NEW YORK—After reviewing data from dozens of clinical trials on scores of slides, two speakers debating the merits of rituximab maintenance therapy in follicular lymphoma agreed that it is a matter of philosophy.
“It's a question of whether you believe progression-free survival is a meaningful benefit in the absence of overall survival—and that's a value judgment,” said Richard I. Fisher, MD, President and CEO of Fox Chase Cancer Center, who argued in favor of rituximab maintenance.
Referring to the debater arguing against maintenance, Andrew D. Zelenetz, MD, Vice Chair for Medical Informatics and Attending Physician in the Lymphoma Service of Memorial Sloan Kettering Cancer Center, Fisher said, “He's a little less for that, and I'm a little more.”
The debate, really a review of the state of the art, was presented here at the National Comprehensive Cancer Network's 9th Annual Congress on Hematologic Malignancies.
Rituximab Era Begins
Fisher began by recalling the triumph of the monoclonal antibody's first clinical trials, in which the four-year overall survival estimate when combined with CHOP chemotherapy was 91 percent.
“Rituximab broke all the paradigms, and ‘R-chemo’ is the standard of care, depending on the chemo you use.”
The first trial of rituximab maintenance he cited was the SAKK trial, in which patients underwent rituximab therapy and then were randomly assigned to rituximab maintenance or to observation (Ghielmini et al: Blood 2004; 103:4416-4423).
Fisher said the outcome was clear, progression-free survival showing a significant benefit from rituximab maintenance and prolonging the time patients remained in remission: “They did not need other additional therapies, other than rituximab.”
Five years later, the safety of rituximab maintenance beyond two years was shown to be feasible in the long-term safety analysis of that trial, which also showed a trend toward increased overall survival: Taverna et al: ASCO 2009;27:Abstract 8534.
The PRIMA study was next on the list, where responders to rituximab-chemotherapy were randomly assigned to rituximab maintenance for two years or observation (Salles et al: Lancet 2011;377:42-51).
Again, progression-free survival was significantly improved with two years of rituximab maintenance therapy after immunochemotherapy—“These were clearly patients who required therapy, and you almost didn't need a statistician to see the significant benefit,” Fisher said. Progression-free survival at 24 months was 82 percent for rituximab maintenance and 66 percent for observation, a hazard ratio of 0.50.
Time to next anti-lymphoma treatment was longer with rituximab maintenance, a hazard ratio of 0.61, as was time to next chemotherapy treatment, with a hazard ratio of 0.60.
No Survival Benefit Yet... But Safe
But to date there is no benefit in overall survival with rituximab maintenance, Fisher said. “If you affect survival, as you do with R-chemo, the debate is over. But if you don't affect survival, then you argue about what it means to remain in remission longer, what does it mean not to be treated with chemotherapy, etc.”
The rituximab maintenance regimen is safe, he said: “Amazingly enough, you can take out the B-cell repertoire for two years and do very well with minimal infection. But don't take it out forever. If you take it out for five years you begin to see problems—mostly sinopulmonary infections.
“And not much happens to immunoglobulins, because you're not taking out the plasma cells, you're taking out the middle of the repertoire, so over time the neo-antigen response will be impaired by rituximab, but still the responses are pretty good.”
And the laboratory values of neutrophils, platelets, and lymphocytes—also very similar between maintenance and observation—in no case affect the life of the patient, he said.
Quality of life, on the other hand, is a very difficult subject to debate: “Who knows what the appropriate measure of quality of life is for a patient? For one patient, the dread of recurrence overwhelms anything, while another might not want to see a doctor again if they don't need to. How you balance those is, of course, complicated.”
He noted that rituximab maintenance therapy versus re-treatment at progression for indolent disease has been studied, and cited the ECOG 4402 RESORT trial (Kahl et al: Blood 2011, Abstract LB-6). Patients with low tumor burden, stage III/IV indolent non-Hodgkin lymphoma were treated initially with rituximab and then randomly selected after response to rituximab maintenance or rituximab re-treatment at progression.
In the primary endpoint, time to rituximab failure, there was no significant difference, although there was a difference in favor of maintenance in the secondary endpoint of time to first cytotoxic therapy.
“There was not a lot of difference between maintenance and re-treatment in this trial. There is a longer time to give chemotherapy but it's not a major difference,” Fisher said.
There are risks associated with prolonged B-cell suppression, including hypogammaglobulinemia, delayed neutropenia, viral reactivation, and increased infections associated with rituximab, he noted. “But there is no doubt that there is benefit in maintenance, for consistently longer time in remission. And the economic costs are coming down with the new analogs of rituximab.”
Fisher concluded by pointing again to the philosophical nature of the question. For patients treated initially with rituximab, the argument really is about what is the meaningful endpoint and what should be valued, he said.
“That is a discussion that requires a lymphoma expert speaking to a very educated patient. This is one of the hardest things you can do.”
Standard of Care?
Taking the lectern next, Andrew Zelenetz used his prerogative as chair of the meeting to change the title of the debate somewhat, addressing the question: “Should maintenance rituximab be the standard of care for follicular lymphoma?”
“No!” was his answer, although he softened that by adding, “That doesn't mean it shouldn't be used, but it should not be the standard of care.”
He echoed Fisher, saying that the decision about maintenance rituximab represents the second longest conversation he has with a newly diagnosed patient with follicular lymphoma. (The longest single consult is on the goals of treatment, he said.)
“Follicular lymphoma is a disease of paradoxes—incurable but with a long natural history; highly responsive to therapy but relapse is inevitable; and the current potentially curative therapy—allogeneic stem cell transplant—is associated with a high risk of treatment-related mortality,” he said.
The main question is whether improvement in progression-free survival is the key endpoint in follicular lymphoma. “When we were discussing this in the NCCN Non-Hodgkin's Lymphoma Panel, the majority of panel members were most influenced that improvement in overall survival [is the key endpoint], and I think Dr. Fisher would agree.”
But it is also quite obvious that overall survival is a very difficult endpoint in follicular lymphoma trials, Zelenetz said.
“When overall survival is improved, the treatment becomes the standard of care. But improvement in overall survival improvement is very unlikely in the absence of improvement in progression-free survival. And unfortunately, progression-free survival doesn't necessarily predict for superior overall survival.”
What everyone would like to see is a good relationship between overall survival and progression-free survival, so as progression-free survival improves, overall survival would also.
“That's what we see in progressive lymphoma,” he said.
“What we see in follicular lymphoma is a ‘gentle trend’ to improvement in overall survival along with improvement in progression-free survival, but you can have major changes in progression-free survival with minimal to no impact in overall survival in indolent lymphoma.”
Zelenetz took his turn reviewing the ECOG 4402 RESORT trial of rituximab maintenance versus rituximab re-treatment at progression. He said that all things considered—both strategies appeared to delay time to chemotherapy compared with historical controls; outcomes were excellent with re-treatment (86 percent chemotherapy free at three years); the lack of quality-of-life difference; fewer rituximab doses required with a re-treatment strategy—rituximab re-treatment is the recommended strategy if opting for rituximab monotherapy in low-tumor-burden follicular lymphoma.
Options for Consolidation
But the RESORT trial patients with low tumor burden, stage III/IV indolent disease were not the same as the typical patient who needs rituximab-chemotherapy to start with, he noted.
There are three options for consolidation for the patient who will start with rituximab plus chemotherapy, he said: observation, rituximab maintenance, and radioimmunotherapy.
None of the three appear to offer a survival benefit. Observation has shorter progression-free survival, but it does allow the option of re-treatment with rituximab and a diminished risk of late toxicity, especially hypogammaglobulinemia.
Rituximab maintenance offers superior progression-free survival versus observation but may result in resistance to rituximab, Zelenetz said.
Radioimmunotherapy is brief and there is limited resistance to anti-CD20 therapy, but there is a potential for late toxicity—although that appears to be low after initial therapy. “But with radioimmunotherapy there was not even a hint of a difference in overall survival [over observation].”
He skimmed over the PRIMA trial data, Fisher having discussed it at length, and went to the six-year follow-up results—improved progression-free survival and time to next treatment with rituximab maintenance versus observation, but with virtually no difference at all in overall survival. “You can get a durable benefit with maintenance rituximab, but it does not translate to an overall survival advantage, and the absence of an overall survival advantage, to me, means that it is a discussion, not a requirement.”
Living with Active Follicular Lymphoma
In the absence of symptoms, living with the disease is pretty much like being in remission, Zelenetz said. “This is not like CML where you worry about accelerated phase, and not like multiple myeloma, where you worry about skeletal events. These patients have very few symptoms when they don't need treatment. The major factor in overall survival is the risk of transformation to diffuse large B-cell lymphoma.”
Zelenetz said from the patient's perspective, the patient who focuses on progression-free survival says, “I can't live knowing I have any active lymphoma.” This accounts for about 30 percent of his practice, Zelenetz said. The other 70 percent of patients are focused on overall survival, and say, “I feel fine, you'll treat me when I need it.”
As Fisher said, it is a matter of philosophy.
After the debate, while taking questions, Fisher said the two experts agreed on most points, but he challenged Zelenetz's concept that rituximab maintenance results in more resistance later on: “It's hypothetical, and I know of no data that supports that,” he said.
Zelenetz replied that he did not say rituximab induces chemoresistance, but that he believes that the more exposure to rituximab, the more likely the cancer will select clones, and when those clones grow out they will not respond as well to rituximab.
A matter, perhaps, for another debate.