Long-Term Follow-Up of the Randomized GITMO/IIL Trial Comparing CHOP-Rituximab vs. High-Dose Therapy with Rituximab (R-HDS) in High Risk Follicular Lymphoma (Fl): Updated Results Suggest the Use of R-HDS as Salvage Treatment.

Background. A randomised trial has been performed among several GITMO/IIL italian centers, comparing Rituximab-supplemented High-Dose Sequential Chemotherapy (R-HDS) and CHOP-R in high-risk FL <60 yrs. The updated results are here presented, after a median follow-up of 50 months.

Patients (pts) and Methods. Eligibility was based on age-adjusted IPI >=2 (125 pts) or on the IIL score >=3 (11 pts). 136 pts were randomized (68/arm). Main clinical features were: median age 51 yrs. (22–59), stage III–IV 98%, elevated LDH 59%, bulky disease 56%, B symptoms 47%, extranodal disease other than bone marrow (BM) 31%, PS >1 (ECOG) 60%. Both R-HDS and CHOP-R have been already described (Ladetto et al ASH 2005, Rambaldi et al Blood 2000). Cross-over was allowed for pts failing CHOP-R. Centralized minimal residual disease (MRD) analysis with the bcl-2/IgH was performed on BM samples. Analysis was intention to treat.

Results. Early toxic deaths were 5 (2 in CHOP-R, 3 in R-HDS); CR rates were 61% with CHOP-R and 85% with R-HDS (p<0.001). At four years EFS and PFS are 32% and 33% for CHOP-R, and 64% and 76% for R-HDS (p<0.001). Despite a better EFS, OS is not different in the two arms (82% CHOP-R and 79% R-HDS). One fatal secondary myelodysplastic syndrome occurred in the CHOP-R arm and five (three fatal) in the R-HDS arm with a cumulative incidence at four years of 3.3% and 7.9% respectively. A stable molecular remission (MR) (achieved in 44% of CHOP-R and 80% of R-HDS pts) (p<0,001) was associated with an improved PFS (22% vs 78% at four years) (p<0,001) and proved the strongest outcome predictor for EFS and PFS by multivariate analysis (Hazard Ratio: 3.98 and 3.83, respectively). Interestingly, the PFS of PCR-negative pts was similar in the two arms, as well as that of PCR-positive pts. Of 39 patients with relapsed or refractory disease after CHOP-R 28 were crossed to R-HDS (71%). Reasons for not undergoing cross-over were: limited relapse in 4, co-morbidities in 2, refusal in 2, other causes in 3. Overall CR rate for second line treatment after CHOP-R failure was 77% (86% with R-HDS and 54% with other therapy). At a median follow-up of 30 months the three-year EFS of patients undergoing salvage R-HDS is 70%.

Conclusions: In high-risk FL: a) first-line R-HDS ensures better EFS and PFS and superior molecular outcome than CHOP-R; b) pts undergoing salvage R-HDS have an excellent clinical outcome; c) the long-term OS is markedly improved compared to the pre-rituximab era, with no difference between CHOP-R and R-HDS; d) both the high efficacy as salvage treatment and the potential side effects suggest that the ideal positioning of R-HDS-like treatments is beyond first line treatment, for relapsed or refractory disease; e) a PCR-negative status is the most important prognostic factor regardless of treatment received and pts with persistent PCR-positivity might potentially be considered for specific experimental intervention.