Clinical and Molecular Results of the Multicenter Randomized GITMO-IIL Trial in Poor Risk Follicular Lymphoma (FL) at Diagnosis: Rituximab-Supplemented High-Dose Sequential Chemotherapy (R-HDS) Is Superior to CHOP-R in Molecular Remissions Rate, EFS and PFS.
Authors: Ladetto Marco , de Marco Federica , Benedetti Fabio , Vitolo Umberto , Patti Caterina , Rambaldi Alessandro , Liberati Anna Marina , Musso Maurizio , Pulsoni Alessandro , Olivieri Attilio , Pavone Enzo , Pogliani Enrico , Scalabrini Delia Rota , Gallamini Andrea , Callea Vincenzo , Ricca Irene , Boccadoro Mario , Majolino Ignazio , Corradini Paolo , Gianni Alessandro M. , Tarella Corrado 
Published: October 2019

Abstract
This is an update of the GITMO-IIL trial comparing R-HDS and CHOP-R in high-risk FL <60 years. The whole patient (pt) population is now evaluable for analysis with a median follow-up of 36 months. Eligibility was based on age-adjusted IPI ≥2 (125 pts) or according to the Italian Lymphoma Intergroup score ≥3 (11 pts).136 pts were stratified according to histology (grade I or II 101, grade III 35) and randomized (68 each). Clinical features were: median age 50 yrs. (22–60), stage III–IV 98%, elevated LDH 78%, bulky disease 66%, B symptoms 47%, extranodal disease (other than BM) 45%, ECOG PS >1 47%. R-HDS has been already described (Ladetto et al ASH 2005). The CHOP-R arm consisted of CHOP and Rituximab delivered sequentially as already published (Rambaldi et al Blood 2002). Cross-over was allowed for pts failing CHOP-R. Centralized minimal residual disease (MRD) analysis with the bcl-2/IgH was planned on BM cells. Analysis was “intention to treat”. Toxic deaths were 4 (2 in each arm); in addition 1 gastric cancer and 2 MDS-ANLL occurred in the R-HDS arm and 1 head and neck cancer in the CHOP-R arm. CR rates were 59% with CHOP-R and 85% with R-HDS (p<0.001). Progressions were 28% with CHOP-R and 10% with R-HDS (p<0.025). At 36 months EFS and PFS for CHOP-R are 36% and 38% while for R-HDS are 66% and 72% (EFS: figure 1a). The better outcome for R-HDS was seen both in grade I, II and grade III pts. OS at 36 months was 83% in each arm. Cross-over from CHOP-R to R-HDS was chosen in 67% patients failing CHOP-R with a CR rate of 73%. MRD analysis is available in 44% of pts. A stable molecular remission (MR) was achieved in 26% of CHOP-R pts and 78% of R-HDS pts (p<0,001). A persistent MR was associated to an improved PFS (p<0,001) (figure 1b). Interestingly, PFS of PCR+ and PCR− pts was similar, regardless of the treatment received: 3-years PFS for PCR+ pts was 25% for CHOP-R and 32% for R-HDS, while 3-years PFS for PCR− pts was 67% with CHOP-R and 76% with R-HDS). This is the first randomized study with a significant proportion of molecularly-studied pts in FL and compares for the first time an intensified versus a conventional schedule in the Rituximab age. Conclusions are: a) R-HDS induces a greater number of CRs and ensures a better EFS and PFS compared to CHOP-R in this rare and aggressive population of pts. Indeed the good OS in both arms compared to historical controls suggests that current treatments are improving the outcome of these pts; b) R-HDS induces more MRs; c) the similar outcome observed in PCR+ and PCR− pts, regardless of the treatment received, indicates that the superior outcome of R-HDS compared to CHOP-R is largely explained by the superior rate of MRs achieved with the former treatment.
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