Most patients with follicular lymphoma present with asymptomatic, advanced-stage disease, and the accepted and long-honored practice has been “watchful waiting” because standard chemotherapy with single or multiple agents did not change the relapsing nature of the disease or overall survival. Now, however, with the availability of rituximab, that is being revisited. Myron Czuczman, David Maloney, and John Leonard weigh in on their current approaches.
NEW YORK CITY—A watch-and-wait approach is not passé in the treatment of patients with asymptomatic follicular lymphoma, says one lymphoma expert, making his case in a presentation here at the Lymphoma & Myeloma 2011 meeting. Others, though, contend that immediate treatment with rituximab is now best.
In his talk, Myron Czuczman, MD, Chief of the Lymphoma/Myeloma Service at Roswell Park Cancer Institute, explained that the majority of follicular lymphoma (FL) patients present with asymptomatic, advanced-stage disease and that the accepted and long-honored practice has been “watchful waiting” because standard chemotherapy with single or multiple agents did not change the relapsing nature or the overall survival of the disease.
“We delayed initiation of toxic therapy until needed,” he said. “This has recently been revisited, though, in the rituximab era.”
Dr. Czuczman presented what he called accepted facts in 2011 about advanced-stage FL: “FL is incurable and is often seen in older patients with comorbid conditions. Initiation of therapy soon after diagnosis in asymptomatic FL patients does not change outcome.
“Therapy begins with sequentially intensive therapy once intervention is necessary — that is, we want to save more aggressive therapy. Palliation of symptoms is acceptable. Transformation is independent of the type or timing of therapy.”
He said that although the median overall survival for FL patients is improving in the rituximab era, a review of databases shows that a small portion of FL patients, possibly 10 to 20 percent, may live 10 or more years without requiring therapy: “We need to be able to accurately identify these patients at the time of diagnosis.”
Two Historically Important Trials
Dr. Czuczman provided a critical re-review of two historically important clinical trials from the pre-rituximab era that contributed to the current therapeutic approach of advanced-stage FL:
- The US NCI Watchful Waiting versus Upfront Aggressive Combined Modality Treatment trial included 104 advanced, indolent non-Hodgkin's lymphoma (NHL) patients randomized between “watchful waiting” (44 patients) and then aggressive therapy versus aggressive upfront prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine (ProMACE-MOPP), and then total nodal irradiation (45 patients). The initial results revealed an overall survival rate at five years of more than 75% in both arms and a four-year disease-free survival rate of 51% in the “watchful waiting” arm and 12% in the treatment arm. “Mature data of 13-year median follow-up shows 75% of patients in both arms are still alive,” he said.
- The BNLI study of immediate versus delayed chlorambucil enrolled 309 asymptomatic advanced-stage indolent NHL patients, including 204 patients with FL, who were randomized to immediate chlorambucil until complete response (CR) or delayed chlorambucil until clinical progression. After a median of 16 years, the two arms had similar overall survival rates — 5.9 years in the immediate-chlorambucil arm and 6.7 years in the delayed-chlorambucil arm.
“In the rituximab era, the duration of rituximab benefit is limited,” Dr. Czuczman said. “Within three years, the majority of patients become refractory to rituximab. New treatments are still needed in follicular NHL. It's unlikely that rituximab maintenance will be utilized with each course of therapy.”
Intergroup Randomized Trial of Rituximab vs Watch & Wait in Advanced, Asymptomatic Non-Bulky FL
Many myeloma experts who favor early treatment point to results of the intergroup randomized trial of rituximab versus a watch-and-wait approach in patients with advanced stage, asymptomatic non-bulky FL. The conclusion of that trial, presented by Kirit Ardeshna, MD, at last year's American Society of Hematology Annual Meeting (Abstract 6), was that rituximab significantly improves the time to next treatment (TTNT) and progression-free survival (PFS) compared with watchful waiting.
But, Dr. Czuczman asked, “Is this clinically meaningful? Is TTNT the best clinical endpoint, or is it subjective?” He also noted that a limitation of the study was that at the time of progression rituximab monotherapy was not an option.
In addition, he noted a handful of other considerations about this trial: “There are no data supporting an overall survival advantage. No optimal rituximab schedule has been identified. There are associated costs of treatment and time requirements. Infectious risks are small, but real. Responsiveness to second-line therapy is unknown.”
Also, he wondered whether a rituximab maintenance schedule was better than rituximab retreatment at relapse.
On the other hand, the advantages associated with watch-and-wait include:
- improved quality of life for prolonged periods of time;
- delayed toxicity associated with chemotherapy, including possible infertility/early menopause in younger patients; and decreased costs and inconvenience associated with early therapy. “Early intervention and excessive therapy can lead to increased risk for development of resistance,” he said.
In conclusion, Dr. Czuczman said, “watch-and-wait is not passé in asymptomatic FL based on historic and current data. Watch-and-wait is the standard-of-care approach for asymptomatic FL around the world.”
He added that “the potential impact from a palliative early intervention includes questions about resistance and responsiveness to subsequent therapies; about adverse events, including hypogammaglobulinemia, neutropenia, and infections; and about medical costs that cannot be justified in respect to no demonstrable improvement in overall survival.”
In the future, he said, “we need biomarkers that can reproducibly predict indolent versus aggressive FL subgroups at diagnosis, and improvements in induction regimens and/or the use of consolidative agents not utilized in the induction therapy.”
He said he believes that clinical trials have curative potential with combinations of immunochemotherapy in patients with asymptomatic follicular lymphoma.
For practicing oncologists, his treatment message was simple: “For now, watch-and-wait.”
Differing Opinions from Others
David Maloney, MD, Professor of Medicine at the University of Washington and member of the Fred Hutchinson Cancer Research Center, said that he practices watch-and-wait in most asymptomatic patients. “The issue is the survival advantage of upfront rituximab-chemotherapy combinations. All studies now demonstrate that what we do first does matter, and we should include rituximab.”
John Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College, commented: “I use watch-and-wait as much as anybody. I talk to patients to help them recognize the pros and cons.
“The patient's perspective on this disease is important, as well as noting if the disease is progressing slowly. There is value in questioning what we do and taking a hard look at the literature to decide the right thing for patients. But there is no evidence that watch-and-wait extends survival. It's hard to argue that watch-and-wait makes patients live longer. The Ardeshna trial shows about 50% of patients can go five to eight years with rituximab and need no further therapy.”
Typically, patients are put on a watch-and-wait approach for two to three years, and by the time they need treatment, I can't guarantee I'll have better treatment available,” Dr. Leonard said, noting, though, that he is optimistic that frontline therapies will improve a few years from now.
He said he also believes that early treatment with rituximab can be improved upon. A CALGB study of the anti-CD22 agent epratuzumab plus rituximab as initial therapy for 60 FL patients showed an 84% overall response rate and about a 70% probability of event-free survival at two years.
And studies of lenalidomide plus rituximab as initial therapy for indolent NHL patients also show very high response rates, he said. The concept is to use earlier combination with biologics.
“To say that FL is incurable is not a true statement,” said Dr. Leonard. “For some patients immediate treatment means they will never need any more treatment. You will not achieve that with watch-and-wait. If we do something early on it will improve survival in FL.”
He added that immediate treatment also helps reduce the anxiety patients feel about their disease during watchful waiting.
His treatment message also was simple: “Think about immediate treatment of patients.”
Dr. Czuczman countered that “FL is still incurable. With rituximab treatments the duration benefit is limited. We can't use rituximab upfront and also as second-line maintenance. That will not happen.”
He did admit that “I don't use watch-and-wait for all of my patients. If we wait until patients become symptomatic, we may have patients we treated whom we did not have to treat. For better quality patients, I wait. Poorer quality patients have less of a chance of achieving a CR or cure without treatment. And CR makes a difference, leading to longer overall survival.”