Updated 13 Yr Follow-Up of the GITMO-IIL Trial Comparing Upfront R-HDS with Autograft vs. CHOP-R in High-Risk Follicular Lymphoma: Prolonged Survival in Both Arms and a High Rate of Long-Term Disease Free Survivors

Background A prospective trial conducted in 2000-2005 showed no survival advantage at a median 4-yr follow-up by high-dose sequential chemotherapy with Rituximab and autograft (R-HDS) compared to conventional cyclophosphamide, doxorubicin, vincristine, prednisone supplemented with Rituximab (CHOP-R) as first-line therapy in high-risk Follicular Lymphoma (FL) patients aged <60 yr. Results have been now updated at 13-yr median follow-up. Methods Between March 2000 and May 2005, 136 patients had been enrolled in the multicenter randomized study, launched in Italy among Centers affiliated to GITMO (Gruppo Italiano Trapianto Midollo Osseo) and/or to the Italian Lymphoma Intergroup known as IIL (now joined into FIL, Fondazione Italiana Linfomi). The trial was registered at www.clinicaltrials.gov as no. NCT00435955. The long-term outcome was assessed by taking information from 28 out of 29 participating Center on the clinical status of each patient entered the prospective trial. Findings As of February 2017, 88 (66%) patients were alive, with Overall Survival (OS) of 66.4% at 13 yrs, without significant difference between R-HDS (64.5%) and CHOP-R (68.5%). So far, 46 patients died, mainly due to disease progression (47.8% of all deaths), secondary malignancies (3 solid tumor, 9 Myelodysplasia/Acute Leukemia, 26.1% of all deaths), other toxicities (23.9% of all deaths). Complete remission (CR) was documented in 98 (73.1%) patients and was associated with OS, with 13-yr estimates of 77.0% and 36.8% for CR vs. no-CR, respectively. Molecular remission (MR) was documented in 39 (65%) out of 60 evaluable patients, also MR achievement was associated with improved OS. In multivariate analysis, CR achievement had the strongest impact on survival, along with younger age and female gender (borderline value). Overall, 50 patients (37.3%) survive in absence of disease recurrence (18 CHOP-R, 32 R-HDS). Interpretation This is the longest follow-up ever reported on FL upfront-treated with Rituximab-chemotherapy and demonstrates an unprecedented improvement in OS compared to the pre-Rituximab era, regardless of the use of intensified or conventional treatment. CR achievement resulted the most important factor for prolonged survival. Unexpectedly, a high proportion of patients had prolonged survival in 1st CR, raising the issue of curability in FL. Funding: This work was supported in part by Ministero Italiano Universita e Ricerca (MIUR), Rome, Italy (grant PRIN 2010-2011, pr. N.: 2010B5B2NL) and by Banca del Piemonte (Torino, Italy): their financial support covered the cost for the present update of the study. The initial clinical trial (March 2000 - May 2005) was made possible by Compagnia di San Paolo (Torino, Italy), Regione Piemonte (Torino, Italy), and by Roche (Milan, Italy), which provided free rituximab for all the patients. We are indebted to GITMO (Gruppo Italiano Trapianto Midollo Osseo) and to IIL, now merged into FIL (Fondazione Italiana Linfomi) for their fundamental participation in the development and completion of the study. Declaration of Interest: M. Ladetto: honoraria from Abbvie, Acerta, Amgen Archigen Celgene ADC therapeutics, Gilead Novartis J&J Roche Roche Diagostics Sandoz Takeda. Francesco Di Raimondo honoraria from Roche Alessandro Rambaldi Travel support, sponsored lectures and advisory board meetings: Roche, Amgen, Pfizer, Novartis, Celgene. Corrado Tarella Travel support from Amgen and Celgene Ethical Approval: The Institutional Review Boards of all the participating centers approved the study.