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Does chemotherapy still have a role in follicular lymphoma treatment?
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Yes.
Follicular lymphoma is an indolent disease that has a heterogeneous presentation at diagnosis. Some patients present with a very low burden of disease, whereas others have extensive disease and potential organ compromise. Management of this disease is similarly diverse, with some patients initially being observed and others treated with combination immunochemotherapy. Although there is great enthusiasm for treating newly diagnosed patients with novel targeted agents and antibody therapy, chemotherapy remains important. The decision to select a more aggressive regimen as initial therapy is generally driven by the presence of adverse prognostic factors and bulky disease. When comparing the efficacy of chemotherapy-containing regimens with novel agents, it is extremely important that the populations of patients are similar, and that risk and prognostic factors are considered.
Commonly used chemotherapy regimens for follicular lymphoma include rituximab (Rituxan; Genentech, Biogen) plus bendamustine or CHOP chemotherapy. In general, these combinations result in an overall response rate of 90%, with approximately 40% of patients achieving complete remission. Studies that utilize novel agents, such as lenalidomide (Revlimid, Celgene), in combination with rituximab have resulted in high response rates that appear similar to — and even better than — those seen with chemotherapy and rituximab. In previously untreated patients, lenalidomide plus rituximab had an ORR of 90% and a complete response rate of 63%, suggesting that this approach may be better than standard chemotherapy–based treatment. However, when assessing whether this result is better than that seen with bendamustine plus rituximab, for example, one must consider prognostic factors. In a trial by Fowler and colleagues of lenalidomide plus rituximab, only 28% of patients were in the high-risk prognostic group as defined by the Follicular Lymphoma International Prognostic Index (FLIPI). In contrast, clinical trials that used bendamustine plus rituximab also have resulted in response rates of 90%, but the complete response rate has more typically been near 40%. Although this may suggest novel agents may be more effective, approximately 50% of patients in the bendamustine-plus-rituximab trials were in the high-risk FLIPI group.
In typical clinical practice, patients with follicular lymphoma can be grouped into three distinct subsets. Some have low-burden, low-risk disease, are asymptomatic and only require observation. Others have a low burden of disease but are more symptomatic, and may be treated with monoclonal antibodies alone. A third group are those with extensive, high-burden disease. These patients typically require a more aggressive approach and commonly receive chemotherapy in combination with a monoclonal antibody. When evaluating trial results, it is important to determine how many patients from each clinical group were included. If many patients in low-risk groups were included, the results may look very good. For example, in original studies of rituximab in low-risk patients, an ORR of 80% with a complete response rate of 39% was seen with just four doses of rituximab. As one compares results with novel combinations to results with more standard chemotherapy, it will be critical to ensure that prognostic factors and patient selection bias are considered so that comparable patient groups are compared.
The randomized controlled RELEVANCE trial is comparing lenalidomide plus rituximab with chemotherapy plus rituximab. The results will allow us to directly compare comparable-risk groups and assess whether novel therapies can replace chemotherapy. Although it is possible that novel combinations may be similarly effective to chemotherapy combinations in low-risk patients, it may be less likely that novel combinations will perform as well as chemotherapy combinations in patients with high-risk, bulky disease. In patients with bulky disease and high-risk features, chemotherapy likely will be necessary and, therefore, will remain important in the management of follicular lymphoma.
References:
Colombat P, et al. Blood. 2001;97:101-106.
Flinn IW, et al. Blood. 2014;doi:10.1182/blood-2013-11-531327.
Fowler NH, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70455-3.
Rummel MJ, et al. Lancet. 2013;doi:10.1016/S0140-6736(12)61763-2.
Stephen M. Ansell, MD, PhD, is professor of medicine and chair of the lymphoma group at Mayo Clinic in Rochester, Minnesota. He also is a HemOnc Today Editorial Board member. He can be reached at ansell.stephen@mayo.edu. Disclosure: Ansell reports no relevant financial disclosures.
No.
To put the role of chemotherapy in follicular lymphoma into perspective, we need to reflect on the origins of chemotherapy itself. Trials of mustard gas derivatives in patients with lymphoma resulted in responses, albeit transient.
Today, most chemotherapy regimens for lymphoma contain at least one of these mustard gas derivatives — alkylating agents. Is this really what we want to infuse into our patients?
It is obvious that patients with lymphoma do not want chemotherapy; thus, the issue is whether they really need it.
The goal of therapy should be to provide the most effective yet least toxic drugs. Whereas chemotherapy has been the mainstay of follicular lymphoma therapy, it wasn’t until a biological agent — rituximab (Rituxan; Genentech, Biogen) — was added that survival was prolonged, regardless of the chemotherapy backbone.
One of the initial attempts to avoid chemotherapy was the study by Colombat and colleagues, in which initial treatment with four weekly doses of rituximab conferred a response in 73% of patients, including 20% complete remissions. In a subsequent randomized trial, Ghielmini and colleagues from the SAKK group randomly assigned patients to the four weekly doses alone or with four additional doses at 2-month intervals. Forty-five percent of patients were progression free at 8 years.
To improve on these results, investigators from the Cancer and Leukemia Group B — now called Alliance — developed a series of biological doublets. First, rituximab was combined with the anti-CD80 antibody galiximab (Biogen), and another combination evaluated rituximab with epratuzumab (Immunomedics). In both of these studies, response rates were about 90%, many being durable, which is comparable to what has been reported with chemoimmunotherapy regimens. However, the most impressive results were with the combination of rituximab and lenalidomide (Revlimid, Celgene), which — in an Alliance study, as well as one from The University of Texas MD Anderson Cancer Center — demonstrated durable responses in more than 90% of patients, with 70% to 80% complete responses, comparable to any published chemoimmunotherapy program and probably more tolerable. The completed but not yet reported RELEVANCE trial of rituximab and lenalidomide vs. rituximab and chemotherapy may permanently alter our approach to patients with follicular lymphoma.
Importantly, there is an ever-enlarging menu of targeted agents for follicular lymphoma, including newer anti-CD20 antibodies and constructs, such as obinutuzumab (Gazyva, Genentech); antibody–drug conjugates; bispecific T-cell engagers; drugs that target intracellular pathways, such as ibrutinib (Imbruvica; Pharmacyclics, Janssen), idelalisib (Zydelig, Gilead) and venetoclax (Venclexta; AbbVie, Genentech); and those that affect the microenvironment, including lenalidomide and checkpoint inhibitors.
It is in the best interests of our patients to abandon nonspecific, cytotoxic therapies. If lenalidomide plus rituximab does not revolutionize the paradigm, other combinations will be created.
How best to combine these agents remains a challenge, as unexpected toxicities have been encountered. Nonetheless, a goal should be to individualize therapy such that the very few patients with follicular lymphoma who might require chemoimmunotherapy can be identified, whereas the great majority can be spared yet experience an excellent outcome with the potential for cure.
References:
Cheson BD. Blood. 2016;doi:10.1182/blood-2016-04-709477.
Colombat P, et al. Blood. 2001;97:101-106.
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Fowler NH, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70455-3.
Ghielmini M, et al. Blood. 2004;doi:10.1182/blood-2003-10-3411.
Goebeler ME, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2014.59.
Gopal AK, et al. Abstract 1217. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
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Marcus RE, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Marcus RE, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2007.13.5376.
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Bruce D. Cheson, MD, FACP, FAAAS, FASCO, is professor of medicine at Georgetown University Hospital, as well as head of hematology and director of hematology research at Lombardi Comprehensive Cancer Center. He can be reached at bdc4@georgetown.edu. Disclosure: Cheson reports consultant roles with AbbVie, Acerta, Celgene, Pfizer, Pharmacyclics and Roche/Genentech; and grants to his institution from AbbVie, Acerta, Gilead Sciences, Pharmacyclics, Roche/Genentech and TG Therapeutics.