Monoclonal antibody therapies and personalized therapeutic vaccines are now offering the promise of improved progression-free survival (PFS) and overall survival (OS) rates in patients with follicular lymphoma. In the past, radiation therapy alone was the standard of care for this disease.
Now, however, PFS and OS rates are on the rise due to the use of radiation, chemotherapy, and the anti-CD20 monoclonal antibodies rituximab (Rituxan®) and ibritumomab tiuxetan (Zevalin®). In addition, a new class of cancer vaccines is offering the hope of establishing immune dominance over malignant lymphoma B-cells following treatment with standard regimens, which include these agents.
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The American Cancer Society (ACS) estimates that in 2013, approximately 69,740 new cases of non-Hodgkin lymphoma (NHL) will be diagnosed; one of five cases of NHL in the United States is follicular lymphoma. The ACS reports that 60 years is the average age for a diagnosis of follicular lymphoma; over time, about one in three follicular lymphoma cases turns into a fast-growing diffuse B-cell lymphoma.1
Efficacy of Monoclonal Antibodies in Follicular Lymphoma
Researchers at the University of Nebraska have just completed a study that shows OS for patients with low-grade follicular lymphoma is significantly improved when rituximab is used as initial therapy or as salvage therapy compared with no rituximab; this result was independent of the Follicular Lymphoma International Prognostic Index (FLIPI) score.2 The study included 226 patients divided into three groups: those who did not receive rituximab (Group I), those who received rituximab as salvage treatment (Group II), and those who received rituximab as initial therapy (Group III). PFS and OS rates for these patients are shown in Table 1.
Table 1. Five- and 10-year PFS and OS Rates with Rituximab for Follicular Lymphoma2
|5-year Survival Rates|| 10-year Survival Rates
|Group I (n = 35)||53%||71%||38%||49%|
|Group II (n = 84)||65%||90%||43%||68%|
|Group III (n = 110)||80%||90%||47%||82%|
|Abbreviations: PFS, progression-free survival; OS, overall survival.|
“It is very good news. There have been many studies that have shown a positive response for follicular lymphoma with rituximab, but our study was different because we showed the response lasted a long time,” said lead study investigator Jairam Krishnamurthy, MD, a hematology/oncology fellow at the University of Nebraska Medical Center, Omaha, NB. “The maximum benefit appears to be when it is given up front. When patients are (treatment) naïve, the maximum effect of the antibody works best compared to any other agent.”
Dr. Krishnamurthy added that the PFS advantage with rituximab wore off in Groups II and III beyond 10 years of follow-up. Due to this response, he theorizes that patients may become rituximab refractory when they relapse, and these patients may be difficult to salvage. Rituximab is sometimes used as maintenance therapy; however, it has not been clearly established that maintenance therapy with this agent improves OS.
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“Maintenance therapy is controversial. I think it is up to the individual patient and the opinion of the oncologist they are seeing. It does put you at increased risk for infections, but that is true for most chemotherapy drugs,” Dr. Krishnamurthy said in an interview with ChemotherapyAdvisor.com. “There is a theoretical risk for infections but that is not the sole reason for not doing 2-year maintenance therapy. The reason is because studies have not shown there is an advantage in terms of overall survival.”
Follicular lymphoma expert Daniel Lebovic, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, MI, indicated some patients who experience a partial response to rituximab therapy may eventually completely respond during maintenance therapy. “Each patient has to be looked at individually. In a high tumor burden setting, it is a good idea, but in patients with low burden there is no evidence that they should be on maintenance,” Dr. Lebovic told ChemotherapyAdvisor.com.
Another promising therapy has been recently investigated by French researchers, who published a study showing that yttrium-90-ibritumomab tiuxetan may be highly beneficial in patients with advanced follicular lymphoma.3 The study included 409 patients (202 controls and 207 ibritumomab-treated patients) and it showed that this approach provided a 3-year median PFS benefit in patients who had achieved partial response or complete response/unconfirmed response to first-line induction therapy with the agent. It also showed this treatment regimen may provide a durable 19% PFS advantage at 8 years and improves median time to next treatment by 5.1 years in patients with advanced follicular lymphoma.
Dr. Lebovic said we are now in a new era of optimism because of new treatment modalities that show considerable promise. According to Dr. Lebovic, studies are underway looking at lenalidomide (Revlimid®) as well as personalized vaccines that specifically target the destruction of lymphoma cells while sparing healthy cells.
Therapeutic Vaccine May Help Improve Disease-free Survival
Currently, a vaccine called BiovaxID is under evaluation for follicular lymphoma and may soon be headed for approval. Initial results have shown that this vaccine may be able to extend disease-free survival by approximately 14 months, according to Larry Kwak, MD, PHD, Chair of the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, Houston, TX. This vaccine approach, according to Dr. Kwak, is a nontoxic consolidation treatment.
“We have lots of great drugs that will put patients into remission. The problem is they all come out of remission at some point. So we need a maintenance treatment that will keep patients in remission,” said Dr. Kwak.
Safety is a critical issue when it comes to maintenance therapy, Dr. Kwak noted, but the investigational vaccine so far appears to be highly safe. The BiovaxID is a personalized, therapeutic vaccine capable of selectively targeting only cancerous B-cells, while sparing healthy cells. This approach involves using the idiotype obtained from a biopsy sample of the patient’s tumor. Unique proteins from each patient’s tumor are isolated and combined with a delivery agent and a growth factor, at which point the mixture is then injected back into the patient. Early studies have shown this approach induces antitumor immune responses with few side effects.
“It may get approved in Europe or Canada before the United States because the regulatory process is further along there,” Dr. Kwak told ChemotherapyAdvisor.com.
Dr. Lebovic indicated the latest data on this vaccine product as well as others that are in development appear to be very promising. New treatment options for patients with follicular lymphoma will probably be significantly different within the next 24 months. “The vaccine work is ongoing research. I think it is interesting, but way too early to know how effective this approach will be,” said Dr. Lebovic. However, he added that over the next 24 to 36 months he expects several new treatment options will become widely available that will help further improve PFS and OS in patients with follicular lymphoma.
1. American Cancer Society. Non-Hodgkin Lymphoma Overview. http://www.cancer.org/cancer/non-hodgkinlymphoma/overviewguide/non-hodgkin-lymphoma-overview-key-statistics. Last accessed September 18, 2013.
2. Krishnamurthy J, Loberiza FR, Bast M, et al. Impact of rituximab on the course of low-grade follicular lymphoma. J Clin Oncol 31, 2013 (suppl; abstr 8572)
3. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol. 2013; 31(16):1977-83.