Treatment of follicular lymphoma

Follicular lymphoma is a malignancy of the lymphatic system and a common type of non-Hodgkin lymphoma. Follicular lymphoma arises from B-cells, mainly affects older adults and because of its slow growth it is called an indolent lymphoma. Follicular lymphoma grows unnoticed for a long time and is recognised by lymph node enlargement, fever, weight loss, sweating or fatigue. It is called follicular lymphoma because affected lymph nodes show rounded structures called "follicles". Using computer tomography scans, bone marrow biopsy and blood tests, follicular lymphoma is classified into the early Ann Arbor stages I and II or the advanced Ann Arbor stages III or IV, which are diagnosed in the majority of patients. Prognosis and therapy are related to the extent of the disease at initial diagnosis. The small number of patients in stages I or II may be cured by radiotherapy. In advanced stages III or IV, patients are regarded as incurable. Chemotherapy plus the monoclonal antibody rituximab is considered as current treatment strategy for symptomatic patients in advanced stages. Positive effects of high-dose therapy with transplantation of patients' own stem cells (autologous) are known for patients in advanced stages, especially for the endpoint progression-free survival. However, this treatment option could have comparatively more treatment-related late side effects than chemotherapy, including secondary malignancies.

With this assumption, we assessed the role of high-dose therapy followed by autologous stem cell transplantation in the treatment of follicular lymphoma in adults. We included five trials with 1093 patients in the main analyses. As a result, the meta-analyses for previously untreated patients (four trials) show no statistical significant differences in terms of survival, treatment-related mortality or secondary malignancies between the patients treated with high-dose therapy followed by autologous stem cell transplantation and those treated with chemotherapy only. However, progression-free survival (tumour control), was significantly improved by the high-dose chemotherapy and stem cell transplantation. Adverse events are more common in patients treated with high-dose therapy followed by autologous stem cell transplantation.

There is an advantage of the high-dose chemotherapy and stem cell transplantation for patients with a relapse of the disease, both in survival and in tumour control (one trial). No data on adverse events are reported in this trial.

Authors' conclusions: 

In summary, the currently available evidence suggests a strong PFS benefit for HDT + ASCT compared with chemotherapy or immuno-chemotherapy in previously untreated patients with FL. No statistically significant differences in terms of OS, TRM and secondary cancers were detected. These effects are confirmed in a subgroup analysis (one trial) adding rituximab to both treatment arms. Further trials evaluating this approach are needed to determine this effect more precisely in the era of rituximab. Moreover, longer follow-up data are necessary to find out whether the PFS advantage will translate into an OS advantage in previously untreated patients with FL.

There is evidence that HDT + ASCT is advantageous in patients with relapsed FL.

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Background: 

Follicular lymphoma (FL) is the most common indolent and second most common Non-Hodgkin`s lymphoma (NHL) in the Western world. Standard treatment usually includes rituximab and chemotherapy. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is an option for patients in advanced stages or for second-line therapy, leading to improved progression-free survival (PFS) rates. However, the impact of HDT and ASCT remains unclear, as there are hints of an increased risk of second cancers.

Objectives: 

We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing HDT plus ASCT with chemotherapy or immuno-chemotherapy in patients with FL with respect to overall survival (OS), PFS, treatment-related mortality (TRM), adverse events and secondary malignancies.

Search strategy: 

We searched CENTRAL, MEDLINE, and EMBASE as well as conference proceedings from January 1985 to September 2011 for RCTs. Two review authors independently screened search results.

Selection criteria: 

Randomised controlled trials comparing chemotherapy or immuno-chemotherapy with HDT followed by ASCT in adults with previously untreated or relapsed FL.

Data collection and analysis: 

We used hazard ratios (HR) as effect measures used for OS and PFS as well as relative risks for response rates. Two review authors independently extracted data and assessed the quality of trials.

Main results: 

Our search strategies led to 3046 potentially relevant references. Of these, five RCTs involving 1093 patients were included; four trials in previously untreated patients and one trial in relapsed patients. Overall, the quality of the five trials is judged to be moderate. All trials were reported as randomised and judged to be open-label studies, because usually trials evaluating stem cell transplantation are not blinded. Due to the small number of studies in each analysis (four or less), the quantification of heterogeneity was not reliable and not evaluated in further detail. A potential source of bias are uncertainties in the HR calculation. For OS, the HR had to be calculated for three trials from survival curves, for PFS for two trials.

We found a statistically significant increased PFS in previously untreated FL patients in the HDT + ASCT arm (HR = 0.42 (95% confidence interval (CI) 0.33 to 0.54; P < 0.00001). However, this effect is not transferred into a statistically significant OS advantage (HR = 0.97; 95% 0.76 to 1.24; P = 0.81). The subgroup of trials adding rituximab to both intervention arms (one trial) confirms these results and the trial had to be stopped early after an interim analysis due to a statistically significant PFS advantage in the HDT + ASCT arm (PFS: HR = 0.36; 95% CI 0.23 to 0.55; OS: HR = 0.88; 95% CI 0.40 to 1.92). In the four trials in previously untreated patients there are no statistically significant differences between HDT + ASCT and the control-arm in terms of TRM (RR = 1.28; 95% CI 0.25 to 6.61; P = 0.77), secondary acute myeloid leukaemia/myelodysplastic syndromes (RR = 2.87; 95% CI 0.7 to 11.75; P = 0.14) or solid cancers (RR = 1.20; 95% CI 0.25 to 5.77; P = 0.82). Adverse events were rarely reported and were observed more frequently in patients undergoing HDT + ASCT (mostly infections and haematological toxicity).

For patients with relapsed FL, there is some evidence (one trial, N = 70) that HDT + ASCT is advantageous in terms of PFS and OS (PFS: HR = 0.30; 95% CI 0.15 to 0.61; OS: HR = 0.40; 95% CI 0.18 to 0.89). For this trial, no results were reported for TRM, adverse events or secondary cancers.

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