Follicular lymphoma (FL) is the most common type of non-Hodgkin Lymphoma (NHL). In 2010 an estimated 65,540 people in the US were diagnosed with NHL, and follicular lymphoma accounts for between 15 to 20%t of these case. Overall, about 35% of all NHLs in the USA, and 22% worldwide, are diagnosed as FL. [2]

Follicular lymphoma, also called ‘indolent’ or ‘low-grade’ lymphoma, is a slow-growing neoplasm arising from follicle center-derived B cells, both centrocytes and centroblasts/large transformed cells, and generally has at least a partial follicular pattern. The disorder is characterized by periods of relapse and remission. Despite substantial progress, Follicular lymphoma remains incurable and patients ultimately relapse and require additional treatment.

Follicular lymphoma has been associated with the translocation of chromosomes 14 and 18, which results in constitutive activation of the BCL2 oncogene and the subsequent inhibition of apoptosis.[3] Warning signs helping the diagnosis often go unnoticed. Enlargement of lymph nodes is a common symptom. Fever, weight loss, sweating and fatigue are other symptoms of lymphoma. The disease, affecting both men and women, can occur at any time during adulthood, though people are typically diagnosed during their 50s and 60s.

Treatment of follicular lymphoma may last for 20 or more years. Radiation therapy has been considered an appropriate front-line therapy for some patients with early stage disease. Other first-line therapy choices may include observation, clinical trials, single agents, or combination therapies. In a relapsed setting, repeating some of these modalities, such as combination chemotherapy, radioimmunotherapy, and transplant are considered suitable treatment. [3]

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For the past three decades, the standard treatment for patients with asymptomatic, advanced-stage follicular lymphoma has been a watchful-waiting approach in which the use of chemotherapy is delayed until the cancer progresses, as this type of cancer is often slow growing before it becomes symptomatic. This strategy has been based on research showing that there is no overall survival benefit in treating these asymptomatic patients with chemotherapy immediately after diagnosis. A watchful-waiting approach can, on average, defer chemotherapy for 2.5 years, and this strategy is often preferred as it results in a better quality of life for patients by sparing them from the debilitating side effects of chemotherapy at a time when they are feeling well.

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A number of phase III trial results demonstrate improvements in outcome using rituximab [4] (Rituxan?, Genentech/ Biogen Idec; or MabThera?, Roche). Rituximab has significantly changed the management of follicular lymphoma. The the most dramatic impact of this agent is observed in combination with cytotoxic chemotherapy.

New research results released today during the 52nd American Society of Hematology Annual Meeting in Orlando, Florida from December 4-7, 2010 included positive data from a Phase III study of rituximab in patients with advanced asymptomatic follicular lymphoma. The study results were presented during Plenary Scientific Session on Sunday, December 5, 2010 by Kirit Ardeshna, M.D, Consultant Hematologist, University College London Hospitals in London, and lead author of the study.

Based on results from previous studies that showed no benefit of immediate chemotherapy after diagnosis, asymptomatic patients are managed by a “watchful waiting” approach and treatment for these patients usually does not begin until specific symptoms occur or their disease worsens. This study showed that immediate administration of single-agent rituximab (induction), followed by continued use of rituximab (maintenance) delayed the need for chemotherapy or radiotherapy and decreased the risk of the disease worsening (progression-free survival or PFS), compared to watchful waiting. The safety profile was consistent with previous experience with rituximab.

Rituximab is a therapeutic monoclonal antibody that binds to a specific protein called CD20 found on the surface of cancerous and normal B-cells. In NHL and rheumatoid arthritis (RA), rituximab works with the body’s own immune system to eliminate marked CD20-positive B-cells. Stem cells (B-cell progenitors, those cells that give rise to B-cells) in bone marrow do not have the CD20 protein. B-cells usually regenerate after rituximab treatment and return to normal levels in about 12 months for most patients.

Rituximab has a more favorable side effect profile than chemotherapy. Researchers wanted to determine whether treating patients with follicular lymphoma with the drug immediately after diagnosis would further delay the time until chemotherapy is needed.

“These are the first Phase III data to have shown that initial use of rituximab monotherapy as induction followed by maintenance had an impact in patients with asymptomatic follicular lymphoma, a disease that is commonly treated only after symptoms appear,” said Hal Barron, M.D., executive vice president, Product Development and chief medical officer at Genentech. “Early treatment interventions in prior studies in this population were not considered to provide meaningful clinical benefit. In this study, the use of rituximab delayed the need for additional treatment.”

Researchers funded by Cancer Research UK and sponsored by the University College London randomized a total of 462 patients with previously untreated asymptomatic Stage II-IV follicular lymphoma to one of three treatment arms. In the first arm, 186 patients underwent a watchful-waiting approach. In the second arm, 84 patients received 375 mg/m2 of rituximab once a week for four weeks. In the third arm, 192 patients received 375 mg/m2 of rituximab once a week for four weeks followed by maintenance therapy with rituximab that was given every two months for two years. The primary endpoints of the study were time to initiation of new therapy (chemotherapy or radiotherapy) and overall effect on quality of life. The study was originally designed to show an improvement of 18 months in the median time to the start of therapy in each of the rituximab arms (i.e., from 30 months to 48 months). A total of 600 patients were set to be enrolled into this study in order to identify 230 patients who required chemotherapy or radiotherapy treatment.

However, three years into the trial, a decision was made to discontinue the second arm of the study as evidence of the efficacy of rituximab as a maintenance therapy became apparent. At that point in time, the study became a two-arm comparison study, and a total of 360 patients were enrolled into the two remaining arms. It was estimated that 192 patients would be required to show the 18-month improvement in the two-arm study.

With a median follow up of 34 months, the results of this phase III study indicate that far fewer patients required a new therapy (chemotherapy or radiotherapy) in both of the rituximab-containing arms compared with the watchful-waiting arm. Immediate use of rituximab monotherapy as induction followed by maintenance when compared to watchful waiting, decreased the risk of needing additional therapy by 80% (hazard ratio of 0.20, 95% CI, 0.13-0.29, p= <0.001). The median time to initiation of new therapy for patients managed by watchful waiting was 34 months and the median PFS was 23 months. In patients given immediate rituximab followed by maintenance, the median of these parameters was significantly longer (p= <0.0001) and has not been reached after four years.

At three years from randomization, 49% of patients in the watchful-waiting arm had
not required new therapy, whereas 80% of patients (hazard ratio of 0.20, 95% CI, 0.13-0.29, p= <0.001) in the rituximab induction arm had not required new therapy, while the risk of their disease worsening (PFS) decreased by 79% (based on a hazard ratio of 0.21, 95% CI, 0.15-0.29, p= <0.001). Ninety-one percent of patients in the rituximab induction and maintenance arm had not required new therapy.

Serious adverse events Grade 3 or higher in patients treated with rituximab in this study included infection (4%), allergy (3%), neutropenia (3%) and neutropenic sepsis (1%). At this time, 96% of patients in the study remain alive, and there is no difference in overall survival between the three arms.

“This study demonstrates that treating asymptomatic patients with rituximab can significantly prolong the time until a patient may require chemotherapy” Ardeshna, said. “These results will increase the options for the management of newly diagnosed patients with advanced asymptomatic follicular lymphoma, and it is likely that upfront rituximab therapy will prove popular with patients when compared with a watchful-waiting approach.”

Other Ongoing Trials
In addition to this study, another ongoing studies in the treatment of follicular lymphoma includes the Eastern Cooperative Oncology Group (ECOG) RESORT trial (Rituximab Extended Schedule or Re-treatment Trial) [6]. This phase III randomized trial of rituximab in patients with low-tumor-burden indolent lymphoma aims to determine whether it is better to give rituximab continuously on a maintenance schedule, or to get re-treated at the time of progression. The study?s endpoints are time to rituximab failure and time to first cytotoxic therapy.

For more information:
[1] An Intergroup Randomized 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 [Abstract 6]

References:
[2] Ganti AK, Bociek RG, Bierman PJ, Enke CA, Vose JM, Armitage JO. Follicular lymphoma: expanding therapeutic options. Oncology (Williston Park). 2005 Feb;19(2):213-28; discussion 228, 233-6, 239.
[3] Friedberg JW Treatment of follicular non-Hodgkin’s lymphoma: the old and the new. Semin Hematol. 2008 Jul;45(3 Suppl 2):S2-6.
[4] Maloney DG. Treatment of follicular non-Hodgkin’s lymphoma. Curr Hematol Rep. 2005 Jan;4(1):39-45.

Clinical trials:
[5] Rituximab in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Follicular Non-Hodgkin’s Lymphoma. [Accessed 12-04-2010]. No authors listed. (NCT00112931)
[6] Rituximab in treating patients with low tumor burden indolent non-Hodgkin’s lymphoma. [Accessed 12-4-2010]. No authors listed. (NCT00075946)

Other information:
– Full preprescribing information

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