Prolonged Survival Of Poor Risk Follicular Lymphoma Patients Following Primary Treatment With Rituximab-Supplemented CHOP Or HDS With Autograft: Long-Term Results Of The Multicenter Randomized GITMO/FIL Trial
Authors: Tarella Corrado , Benedetti Fabio , Boccomini Carola , Patti Caterina , Barbui Anna Maria , Pulsoni Alessandro , Musso Maurizio , Liberati Anna Marina , Gini Guido , Castellino Claudia , Rossini Fausto , Ciceri Fabio , Scalabrini Delia Rota , Stelitano Caterina , Di Raimondo Francesco , Perrone Tommasina , Tucci Alessandra , Billio Atto , Zallio Francesco , Zoli Valerio , Congiu Angela , Narni Franco , Dondi Alessandra , Parvis Guido , Semenzato Gianpietro , Corradini Paolo , Bruna Riccardo , Gueli Angela , Mantoan Barbara , Passera Roberto , Magni Michele , Ladetto Marco 
Published: October 2019

Abstract

Introduction
A randomized multicenter study of 134 Follicular Lymphoma (FL) patients, selected for age less than 60 yrs. and poor prognostic features according to age-adjusted IPI (2-3) and IIL-score (3 or greater) was conducted between March 2000 and May 2005, among 30 Italian Centers. The study compared efficacy and tolerability of CHOP-R vs. R-HDS with autograft as primary treatment in poor-risk FL. Initial results have been already reported (Ladetto M et al, Blood 2008), showing superior disease control with R-HDS without any survival advantage. We have recently updated the long-term outcome and the results at long-term are here presented at a median follow-up of 9.5 yrs.

Patients and Methods
Of the original 134 randomized patients, the long-term outcome has been updated for 125 patients, 61 of CHOP-R and 64 of R-HDS arms. Clinical characteristics at study entry and treatment schedules have been already reported. Briefly, the main features of the updated patients included: median age 51 yrs. (22-60), M/F ratio 74/51, aaIPI 2-3 90%, FLIPI >2 (retrospectively assigned) 60%, high LDH 49%, bulky disease 62%, B-symptoms 45%, BM involvement 86%. Clinical characteristics were balanced among the two arms. Treatment schedule consisted of: i. standard arm: 6 courses of cyclo-phosphamide/doxorubicin/vincristine/prednisone followed by 4-weekly rituximab courses (CHOP-R); ii. experimental arm: rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS). The analysis was intention to treat with event-free survival as the primary endpoint. Minimal residual disease was evaluated post treatment in 58 patients with a bcl-2/IgH MBR or mcr translocation confirmed at diagnosis by nested PCR. The trial was registered at www.clinicaltrials.gov as no. NCT00435955. The long-term outcome has been updated in July 2013 by 28 out of 30 participating Centers accounting for 125 patients (93% of the whole series).

Results
Complete remission (CR) was achieved by 88 (70.4%) patients, including 35 (57%) with CHOP-R and 53 (83%) with R-HDS (p < .001); in addition, 37 out of 58 (64%) patients achieved a Molecular Remission (MR). At a median follow-up (MFU) of 9.5 yrs., 88 patients (70.4%) are alive. Overall, 19 patients died for lymphoma progression (11 in the CHOP-R, 8 in the R-HDS arms), there were nine deaths for secondary malignancy (3 in the CHOP-R, 6 in the R-HDS arms), nine more patients died for other causes, including four early toxic deaths. The overall survival projection for the whole series is 78% and 70% at 5 and 10 yrs., respectively. As shown in Figure 1, there were no main differences in the long-term OS between the two arms, with 5 and 10 yrs projections respectively of 75% and 70% for CHOP-R and 81% and 70% for R-HDS (p=0.96). Response to primary treatment had a major impact on the OS, with 5 and 10 yr survival projections respectively of 90% and 80% for patients achieving CR, and of 49 and 43 for those with less than CR (p < .001) (Figure 2A). Similarly, MR achievement was associated with prolonged overall survival, with 5 and 10 yr survival projections respectively of 89% and 83% for patients with PCR-ve on BM cells, and of 76 and 57 for those with persistent PCR-positivity (p = .03) (Figure 2B).

Conclusion
The long-term follow-up of the randomized CHOP-R vs. R-HDS trial indicate that: i. poor risk FL may now experience a prolonged survival, with approximately 70% of patients alive at 10 yrs., due to the combined efficacy of both primary chemo-immunotherapy and salvage treatments; ii. the superior disease control of R-HDS compared to CHOP-R does not translate in any survival advantage, with analogous OS regardless of which treatment is used; iii. also in FL like in other lymphoproliferative malignancies, achieving CR and MR is crucial not only for the disease control but also for long-term overall survival; iv. lymphoma progression remains the major cause of death, while secondary neoplasms, in particular secondary leukemias represent the second cause of treatment failure. Thus, efforts are still needed in order to increase the anti-tumor efficacy while reducing any potential late effect in treatment options for FL.

Disclosures:
Tarella: Roche Co.: support and honoraria for Conference participation Other. Ladetto:Roche: Honoraria, Research Funding, Speakers Bureau.