Quantitative Assessment of Circulating t(14;18) Positive Cells by RQ-PCR at Diagnosis and Follow-Up Correspond to Clinical Characteristics and Predicts Time to Treatment Failure in Follicular Lymphoma.

Abstract

Follicular lymphoma (FL) is characterized by the t(14;18) translocation and is incurable with standard treatments in advanced stages. However, the prognosis of FL is heterogeneous and there are long term survivor with a slow disease progression. The detection of residual t(14;18) positive cells by PCR has become an important tool in the diagnostic work-up and during the clinical follow-up in patients with FL. Therefore we evaluated the prognostic value of RQ-PCR assessment at diagnosis and follow-up in patients with advanced FL.Patients and methods: PB and bone marrow (BM) of 80 patients with advanced stage, t(14;18)+ FL treated frontline with CHOP (n=42) or CHOP+ Rituximab (n=28) in a prospective trial of the German Low-Grade Lymphoma Study Group (GLSG) was analysed. t(14;18)+ cells were quantified by RQ-PCR (ABI PRISM 7700).Results: Patients with stage IV disease (p=0.003), presence of B-symptoms (p=0.002) or >4 involved lymph node regions (p=0.004) had significantly higher level of PB t(14;18)+ cells, whereas the RQ-PCR levels did not correlate with sex, bulky disease, LDH and age. RQ-PCR level seemed to correlate also with the FLIPI defined risk groups (median level 0.00015 low risk, 0.00275 intermediate risk, 0.008 high risk, p=0.059). RQ-PCR values showed a significant influence on TTF (p=0.037, univariate Cox Regression). Circulating lymphoma cells in diagnostic PB above a threshold of 0.01 corresponded to the time to treatment failure (TTF), patients with a high lymphoma load (>0.01) demonstrated a significant lower TTF (median 2.8 years) compared to patients with levels <=0.01 (median not reached at a median observation time of 27 months, p=0.0396).MRD quantification after CHOP induction demonstrated a significant reduction of about 2 logs of lymphoma cells (p=0.0021) in PB, but the majority of patients (77%) remained MRD positive. R-CHOP removed lymphoma cells more efficiently (>2 logs) inducing a molecular remission (MR) in 76% (p<0.0001). Achievement of MR after induction tended to correlate with improved PFS (PFS at 2 years MRD+ 53%, MRD neg. 90%, p=0.068).Conclusions: Quantitative assessment of circulating t(14;18)+ in diagnostic PB as well as after treatment has demonstrated prognostic relevance and can be used as a surrogate marker for clinical outcome of patients with FL. The results provide further evidence for the value of RQ-PCR based MRD assessment and demonstrate that achievement of MR is one of the major goals in the therapy of FL.