The incidence of NHL has increased nearly two-fold over the past few decades, with AIDS-related lymphoma accounting for some of this expansion and environmental factors probably playing a role.³ NHL accounts for approximately 8–10% of all childhood malignancies.⁴ The prognosis of both localised and advanced childhood and adolescent NHL has improved considerably over the past 30 years.^5,6

Follicular Lymphoma
Follicular lymphomas represent the second most frequent subtype of nodal lymphoid malignancies in Western Europe. The Non-Hodgkin’s Lymphoma Classification Project, which examined a cohort of 1,403 lymphoma biopsies from previously untreated NHL patients from nine sites worldwide, diagnosed FL in 22% of cases.⁷ Furthermore, in recent decades the annual incidence of FL has increased rapidly, rising from two to three per 100,000 persons during the 1950s to five per seven per 100,000 persons.⁸ The World Health Organization (WHO) classification of NHL separates follicular lymphoma into three grades based on the proportion of centroblasts in neoplastic follicles.⁹

FL grade 1 is diagnosed when up to five centroblasts per high-power (microscope) field (hpf) are counted, while FL grade 2 is diagnosed when six to 15 centroblasts per hpf are counted. FL grade 3 is characterised by more than 15 centroblasts per hpf, and it is subdivided into grade 3a when centrocytes are present and 3b when solid sheets of centroblasts are observed. FL grades 1, 2 and 3a are considered to be indolent, whereas 3b is considered to be an aggressive variant of FL. FL grade 3b has displayed similar histological features to the DLBCL component. In the presence of the DLBCL component, patients with FL grade 3b were less likely to harbour the t(14;18) translocation, which is quite common in the other grades, but were more likely to display aberrations in chromosome band 3q27 and overexpress the tumour suppressor gene p53.¹⁰

The current European Society for Medical Oncology (ESMO) guidelines recommend radiotherapy as first-line therapy in patients with limited stage I–II disease, and advise that systemic therapy should be considered in patients with large tumour burden.¹¹ In patients with advanced stage III and IV disease, no curative therapy is yet established. In these patients, ESMO recommendations include the initiation of chemotherapy in combination with rituximab as first-line treatment only upon the occurrence of symptoms with the aim of inducing complete remission. Recommended chemotherapy regimens include cyclophosphamide plus doxorubicin, vincristine and prednisone (CHOP), cyclo-phosphamide, vincristine, prednisone (CVP) and purine analogue-based schemes such as fludarabine, cyclophosphamide and mitoxantrone (FCM) or bendamustine. Interferon-α maintenance therapy may have a benefit with regard to duration of response, which must be balanced against toxicity, while rituximab maintenance and autologous stem-cell transplantation (ASCT) is investigational in first-line therapy.¹¹

Rituximab in conjunction with chemotherapy is the first-line treatment for advanced disease. Subsequent consolidation aims to stabilise remission once cytoreduction is achieved by induction treatment. The ultimate goal is to avoid relapse altogether, but currently this can only be postponed. In relapsed disease, the chosen salvage therapy is dependent on the efficacy of the initial regimen. A non-cross-resistant regimen, such as fludarabine or bendamustine after CHOP, is preferred in early relapses (<12 months). Rituximab should be added if the initial antibody-based regimen achieved a remission duration of more than six months. Moreover, rituximab maintenance has also demonstrated benefits in terms of progression-free survival (PFS) after initial rituximab/chemotherapy in the salvage situation. Myeloablative consolidation followed by ASCT may also prolong PFS in relapsed disease. The effects of high-dose therapy (HDT) with ASCT and rituximab were compared on two successive cohorts of patients with advanced FL treated by the same induction and consolidation regimen.