FDG-PET-Stratified R-DICEP and R-BEAM/ASCT For Diffuse Large B-Cell Lymphoma

BACKGROUND AND RATIONALE:

Although the addition of Rituximab anti-CD20 monoclonal antibody therapy to standard CHOP chemotherapy (R-CHOP) results in a 15-20% increase in absolute EFS rate over CHOP alone for DLBCL patients, it is likely that 40-50% of patients with poor prognosis DLBCL will not be cured by R-CHOP. High dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has been shown to salvage a substantial proportion of patients with relapsed DLBCL. A meta-analysis of randomized controlled trials comparing standard-dose chemotherapy (SDCT) alone to SDCT followed by HDCT/ASCT as initial treatment for poor prognosis DLBCL demonstrated a significant benefit for HDCT over SDCT in terms of EFS and OS. A single centre prospective phase II study was conducted in Calgary to assess feasibility, toxicity, and efficacy of two cycles of HDCT following just one cycle of CHOP induction therapy for patients under 65 years of age who were diagnosed with aggressive histology lymphoma and 2-3 Age Adjusted International Prognostic Index (AAIPI) risk factors. The study was conducted prior to the widespread use of Rituximab plus CHOP (R-CHOP). The treatment protocol involved one cycle of standard dose CHOP followed by one cycle of dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2, cisplatin 105 mg/m2 (DICEP), then autologous blood stem cell collection, followed by one cycle of high dose BCNU 300 mg/m2, etoposide 800 mg/m2, Ara-C 1600 mg/m2, melphalan 140 mg/m2 (BEAM) and autologous stem cell transplantation (ASCT) and radiotherapy to prior bulk. With a median follow up of 49 months, 4 year event free (EFS) and overall survival (OS) rates for the 55 patients accrued to the study were 72% (95% CI=60-84%) and 79% (95% CI=69-90%), respectively.

The two major advances in lymphoma management that have occurred since the design of our CHOP-DICEP-BEAM/ASCT phase II study are the addition of Rituximab anti-CD20 monoclonal antibody therapy to chemotherapy (as described above), and the use of FDG-PET functional imaging/response assessment. Several studies have reported the strong correlation of early response assessment using FDG-PET with PFS and OS following standard chemotherapy for aggressive NHL. In one of the largest, best designed studies, PET-negativity following 2 cycles of RCHOP was associated with higher 2-year estimates of EFS (82% vs 43% , p < .001) and OS (90% vs 61%, p = .006). The incorporation of Rituximab and PET-guided HDCT/ASCT into our intensive chemotherapy protocol may lead to further improvements in EFS while decreasing the overall need for HDCT/ASCT by targeting those patients destined to fail R-CHOP by early PET-based response assessment.

STUDY OBJECTIVES:

1. To determine if negative FDG-PET imaging following 2 cycles of R-CHOP chemotherapy is able to identify a group of patients with excellent prognosis (80% 3-year EFS) following standard 6 cycles of R-CHOP chemotherapy alone.
2. To determine if a group of patients with positive FDG-PET imaging following 2 cycles of R-CHOP chemotherapy are able to achieve excellent outcome (80% 3-year EFS) following intensive chemotherapy with R-DICEP and R-BEAM/ASCT.
3. To determine if PET-guided R-DICEP and R-BEAM/ASCT is feasible and associated with acceptable toxicity rates in a multi-centre study.