Session Item

To present mature data on overall survival (OS), progression free survival (PFS), transformation to aggressive lymphoma and preliminary translational research on biospecimens for the TROG 99.03 international randomised trial of radiotherapy vs radiotherapy plus systemic therapy in stage I-II Follicular Lymphoma (FL). This report adds 2 years additional follow up, new analyses and initial translational research results from trial biospecimens.

Patients with stage I-II FL, grade 1-3a, staged with CT and bone marrow biopsies +/- FDG-PET were randomized to either; Arm A: 30Gy IFRT alone or Arm B: IFRT followed by 6 cycles of cyclophosphamide 1000 mg/m2 IV D1, vincristine 1.4 mg/m2 D1 and prednisolone 50mg/m2 D1-5 (CVP). From 2006 Rituximab 375 mg/m2 D1 was added to arm B (R-CVP). PET staging gradually became widely adopted. Stored trial biospecimens were analysed for potential prognostic factors, including plasma beta 2 microglobulin (B2M) and gene expression in FFPE tumour biopsies, assessed by nanostring analysis.

From February 2000 to July 2012, 150 patients were, recruited: 75 to arm A (IFRT) and 75 to arm B (44 CVP and 31 R-CVP). Median age was 57, 75% had stage 1 and 48% were PET-staged. At the trial close out date, (median potential follow-up 11.3 years), PFS remained significantly superior for arm B (IFRT + systemic therapy) compared to arm A (HR 0.6 (0.37-0.98); p=0.043). 10 years PFS was 62% for arm B and 43% for arm A. 10 year OS was 95.3 and 84% respectively for arms A and B (HR 0.44, p=0.10). Patients treated with R-CVP had substantially superior PFS compared to those who received IFRT or CVP (81% vs 52% at 8 years, P=0.013, figure 1). When analysis of PFS was confined to 72 PET-staged patients the difference between arms A and B increased (HR 0.35 p=0.027, Figure 2), whereas analysis confined to 78 non-PET staged patients showed no significant difference between arms (HR 0.8, p=0.42).  More than twice as many deaths (13 vs 6) and transformations to aggressive lymphoma (11 vs 5) occurred in Arm A than Arm B. By last follow-up 16 patients had experienced transformation with 11 and 5 cases detected in arms A and B respectively. The HR for either histological transformation or death was 4.0 (p=0.045), consistent with a favourable change in natural history with systemic therapy. Emphasizing the importance of the cytotoxic CD8+ T-cell response, both elevated plasma B2M (HR 2.27, p=0.044) and low intratumoural CD8A gene expression (HR 2.21, p=0.0042) were associated with inferior PFS.

Systemic therapy, especially with rituximab, increased progression free survival and significantly reduced the risk of death or transformation to aggressive lymphoma in stage I-II FL. Most benefit was seen in PET staged patients.  Elevated B2M and lower gene expression associated with anti-tumour immunity were associated with worse outcomes.