Consolidation Therapy for Follicular Lymphoma

Consolidation Therapy for Follicular Lymphoma

Christian Buske


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Several studies have evaluated rituximab’s efficacy as maintenance therapy in both the first-line and relapsed settings.30–34 These studies have reported promising data regarding ORR as well as PFS in a salvage situation. The important question of whether rituximab maintenance is beneficial after initial immunochemotherapy first-line therapy is addressed by the Primary Rituximab and Maintenance (PRIMA) trial, which has completed patient accrual. Its primary objective is the evaluation of maintenance therapy with rituximab in first-line patients with advanced FL after induction of response with rituximab–chemotherapy combination compared with no maintenance therapy. The results from this international open-label, multicentre, randomised study are expected in 2009.

Consolidation Therapy for Follicular Lymphoma
The aim of consolidation therapy is to further improve the quality of response, preferably with the eradication of minimal residual disease (MRD) after successful cytoreduction by chemotherapy. Myeloablative therapy before ASCT and RIT are two potential consolidation strategies that have been investigated in the clinical setting as both first- and second-line therapy. Consolidation therapy with rituximab as a single agent delivered short-term has not been established for either FL or aggressive lymphoma. As opposed to myelablative therapy followed by ASCT or RIT, which both take around 14 days, rituximab maintenance treatment continues over a period of two years.

Radioimmunotherapy
RIT is a treatment modality that combines the specificity of monoclonal antibodies against tumour antigens with therapeutic radioisotopes delivered to sites of disseminated disease. Encouraging results have been reported for the 90Y-labelled IgG1 κ anti-CD20 antibody ibritumomab tiuxetan and also for the 131I-labelled IgG2 κ anti-CD20 antibody tositumomab in the treatment of FL. Currently, only 90Y-ibritumomab tiuxetan is approved for use in Europe as single-agent therapy in patients with relapsed follicular lymphoma who have been treated with rituximab. It was recently approved for consolidation therapy after remission induction in previously untreated patients with follicular lymphoma. In the non-myeloablative approach, both agents have demonstrated comparable activity, with response rates of 60–80% and CR/CRu rates of between 4 and 15%, including patients who relapsed after or were refractory to previous chemotherapy and rituximab.35

Radioimmunotherapy as Consolidation Therapy
Studies evaluating RIT as consolidation therapy have shown promising data. A phase II trial of CHOP followed by tositumomab/ 131I-tositumomab for previously untreated FL in 90 eligible patients with previously untreated advanced-stage FL reported an OR of 91%, with a 69% CR rate. The estimated five-year OS rate was 87%, and the PFS rate was 67%.

These data were superior to corresponding figures for patients treated on previous Southwest Oncology Group protocols with CHOP alone.36 Interestingly, 21% of patients with FLIPI high-risk features had worse OS than lower-risk patients (p=0.05), although no differences were reported in PFS between FLIPI-stratified groups. Another phase II study evaluated the efficacy of abbreviated chemotherapywith fludarabine followed six to eight weeks later with tositumomab/131I-tositumomab. After the fludarabine course, 89% of 35 patients and 9% of 31 patients achieved CR. Following 131I-tositumomab consolidation therapy, all 35 patients responded and 86% achieved CR.37

A preliminary study evaluated 90Y-ibritumomab tiuxetan following CHOP–rituximab. After CHOP–rituximab, the CR rate was 28%. After RIT, the CR rate was 67%.38 Two-year PFS was 85%. A phase II study investigating the efficacy of fludarabine and mitoxantrone (FM) chemotherapy followed by 90Y-ibritumomab tiuxetan in patients with stage III or IV untreated indolent FL showed an ORR of 98% and a CR rate of 71% after FM chemotherapy. Of the patients who completed the sequential treatment (chemotherapy plus RIT), 97% achieved CR.39 At a median follow-up of 30 months, the estimated three-year PFS rate was 76%, and the three-year OS rate was estimated to be 100%.

Recently, the results of the first phase III trial evaluating RIT consolidation treatment were presented. The phase III First-line Indolent Trial (FIT) evaluated the efficacy and safety of 90Y-ibritumomab tiuxetan consolidation in patients with advanced FL responding to first-line chemotherapy.40 The multicentre study tested whether a single infusion of 90Y-ibritumomab tiuxetan would prolong PFS in patients responding to initial cytoreduction.

Major inclusion criteria were: CD20-positive grade 1 or 2 FL, stage III or IV at diagnosis, normal peripheral blood cell counts, <25% bone marrow involvement, age ≥18 years and CR/CRu or PR after first-line chemotherapy determined by physical examination, CT scans and bone marrow biopsy. After completing induction therapy that included various regimens, patients were randomised to receive either 90Y-ibritumomab tiuxetan (208 patients) or no further treatment (206 patients).

For patient subgroups in PR or CR after induction, median PFS was 6.3 versus 29.7 months (p<0.0001) and 29.9 versus 54.6 months (p=0.01), respectively, in favour of 90Y-ibritumomab tiuxetan treatment. After 90Y-ibritumomab tiuxetan consolidation, 77% of patients in PR after induction therapy converted to CR; in total, 87% of patients were in CR/CRu, 76% in CR and 11% in CRu. Toxicity encompassed primarily haematological effects. Median platelet count nadir was at 45x109/l approximately five weeks post-90Y-ibritumomab tiuxetan, and the median neutrophil nadir was 1.0x109/l almost six weeks post-RIT. Grade 3/4 infections occurred in 8% in the 90Y-ibritumomab tiuxetan arm versus 2% in the control arm. This is the first phase III study to convincingly show a benefit with RIT in the consolidation setting.

Further prospective studies are needed to confirm the potential benefits of RIT, particularly following rituximab chemotherapy. Following this line, a new international trial (the Randomized intergroup trial Zevalin [RitZ]) co-ordinated by the German Low-grade Lymphoma Study Group (GLSG) and the Dutch–Belgian Hemato–Oncology Co-operative Group (HOVON) will begin soon, testing whether a single infusion of 90Y-ibritumomab tiuxetan followed by rituximab maintenance will prolong duration of response after initial successful rituximab/chemotherapy compared with rituximab/chemotherapy followed by rituximab maintenance alone in patients with recurrent FL.

Follicular Lymphoma in the Future
One issue that will become the centre of attention in the future is the treatment of elderly and medically non-fit cancer patients. Due to the general ageing of the population in the western world, FL will become the burden of the elderly. The number of lymphoma patients aged between 65 and 90 years will increase and their treatment will present a serious challenge. Non-lymphoma-related co-morbidities such as heart and renal disease that are common in elderly patients will render high-dose intensive chemotherapy not feasible for their treatment. These patients urgently need a new concept of treatment, and monoclonal antibody therapy is an attractive alternative for these difficult-to-treat patients.

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