A major UK-led trial, presented at the American Society of Haematology's annual meeting, could represent a completely new treatment approach for a common cancer of the immune system, follicular lymphoma (FL). Up until now, some patients diagnosed with this cancer do not receive any form of treatment and are consigned to 'watch and wait' until they start showing symptoms. When symptoms do appear, patients have to embark on a treatment that includes chemotherapy. However, a new UK-led study effectively nullifies this practice, providing the first strong evidence that the time to starting chemotherapy and the time to cancer progression can be extended for longer if patients are treated with the targeted antibody MabThera® (rituximab) immediately on diagnosis, compared to 'watch and wait'. As rituximab is an antibody therapy, it is more discriminate than chemotherapy2 and therefore has fewer of the associated unpleasant side effects3 e.g. nausea/vomiting, hair loss and mouth ulcers.4

The study, led by clinicians at the University College London Hospital, investigated what happens when patients receive treatment with the targeted therapy rituximab upon diagnosis, before symptoms appear, and stay on it for two years. Results showed that after three years 91 per cent of patients who received rituximab monotherapy as induction and maintenance (four weekly doses followed by maintenance doses once every two months for two years) were spared any 'cytotoxic' therapy (chemotherapy or radiotherapy) compared with 48 per cent of patients who received no treatment at diagnosis (watch and wait group).1

At the same time point, 81 per cent of patients who received induction and extended rituximab therapy had not experienced a worsening of their disease (progression free survival or PFS) at three years compared with 33 per cent in the watchful waiting arm.1

"We have found another way of managing this disease in its early years," commented Dr Kirit Ardeshna, University College Hospital, London, UK and Chief Investigator for the Watch and Wait trial. "For many patients it is important to delay the onset of chemotherapy and for them the results of this study are a great advance."

"The side effects of chemotherapy can have a profound effect on someone's quality of life, which is why watchful waiting for FL to progress was, until now, thought to be the best option for patients," commented Sally Penrose, chief executive of the Lymphoma Association. "However, a new option that further delays the need for chemotherapy is fantastic news for the thousands of people in the UK living with this type of lymphoma."

Follicular lymphoma is a slow-growing form of non-Hodgkin's lymphoma (NHL) characterised by periods of relapse and remission and it affects more than 15,000 people in the UK.5 As FL is an incurable cancer, the primary goal of treatment is to keep the cancer in check for as long as possible, to enable people to sustain close to normal lives.

Previous studies have failed to show that asymptomatic patients treated immediately with chemotherapy live any longer when compared with watchful waiting.6 On average, asymptomatic patients could be observed for 2.5 years before chemotherapy or radiotherapy is required.6 Based on evidence to date, clinicians have delayed cytotoxic therapy as long as possible to spare patients some unpleasant side effects at a time when they are otherwise feeling well.

The safety profile in the Watch and Wait study was consistent with previous experience with rituximab. The side effects of rituximab include infusion-related side effects such as flu-like symptoms, nausea and low blood pressure, and later side effects including lower resistance to infection, bruising and anaemia.3 Sixteen serious adverse events were considered probably, possibly or definitely related to rituximab, namely infection, allergy, neutropenia and neutropenic sepsis.

The provision of rituximab as induction therapy followed by maintenance for asymptomatic patients is not licensed in the UK.

Notes:

About the Watch and Wait study

Conducted by the University College London Hospital, this phase III study was an international, multicentre, randomised trial that enrolled 462 patients (UK 376) with previously untreated asymptomatic stage II-IV follicular lymphoma.

The trial compared the safety and efficacy of induction followed by extended (two-year) use of rituximab alone compared to careful observation (watchful waiting) and a third group who received four weeks of rituximab (induction) only. Patients were randomised to receive one of the following:

- Arm A: No therapy (watchful waiting)

- Arm B: Rituximab alone (375mg/m2 weekly) for four cycles only (without extended rituximab)

- Arm C: Rituximab alone (375mg/m2 weekly) for four cycles followed by rituximab at the same dose given once every two months for two years

Three years after the enrollment of the first patient, arm B was closed and the trial was amended to compare extended two-year use of rituximab following an initiation cycle of rituximab, with watchful waiting alone.

About follicular lymphoma

- FL is a cancer of the immune system in which an over-abundance of B-cells overcrowds other cells, eventually pressing on organs and spreading to other parts of the body such as the bone marrow, liver, lungs or skin

- The first sign of FL is often a swelling in the neck, armpit or groin, caused by enlarged lymph nodes

- FL is one of the most common forms of non-Hodgkin lymphoma (NHL)7, and is estimated to affect over 15,000 people in the UK5

- FL can occur any time during adulthood, the average patient being in their 60s. The incidence is similar in men and women8

- Most patients with FL will have advanced disease before symptoms even develop. This means that 80 to 85 per cent of patients will have advanced disease when diagnosed7

- Despite its slow-growing nature, in 30 per cent of cases FL may morph into a more aggressive high grade type lymphoma and can result in early death9

About rituximab

Rituximab binds to a particular protein - the CD20 antigen - on the surface of normal and malignant B-cells. It then recruits the body's natural defences to attack and kill the marked B-cells. Unlike chemotherapy, rituximab kills only B-cells10

Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months10

The side effects of rituximab fall into two groups: infusion-related side effects, including flu-like symptoms, nausea and low blood pressure, and later side effects, including lower resistance to infection, bruising and anaemia3

Please refer to the Summary of Product Characteristics for full details: www.emc.medicines.

Rituximab indications10

In the UK rituximab is indicated in oncology:

- As maintenance therapy in follicular lymphoma patients who have responded to induction treatment

- For the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukaemia (CLL) in combination with chemotherapy; only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including rituximab, or patients refractory to previous rituximab plus chemotherapy

- For the treatment of previously untreated patients with stage III-IV FL, in combination with chemotherapy

- For the treatment of patients with CD20 positive diffuse large B-cell non-Hodgkin lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy

- As monotherapy for the treatment of patients with stage III-IV FL who are chemoresistant or are in their second or subsequent relapse after chemotherapy

References:

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) - Sunday, December 5, 2010, 3:15 p.m. EST, Hall D, Orange County Convention Center

2. Lymphoma Association. Low grade non-Hodgkin lymphoma. Available here. [last accessed November 2010]

3. See here [last accessed November 2010]

4. Chemotherapy for lymphoma, Lymphoma Association. [last accessed November 2010]

5. Figure has been calculated by applying the 2007 NHL (22% FL) Scottish prevalence rates per 100,000 to the 2007 UK population (61m) - Office for National Statistics [accessed November 2010]

6. Ardeshna 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. The Lancet, Vol 362, August 16, 2003: 516-522

7. Lymphoma Association. Low grade non-Hodgkin lymphoma. Available here. [last accessed November 2010]

8. See here [Last accessed November 2010]

9. New targets for the treatment of follicular lymphoma; Tageja, N. et al, Journal of Hematology and Oncology 2009, doi: 10.1186/1756-8722-2-50, jhoonline/content/2/1/50 [Last accessed November 2010]

10. SPC: Mabthera 100mg and 500mg concentrate for solution for infusion. See here [last accessed November 2010]

Source:
Roche