NEW YORK CITY—Watchful waiting to monitor early-stage follicular lymphoma in selected asymptomatic patients is an acceptable option, but its use in other stages of the disease should be reevaluated. So said a speaker here at this year's Lymphoma & Myeloma International Congress on Hematologic Malignancies.
The overall question tackled by David G. Maloney, MD, a member of the clinical research division at Fred Hutchinson Cancer Research Center and Associate Professor of Medicine at the University of Washington, was whether there is a gold standard for frontline therapy of follicular lymphoma.
Dr. Maloney deemed this an unanswerable question, and he provided substantial data from many trials to support that opinion.
But on the subject of initial management with watch and wait—also known as active observation, or “watch and worry” by patients—he said he believed that the approach should be re-evaluated, since newer studies clearly show a survival advantage for rituximab-chemotherapy-based regimens.
Some physicians might still choose observation in advanced-stage asymptomatic follicular lymphoma because early studies of initial chemotherapy versus observation (until treatment when required) did not show a survival advantage for either option, he said.
“I would argue that these were small studies, done with ineffective therapies prior to the introduction of immunotherapy with anti-CD20 antibodies, and very seldom did patients achieve true complete remission.”
Since none of those studies randomized totally asymptomatic patients to an aggressive chemotherapy or rituximab-based regimen now commonly used, the answer is not clear, he said.
“I personally think for asymptomatic patients, observation is still appropriate but becoming increasingly difficult. If a patient wants to be treated, I don't twist their arm and say you can't be treated.”
Patterns of Care Data
But many patients are still only under observation initially. Dr. Maloney cited a study published by Jonathan Friedberg, MD, of the University of Rochester, that looked at patterns of care in patients from the LymphoCare study (JCO 2009;27:1202-1208). The study showed that the 2,728 patients with low-grade follicular lymphoma included were initially managed after diagnosis by: 3.2% with chemotherapy alone; 5.8% radiotherapy; 6.1% on a clinical trial; 13.9% with rituximab monotherapy; 17.1% with observation; and 51.9% with chemotherapy with rituximab anti-CD 20 antibody added onto it.
Among the 17.4% (474 patients) with Stage I disease at diagnosis, 28.7% (136) were observed.
“These data doesn't necessarily mean the choices are correct,” Dr. Maloney said, “so the question is: Is there any data that would support doing any one thing over anything else in this disease?”
He said he would consider rituximab followed by rituximab maintenance in asymptomatic patients, although one could also make a strong argument to give rituximab-chemo, he said.
Single-agent rituximab with or without maintenance or retreatment can be a choice for patients who are minimally symptomatic, elderly, or for whom chemotherapy is not indicated.
Four main studies have shown a response in about 75% of patients receiving single-agent rituximab as initial therapy, Dr. Maloney said, with complete response rates ranging from about 25%. And event-free survival is generally around 36 months, depending on whether maintenance is given.
Dr. Maloney said the single-agent approach can work for two to three years, if it is given on either an extended schedule of four extra doses such as in the Swiss SAKK trial led Dr. Michele Gielmini (Blood, 2004), or four doses every six months for two years as in the Minnie Pearl Cancer Center study by Dr. John Hainsworth (JCO, 2002).
This is a reasonable approach, he said, but he questioned whether it is really warranted when a much higher response rate and longer duration can be achieved with rituximab plus chemotherapy.
“There have been multiple studies comparing rituximab plus chemotherapy to chemotherapy alone, and every single one shows an advantage to rituximab with chemotherapy, regardless of what the chemotherapy is,” he said, with response rates usually in the 90% range and time-to-progression ranging from about two to about five years.
The most common approach for aggressive presentations of the disease is rituximab with chemotherapy—CHOP, CVP, or bendamustine—followed by maintenance rituximab, he said.
“I don't think it's R-CVP, because the patients are just going to relapse very quickly. I'm sure that this will provoke a lot of discussion, but that this is my choice, based on the PRIMA study.”
Finally, he said, there is rituximab with chemotherapy or chemotherapy alone followed by either consolidative radioimmunotherapy or maintenance rituximab.
For the future, he said, “We're all hoping that the next anti-CD20 antibodies will all beat rituximab. Unfortunately, we've been waiting a while, and I haven't seen one yet that has beaten rituximab.”
Dr. Maloney reminded the audience that patients with follicular lymphoma can have many different outcomes. With a high score on FLIPI (Follicular Lymphoma International Prognostic Index), the 10-year survival rate is only 35%, and five-year survival is about 50%.
“That's clearly not an indolent disease,” he said.
On the other hand, a low FLIPI score predicts a 10-year survival rate of 70%, and a five-year survival of more than 90%, indicating an indolent disease.
“This does need to be taken into consideration when you think about what to do for your patients,” he said.