An Interview with Dr. Gilles Salles on Follicular Lymphoma
At the CCOLD 2011 meeting, New Evidence spoke with Dr. Gilles Salles, Professor of Hematology at the Centre Hospitalier Lyon-Sud in Lyon, France, about his presentation on recent advances in follicular lymphoma.
New Evidence: What are the greatest milestones in follicular lymphoma that have been achieved in recent years?
Dr. Salles: In the year 2010, some important results were presented in the area of follicular lymphoma (FL). A number of studies examined the role of maintenance treatment, including the Swiss Group for Clinical Cancer Research (SAKK) study, which presented updated data showing the long-term favourable effect of prolonged rituximab treatment on event-free survival (EFS).1 A second key study, the RWW study by Ardeshna, et al., compared rituximab induction and maintenance versus a watch and wait strategy in asymptomatic patients.2 Finally, our group presented final results of the PRIMA study, which examined the benefit of two years of rituximab maintenance following induction treatment.3 The development of newer molecular antibodies, such as GA101, and small molecules, such as CAL101 and Bruton tyrosine kinase (BTK) inhibitors, have also shown promising results.
New Evidence: Has your practice changed based on the results of these studies?
Dr. Salles: Changes to the practice of treating patients with FL are mostly based on the results of the PRIMA study.3 Given the strength of the PRIMA results, most centres in Europe now use first-line rituximab maintenance, as recommended by European agencies and health authorities.
New Evidence: In asymptomatic patients, what is the previous justification for the watch and wait strategy?
Dr. Salles: Asymptomatic patients with FL experience a quiet life without symptoms related to their disease. According to previous studies, around 20% of these patients can remain treatment free for a period of up to ten years. A number of randomized studies have shown that there is no benefit to giving alkylating agents alone versus observation until patients become symptomatic. For this reason, observation alone became the standard of care in asymptomatic patients with FL.
New Evidence: Please describe the strength of the results from the rituximab watch and wait study.
Dr. Salles: The RWW study randomized patients between a watch and wait arm, a rituximab induction only arm, and a rituximab induction plus maintenance arm. The eligibility criteria were well described and included patients with low tumour burden. The results showed a delay in time to treatment with chemotherapy, prolongation of progression-free survival (PFS), and very high response rates (RRs) after treatment with rituximab. It would have been interesting to know whether the rituximab induction arm responded as well as the extended treatment arm; however, the investigators prematurely closed this arm of the study. RWW was, however, a good study and does provide very important results. The study provides evidence of a prolongation of the treatmentfree interval, improved disease control, and high remission rates with early rituximab treatment.
New Evidence: Are you concerned about resistance to rituximab if given to asymptomatic patients?
Dr. Salles: Based on all the data that have been collected in this area, it is very likely that the use of rituximab will change the natural history of FL. However, the RWW study does raise two important questions. First, there is some concern that early use of rituximab will result in resistance. However, relapsed patients may respond to rituximab when it is added to chemotherapy (R-chemo) or used with a different treatment schedule. Second, delaying treatment may not be beneficial for all patients. In our experience and in previous trials in asymptomatic patients, we have found that within a period of one to two years, a group of about 20%–30% of patients develop disease justifying the use of chemotherapy plus rituximab.4 Delaying treatment in these patients may not be necessary, since we know R-chemo does provide an overall survival (OS) benefit. Thus, although the RWW study is very important, we need further data to determine how these results should influence clinical practice.
New Evidence: How might results of the rituximab watch and wait study impact clinical practice?
Dr. Salles: Although the RWW study does demonstrate that using rituximab confers a disease control benefit, it is not clear whether we should adopt this strategy in all asymptomatic patients with FL. Two other studies that address the use of rituximab maintenance in patients with FL may give us further insight into this issue. The SAKK study has shown improved event-free survival (EFS) with prolonged rituximab treatment and is now assessing long-term maintenance (5 years).1 The rituximab extended treatment versus re-treatment (RESORT ) study is examining the time until rituximab resistance as well as the duration of the effect of second-line treatment.5
I do continue to observe patients with low tumour burden for three to six months and then decide whether to treat these patients or not. In patients who are happy to wait for treatment, I tend to observe until they require immunochemotherapy, because no current evidence suggests that early treatment will extend survival. In other patients I do give rituximab, followed by maintenance using the extended protocol described in the SAKK study.
New Evidence: Based on the results of the rituximab watch and wait study, would you use rituximab induction only or induction plus maintenance?
Dr. Salles: In asymptomatic patients, induction treatment is needed to reduce tumour burden. I also think it is important to give extended treatment in addition to induction, although the optimal maintenance scheme is unclear. In the PRIMA study, we gave one infusion of rituximab every two months for two years, but PRIMA was in a very different group of patients. I would tend to use one infusion every two months for a total of four infusions, as was used in the SAKK study. The optimal treatment schedule may change when long-term results from the RWW study and results from the RESORT study become available.
New Evidence: Were there any demographic differences between the R-CHOP and R-CVP groups in the PRIMA study? Which treatment regimen do you use in follicular lymphoma?
Dr. Salles: The choice of induction treatment in the PRIMA study was left to the discretion of the investigator. The majority of study centres used R-CHOP, but around 25% of the centres used R-CVP. We found no differences in demographic variables between the induction groups, with the exception of a 1.5 year difference in median age between the R-CHOP and R-CVP groups. It is therefore unlikely that demographic differences between the induction groups would have influenced the results. In our practice, when a patient requires cytotoxic treatment, I tend to use R-CHOP.
New Evidence: Were there higher rates of adverse events with R-CHOP versus R-CVP in the PRIMA study?
Dr. Salles: The incidence of adverse events (AEs) was not dramatically different between the R-CHOP and R-CVP groups, except for a higher incidence of hematological toxicity with R-CHOP. However, R-CHOP is well tolerated by FL patients, and few patients present with febrile neutropenia, as compared to other disease states, such as diffuse large B-cell lymphoma.
New Evidence: How openly do you discuss the potential risk of progressive multifocal leukoencephalopathy with your patients given rituximab?
Dr. Salles: There have been a few cases of progressive multifocal leukoencephalopathy (PML) with the use of rituximab. However, I do not talk about PML with patients prior to giving rituximab, since the main risk for these patients is dying from their disease and the risk of PML is very low. I may discuss the risk of PML with patients who have non-malignant disease or with those being given rituximab as re-treatment. The data on PML are very limited, and there are other treatments that may increase the risk of developing this condition, such as purine analogues and transplant. Given the large numbers of patients treated with rituximab, the risk of PML appears to be very low.
New Evidence: With more cycles of rituximab, do you find higher rates of bowel perforation or secondary malignancies?
Dr. Salles: The PRIMA study was a randomized trial, so we are able to use it to look at the risk of AEs with prolonged exposure to rituximab. Thus far, we have not seen any increased risk of secondary malignancies between the observation and maintenance arms of the study. In addition, we did not observe any bowel perforation during treatment with rituximab maintenance. In a long-term survey of our patients, we observed two cases of PML. These patients had relapsed, with one receiving autologous transplant and both receiving some experimental treatments. One of these patients was in the observation arm and one was in the rituximab maintenance arm. Therefore, it is not possible to say that the risk of these secondary effects increases in patients given prolonged treatment with rituximab.
New Evidence: In which patients do you re-treat with rituximab after relapse?
Dr. Salles: In patients who relapse, I use R-chemo in younger patients prior to autologous stem cell transplant (SCT). Even when a patient relapses early or during maintenance, I tend to give R-chemo to patients where I plan to intensify treatment. For elderly patients or those not eligible for transplant, I tend to give chemotherapy alone for early relapse and to administer rituximab again (alone or in combination with chemotherapy, depending on patient and disease features) when progression occurs more than one year after the last rituximab infusion.
New Evidence: If patients do not respond well to prior rituximab, are there any cases where you would re-treat with rituximab?
Dr. Salles: If patients do not respond well to rituximab alone, no real evidence indicates that they will respond well to R-chemo. However, since we know that rituximab plus chemotherapy is better than chemotherapy alone, there may be a synergy between these agents. I would therefore still add rituximab to chemotherapy in patients who were initially given rituximab alone. However, if a patient fails R-chemo, it is not necessarily beneficial to give rituximab again.
New Evidence: Do you think the PRIMA trial will show an overall survival benefit with further follow up?
Dr. Salles: We do hope to see an OS benefit in the PRIMA study, and some indices suggest this may occur. First, a meta-analysis of studies performed in relapsed patients demonstrated that there is a significant OS benefit of rituximab maintenance.6 Second, the very high response rates shown with rituximab maintenance in the PRIMA study may translate into an OS benefit after greater follow-up.
New Evidence: Do you think we should use R-maintenance every two or three months?
Dr. Salles: Regarding the use of rituximab maintenance, we need to adopt schemes that have been validated in clinical studies. In first-line treatment, the PRIMA study tested the infusion of rituximab every two months. On the other hand, evidence for relapsing patients came from the European Organization for Research and Treatment of Cancer (EORTC) study that used rituximab every three months.7 I therefore use rituximab maintenance every two months for first-line treatment and every three months in relapsing patients.
New Evidence: In the PRIMA study, it appears that the R-CVP induction group fared worse than the R-CHOP subgroup after rituximab maintenance. Please discuss this result.
Dr. Salles: We do need to be careful in interpreting this data from the PRIMA study, since PRIMA is not a randomized study comparing R-CHOP and R-CVP. Overall the benefit of maintenance appears to be highly significant in the R-CHOP subgroup and borderline significant in the R-CVP subgroup. We were surprised to see that the benefit of R-maintenance was slightly better in patients given R-CHOP than in those given R-CVP. This finding indicates that maintenance is not just completing a treatment but may also be controlling the disease to prevent relapse. We need to look further at this data with longer follow-up to determine whether the difference in PFS between these induction groups does eventually result in a survival advantage.
New Evidence: In the PRIMA study, did you look at the positron emission tomography (PET) scan results by induction subgroup?
Dr. Salles: We had the opportunity to look at more than 120 PET scans performed at the end of induction treatment. Around 26% of these patients had positive PET scans, as measured using a visual scale. The proportion of positive PET scans was somewhat higher in patients receiving R-CVP than in those receiving R-CHOP. We observed that a positive PET scan was highly predictive of an increased risk of disease progression in patients receiving either R-CVP or R-CHOP. Therefore, while the type of induction treatment is important, achieving an optimal response that results in a negative PET scan is more critical.
New Evidence: Do you use a second round of rituximab maintenance? When do you stop using rituximab maintenance?
Dr. Salles: When a patient shows a benefit of first-line maintenance with rituximab, I may use it again a second time. I would define a benefit as a prolongation in the time without disease that is expected by the trial. If a patient benefits from at least one year of disease-free interval following maintenance, I am more likely to offer this treatment again. Also, in light of the results of PET scans, I may consider giving a more intensive treatment if a patient relapses early to bring them into a true complete response and then give maintenance.
New Evidence: For relapsed patients, was CD20 expression different between the observation and rituximab groups?
Dr. Salles: Unfortunately, we do not have data on CD20 expression at the time of relapse, but we are collecting this data and hope to discuss these results in the future.
New Evidence: Do you use rituximab maintenance in other indolent lymphomas?
Dr. Salles: I do think rituximab maintenance has a role to play in mantle cell lymphoma (MCL), as MCL has some features that resemble indolent disease. Some data indicate that rituximab maintenance may be of benefit for these patients. For other patients with indolent malignancies, I tend to give induction treatment that includes four infusions of rituximab and then extend treatment by giving an additional four infusions of rituximab, similar to maintenance treatment. I do not tend to use rituximab maintenance in marginal cell or MALT lymphoma, as there is no evidence for its benefit in these diseases.
New Evidence: What are the most exciting new treatments being examined in follicular lymphoma?
Dr. Salles: Some small molecules have been developed, many of which are generating a great deal of interest. Given the favourable results seen with anti-CD20 antibodies in the last decade, any treatment that will optimize the use of anti-CD20 antibodies is interesting. Several antibodies have been engineered to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. One of these new agents is GA101, which is a type II glyco-engineered anti-CD20 antibody.
New Evidence: What is the potential role of rituximab plus bendamustine in patients with follicular lymphoma?
Dr. Salles: Bendamustine is a treatment that was developed many years ago in Germany and is now being marketed in several countries. It is an interesting drug with important activity that is superior to purine analogues alone. Currently, evidence from one study indicates that rituximab plus bendamustine (R-bendamustine) achieves improved PFS compared to R-CHOP. We need to examine this study in further detail, since the PFS curve for R-CHOP is lower than we would have expected in FL patients. We know that thus far no OS difference has been observed between the two study arms. So we need to examine the data after longer follow-up before arriving at strong conclusions about the efficacy and safety of this compound.
New Evidence: Are there any patients where you currently give rituximab plus bendamustine?
Dr. Salles: In France we are able to use bendamustine in relapsing patients; we do therefore use R-bendamustine in some patients who are not undergoing transplant and have failed first-line treatment. We are currently performing a study in elderly patients with intermediate-to-high follicular lymphoma international prognostic index (FLIPI) scores, in which we are giving two courses of R-bendamustine followed by R-maintenance (BRIEF study). If R-bendamustine were currently available as firstline treatment, it would be my treatment of choice in elderly patients where I do not want to give anthracyclines.
References: 1. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010;28:4480–4484. 2. Ardeshna KM, Qian W, Smith P, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a): a preliminary analysis. Blood (ASH Annual Meeting Abstracts) 2010;116:6. 3. Salles GA, Catalano J, Feugier P, et al. Updated results of the PRIMA study confirms the benefit of 2-years rituximab maintenance in follicular lymphoma patients responding to immunochemotherapy. Blood (ASH Annual Meeting Abstracts) 2010;116:1788. 4. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003;362:516–522. 5. Kahl BS, Williams ME, Hong F, et al. Preliminary pharmacokinetic (PK) analysis of Eastern Cooperative Oncology Group protocol E4402: Rituximab Extended Schedule or Re-Treatment Trial (RESORT). Blood (ASH Annual Meeting Abstracts) 2007;110:3420. 6. Vidal L, Gafter-Gvili A, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2009;101:248–255. 7. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858.