would have been overall survival—“which I realize would take a long time to find in this disease”—or quality of life.
Needs Significant Secondary Outcome
Session co-moderator and ASH 2011 President J. Evan Sadler, MD, PhD, Professor of Medicine and of Biochemistry and Molecular Biophysics at Washington University Medical School in St. Louis, said the questions from the audience were quite valid.
“People are wishing there were five more years of follow-up,” he said in an interview after the session. “If you're going to give therapy that is very expensive but does not change important primary outcomes, you need a very significant secondary outcome to justify it.”
A quality of life with rituximab equal to watch-and-wait is not enough, he said.
“You'd need better quality of life, or better cosmesis, or better survival—something to justify rituximab treatment, or a dramatic fall in the cost of rituximab.”
Changing His Practice
Anas Younes, MD, Professor in the Division of Cancer Medicine and Director of the Clinical and Translational Research Program in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, has been closely following the trial's progress, and says he considers watch and wait to be on the way out.
An avid user of social media (OT,9/25/10), Dr. Younes posted impressions of the ASH meeting on his Facebook page, including his thoughts on this trial.
“Clearly, early treatment with rituximab improved the progression-free survival and time to next therapy,” he wrote. “It is too early to see any effect on survival, [but] my guess is that watch and wait will disappear as patients and doctors will start recommending early use of rituximab instead of watch and worry!”
In a telephone interview before the ASH meeting, Dr. Younes said, “There is no way [rituximab-maintenance] won't translate into improved survival.”
“Watch-and-wait buys you about three years average until next therapy; rituximab is certainly buying you more than three years,” he said. “Median progression-free survival hasn't even been reached. With short-term follow-up it looks pretty good.”
Dr. Younes said he is considering whether more intensified early intervention would be even better than rituximab maintenance.
“The argument is that rituximab is better than watch-and-wait, so can you extend this to rituximab-chemotherapy?” he said. He added, however, that a randomized trial to test this would take about 30 years.
“In my practice, unless there is a contraindication for rituximab-chemotherapy, my preference, especially based on this new data, is to go for rituximab-chemotherapy in asymptomatic patients,” he said. This will change practice for sure—I've been waiting for this.