This article is more than 5 years old. Information may no longer be current.
Early rituximab therapy offers option for treating asymptomatic follicular lymphoma
Data show promise and may change future of the watchful waiting strategy, some experts said.
Click Here to Manage Email Alerts
In a cohort of patients with asymptomatic follicular lymphoma, the time to initiation of new therapy was longer in those who were treated with rituximab than in those who had simply been observed, according to findings presented at the most recent American Society of Hematology meeting.
The findings caused a ripple in the clinical and research communities.
There were 186 patients in the watchful waiting arm, 84 patients who received a 375-mg/m2 induction regimen of rituximab (Rituxan; Genentech, Biogen Idec) for 4 weeks and 192 patients who received the same rituximab induction regimen followed by maintenance every 2 months for 2 years.
The time to initiation of new therapy was significantly longer among patients receiving rituximab compared with the watchful waiting patients (P log-rank test <.001 for each rituximab arm vs. watchful waiting). Significant differences in PFS also were reported in the rituximab and observation arms (P log-rank test <.001 for each rituximab arm vs. watchful waiting arm).
|
Photo by Russell Lee |
“These data indicate that initial treatment with rituximab significantly delays the need for new therapy, and this finding may change the management of patients with newly diagnosed asymptomatic follicular lymphoma,” Kirit M. Ardeshna, MD, of the department of hematology at University College London Hospital, and colleagues wrote.
The presentation at ASH generated a flurry of questions from the floor, many of which continue to be debated.
HemOnc Today followed up to determine the effect, if any, these findings will have in the clinic and how the future of the watchful waiting strategy looks in the rituximab era.
Reaction to ASH findings
Kanti R. Rai, MD, chief of the division of hematology/oncology at Long Island Jewish Medical Center in New Hyde Park, New York, said the Ardeshna findings are important because “many clinicians treating [follicular lymphoma] ask themselves from time to time, about the validity of the watch and wait approach. This trial shows that the use of rituximab, in some manner, improves the outlook for [follicular lymphoma] patients.”
However, Rai said he had reservations about a paradigm shift in light of the results. “To me, this is by no means the last nail in the coffin for watch-and-wait,” he said.
Even Ardeshna agreed. “When deciding therapy for patients with asymptomatic [follicular lymphoma], there are always choices to be made,” he said. “This is an additional option for doctors and patients, and it may become popular with patients in whom it is important to defer chemotherapy.”
Although most researchers concluded that Ardeshna and colleagues designed and executed a fine study, there were concerns with the selection of time-to-next treatment as a primary endpoint. Ardeshna said further research will measure response and duration of response to new treatment and time to second new treatment.
“The biggest issue is that we see relapse-free survival and time to chemotherapy but not OS,” said John Sweetenham, MD, of the department of hematologic oncology and blood disorders at the Cleveland Clinic. “We need to see OS data.”
Sweetenham said the surrogate endpoint of time-to-next treatment may be a “soft decision,” and that the natural history of the disease makes the necessity of OS data critical.
|
|
“All patients with this type of [follicular lymphoma] are likely to relapse or progress,” he said. “Many patients will get multiple courses of therapy over the career of this disease, so the differences in time-to-next treatment will get washed out.”
The other concern with Ardeshna’s study, currently, is that the quality-of-life (QOL) data have not yet been presented. Ardeshna said the premise of the study was to defer chemotherapy and maintain QOL. “If QOL turns out to be no worse in the rituximab-containing arms, then initial treatment with rituximab is likely to gain traction,” he said.
Although many researchers await the presentation of the QOL results, it has been suggested that the very notion of QOL itself has proved difficult to define.
Quality of life
“Regular measurement and interpretation of QOL is an area where oncologists have failed dismally in the past,” Rai said. “The assessment of QOL is particularly lacking in [follicular lymphoma]. QOL is something that ought to be studied properly, and it is not.”
He said for any particular treatment, there are “expected” adverse events that can be significant for patients, or at least worth mentioning, but because they are expected, they may be ignored or downgraded in the research. “It is only if the side effects occur that have not been listed in the package insert that they are required to be noted and thus are considered bad for QOL,” he said.
Tumor lysis syndrome, severe infusion reactions and progressive multifocal leukoencephalopathy are highlighted on the label of rituximab. Beyond these complications, many clinicians believe that relatively minor infusion reactions and the inconvenience of treatment are outweighed by the potential benefit from the treatment, and thus, might render any resultant reduction in the QOL somewhat irrelevant.
Regarding the QOL issue in the context of symptoms, Sweetenham said some symptoms are easier to identify than others. This is factored under the QOL umbrella, but it also has clinical implications.
“Fatigue is one of the things we look for as a sign of disease progression,” he said. “But fatigue, in the clinical sense, is difficult to quantify. When does it become significantly bad that treatment is necessary? This is a QOL issue that is difficult to assess in a patient or a trial.”
Bruce D. Cheson, MD, professor of medicine and head of hematology at Georgetown University Hospital Lombardi Comprehensive Cancer Center, was more pointed in his comments. “There are long-term toxicities, infections, hospitalizations and chronic immunosuppression factors associated with rituximab,” he said. “There is also the expense, and the question of subjecting patients to unnecessary treatment.”
|
|
Scott W. Hall, MD, PhD, of the department of hematology in the Helen F. Graham Cancer Center at Christiana Care in Wilmington, Del., put the toxicity issue in historical perspective. “Let’s back up 15 years,” he said. “Treatments at that time were much more toxic, so it was a mistake to use them in the asymptomatic setting. We may be saying the same thing about rituximab 15 years from now. It may seem incomprehensible to us that we even considered giving them this treatment.”
Hall added that treatment, even with something as relatively non-toxic as rituximab, may only serve to make asymptomatic patients feel worse. “There is nothing to gain. I can’t cure their disease [with rituximab in asymptomatic patients],” he said. “However, I do understand that when someone hears that they have cancer, they want to be treated, and this is something we all have to deal with.”
Patient perspective
Rai reminded clinicians of the role patients play in the decision-making process, particularly in the gray area of asymptomatic disease. He stressed the importance of communication going both ways and urged clinicians not to dictate treatment based solely on research.
“We should not say we improved QOL because we took them off watchful waiting and put them on rituximab, and as a result, the patients felt relieved,” he said. “For every patient in this category, there is a person who is thankful for watch and wait because they feel that as soon as treatment is required, they become convinced that thereafter their days are numbered. We need to disabuse our patients of their anxieities and fears in both directions.”
Philip J. Bierman, MD, associate professor in the department of oncology/hematology at the University of Nebraska in Omaha, said there is a delicate balance between listening to the needs and wants of patients and making sound clinical decisions.
“Some patients will not accept watch and wait,” he said. “In that case, I would tell them that rituximab is relatively safe and may prolong the time to progression. I would mention that there are some side effects, but they are minimal. But I would also explain that it costs a lot and we don’t know if it makes you live longer.”
Hall agreed with this strategy and then focused on more practical scenarios. “For younger patients who insist on being treated, I would try to get them enrolled in a trial,” he said. “If we are going to expose our patients to this treatment, it would be a positive step if we could get a research benefit from it as well.”
Sweetenham picked up on the age issue. “Older patients may be more comfortable with watch and wait, but even this trend is difficult to define,” he said. “There is no magical age cutoff.”
Lauren Pinter-Brown, MD, director of the UCLA Lymphoma Program and a researcher with UCLA’s Jonsson Comprehensive Cancer Center, brought the issues of QOL and patient input back to the clinic.
|
|
“If we knew that patients had an improved quality of life on rituximab, the push to consider it as a new standard of care may be reasonable,” she said. “But, as presented, there are more questions than answers. The key one for me is how they would respond to the next treatment.”
Complications down the road
Bierman said the long-term complications associated with rituximab — including infections and low blood counts — may not be worth the benefits, adding that the question of whether rituximab use in asymptomatic follicular lymphoma jeopardizes the efficacy of the drug in subsequent treatments has not been answered.
“You increase the time until the next treatment, but is it harder to treat them when they do relapse? We don’t know that yet,” he said.
Pinter-Brown agreed. “The key question for me is how they would respond to the next treatment,” she said. “Rituximab shows great benefit when given with chemotherapy in symptomatic patients. However, we don’t know if this benefit is compromised by prior treatment when the patient is asymptomatic. The prolonged PFS it gives you in asymptomatic patients may not be worth this trade-off.”
Cheson noted findings from the Primary Rituximab and Maintenance (PRIMA) study, which was conducted to determine the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma who had been receiving rituximab plus chemotherapy.
Patients who had achieved a complete or partial response with one of three chemotherapy regimens were randomly assigned 2 years of rituximab maintenance therapy or observation.
Rituximab was associated with a PFS rate of 74.9% (95% CI, 70.9-78.9) compared with 57.6% (95% CI, 53.2-62.0) in the observation group (HR=0.55; 95% CI, 0.44-0.68). Complete or unconfirmed complete response rates 2 years after randomization were 71.5% in the rituximab group and 52.2% in the observation group (P=.0001). However, the researchers observed no statistically significant differences for OS between the two groups (HR=0.87; 95% CI, 0.51-1.47).
“These data remain controversial,” Cheson said. “There is no survival difference. The only thing we know very clearly is that patients respond to rituximab. There are still many questions to be answered.”
Future research
The researchers and clinicians interviewed provided HemOnc Today with a broad cross-section of answers when they were asked where they would like research in this area to go. Most suggested that they would like to see how the two groups in Ardeshna’s study — those who had received rituximab vs. those who had not — responded to therapy once the disease had progressed.
“The only other question is about the second treatment that you end up with after rituximab,” Pinter-Brown said. “I would like to see how each of these groups of patients — those who got rituximab and those who didn’t — respond to the next level of treatment. We don’t want to burn bridges.”
Hall agreed and said taking it to the next progression would “level the playing field and make it a fairer study.”
Cheson said he would also like to see a more detailed analysis of toxicities, both during the 2 years and after. “The study as itself is a well-designed study that addresses an important question,” he said. “There is no argument about that in my mind. But I don’t think it’s time to give up watch and wait and move on to expensive therapy, which is somewhat inconvenient and can be associated with morbidity based on these data.”
The question generally comes back to QOL and OS. Rai put the matter into practical terms. “The researchers appear to have used surrogate endpoints because the life expectancy for this disease is 10 years plus or minus,” he said. “In order to demonstrate clear improvement, we need to show that the median life expectancy is 15 years. To even begin to do that, we would need a sample size in the thousands, with half in watch and wait and half in rituximab, but it is impractical that anyone would conduct such a study.”
There is a growing school of thought that because rituximab is so effective combined with chemotherapy in symptomatic patients, it may be beneficial to start asymptomatic patients on the full combination at the outset. Although no studies have explored this yet, there is speculation that this strategy could have the desired effect on OS.
“It is not inconceivable that we may move away from single-agent rituximab,” Sweetenham said. “Of course, we are a long way from this kind of practice-changing strategy as yet, but there has been talk of CHOP and rituximab, CVP and rituximab, bendmustine and rituximab.”
Sweetenham acknowledged the potential dangers of introducing chemotherapy in asymptomatic patients, a point that was highlighted by Pinter-Brown.
“As far as chemotherapy plus rituximab goes, sometimes patients have genetic factors that make them have a complete response to rituximab alone,” she said. “In these cases, obviously the chemotherapy is unnecessary. Until we can pick these patients out, we should be careful of this approach.”
Rai was more direct in his assessment of treating asymptomatic patients with chemotherapy plus rituximab. “People who say that we might as well give chemotherapy with rituximab at the outset because of the effectiveness of that combination ought to be muzzled,” he said.
Moving forward
Sweetenham said the paradigm may change, but not necessarily with rituximab as the only solution. “If we are looking at this in terms of managing a chronic disease, we may find that other options open up,” he said. “Some second-generation monoclonal antibodies may be the solution we are looking for.”
Cheson said he is currently involved in a series of studies of follicular lymphoma in patients with low tumor-burden using doublets of biological agents using either other monoclonal antibodies or lenalidomide. “Response rates have been extremely impressive,” he said. “If you really want to make an impact, the way to go may be to use rituximab in combination with another drug which is also relatively innocuous.”
In the end, a decision has not been reached on rituximab. Bierman’s view on the drug reflected what appears to be the general trend among researchers and clinicians.
“This may be a great treatment or a standard of care in the future, but not right now,” Bierman said. “In general, I probably would not use it for asymptomatic patients for a variety of reasons, not the least of which is that patients may go years before they need any kind of therapy at all.”
Sweetenham agreed. “As far as being a paradigm changer, it seems pretty split,” he said. “Some say it has changed their strategy and many may adapt this as an upfront approach, but others are still uncertain. Let’s wait and see how it plays out.”
For more information:
- Ardeshna KM. #6. Presented at: 52nd ASH Annual Meeting; Dec. 4-7, 2010; Orlando, Fla.
- Salles G. Lancet. 2011;377:42-51.
Disclosures: Dr. Ardeshna reports receiving honoraria from and membership on an entity’s board of directors or advisory committees with Roche. Drs. Cheson, Hall and Sweetenham report no relevant financial disclosures. Dr. Pinter-Brown has received consulting and speaker’s honoraria from Genentech. Dr. Rai has served as a member of the medical advisory board for Genentech. Dr. Bierman could not be reached for disclosure.
Will rituximab replace watchful waiting as the most attractive strategy for treating asymptomatic follicular lymphoma patients?
Watchful waiting is not meant for every patient. It is used only in patients whose tumor is not associated either with symptoms or other problems such as cytopenias and is not threatening to obstruct vital organs such as the kidneys.
With the relatively recent advent of rituximab, an effective treatment for indolent non-Hodgkin’s lymphoma with little toxicity, the pendulum has been shifting from watch and wait to active therapy. The recent results from ASH have contributed to the paradigm shift for a few reasons.
|
|
The first is the striking difference in the proportion of patients not requiring initiation of new therapy when compared with watch and wait. In the rituximab induction and maintenance arm (arm C), 91% of patients did not require new therapy in contrast to 40% in watch and wait (arm A). This means that patients are psychologically better off because they do not have to face the devastating news about relapses requiring initiation of new therapy. When these patients fail on watch and wait, they usually end up on a spiral of multiple subsequent salvage therapies over their lifetimes.
The next is that rituximab is much less toxic than chemotherapy, which has contributed to its keen acceptance by both clinicians and patients.
Finally, a difference in OS might still emerge in the future with longer follow-up, although this might not actually happen early during follow-up in view of the fact that patients in the watch-and-wait arm can be treated with effective chemoimmunotherapy regimens when they progress.
The watch-and-wait strategy has been based on the paradigm of incurability of these disorders which, from my personal standpoint, is not correct. This paradigm of incurability stems from the fact that patients have either not been treated with adequate chemoimmunotherapy regimens or not followed long enough for the investigators to realize that there is indeed a plateau in the failure-free survival curve, suggesting a cure. Most of the publications that claim incurability have only followed these cases for a maximum of 5 years, while it actually takes 7 to 8 years for the plateau to start manifesting itself and even longer for it to become obvious.
Because most patients in the watch-and-wait strategy will eventually require systemic therapy, usually within the first 4 to 5 years of follow-up, it is difficult to understand the advantage of this approach, except in patients who are either very elderly or with considerable comorbid illnesses.
Fernando Cabanillas, MD, is a HemOnc Today Editorial Board member. He reports no relevant financial disclosures.
Rituximab is on the way to replacing watchful waiting as the optimal strategy for treating asymptomatic follicular lymphoma patients, but we are not all the way there yet. Full data and more mature follow-up from the Ardeshna study will be helpful. However, investigators should be planning ways to further elucidate the role of rituximab for asymptomatic patients now.
|
|
Early intervention with rituximab may not be best for all patients with asymptomatic lymphoma because it is conceivable, although quite unlikely, that early rituximab will leave patients with lymphoma that is more difficult to manage and more resistant to treatment on subsequent relapse. In addition, the arm of the Ardeshna study in which patients were given both induction and then maintenance rituximab called for exposure to rituximab for a prolonged period of time, which exposes them to increased toxicity. It is also notable that at least 20% of patients started on watchful waiting still require no treatment 5 years later. These patients, who would not otherwise have required treatment, would have been treated without benefit, at least in the first 5 years of follow-up.
Management of asymptomatic patients with follicular lymphoma should be individualized, not standardized. Factors of importance are tumor bulk, patient age, sites of lymphoma involvement, serum LDH, cosmetic acceptability of visible lymph nodes, presence of comorbid conditions, performance status and others. Watchful waiting may be appropriate, but intervention with systemic treatment, especially since we know this confers an overall survival advantage, should be started once symptomatic or threatening disease develops. Given these considerations early rituximab may be quite desirable for selected asymptomatic patients.
As clinicians, we must remember that watchful waiting requires careful observation. The patient and physician must be committed to planned monitoring of the lymphoma. If the watching is not careful and faithful, threatening progression of the lymphoma may occur, endangering the patient and reducing the likelihood of good disease control. In addition, we should be vigilant of silent progression in an important site such as the retroperitoneum, where ureteral obstruction can occur. This occurrence may not be evident until advanced.
Joseph M. Connors, MD, is a clinical professor and director, British Columbia Cancer Agency Centre for Lymphoid Cancer. Disclosure: Dr. Connors reports receiving research funding from F. Hoffman-La Roche.