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13-year update of the R-HDS vs. CHOP-R trial in FL
with rituximab is currently the first choice for the upfront treatment of advanced stage FL, ensuring prolonged sur- vival, with adequate information about possible late side effects.
In our whole series, lymphoma progression remained the most frequent cause of failure, accounting for 47.8% of all causes of death. This is in line with several previous obser- vations, including a recent report on a large series of FL.31 Indeed, lymphoma progression was much more often responsible for fatal outcome among patients allocated to the CHOP-R arm, with 65% of all deaths, compared to the R-HDS arm with only 35% of all deaths. On the other hand, early and late toxicities were the most frequent cause of failure for patients in the R-HDS arm, which counterbal- anced the increased anti-lymphoma activity of R-HDS compared to CHOP-R, resulting in analogous overall sur- vival for the two treatment arms. Rituximab maintenance is now used with the aim of reducing disease recurrence risk.32 In addition, both bendamustine and the novel anti-CD20 obinutuzumab antibody have been proposed as more effec- tive first-line treatments compared to R-CHOP.33,34 In partic- ular, bendamustine is now frequently used as first-line treatment in place of the CHOP schedule. However, no evi- dence is currently available to suggest that these novel treat- ment strategies will substantially reduce the risk for dis- ease-related deaths without affecting the treatment safety profile in the long term. Indeed, our update reinforces the need for prolonged observation to define the true survival advantage of any novel treatment for FL. Novel treatments for FL should combine potent anti-lymphoma activity along with low risk of both early and late toxicities.
Most late toxicities were secondary malignancies associ- ated with the use of high-dose therapy with autograft deliv- ered either upfront in the R-HDS arm or as salvage therapy in a good proportion of patients failing after upfront CHOP- R. This finding is in line with previous reports, including a retrospective study from the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) group indicating increased risk for secondary MDS/AL in lymphoma patients receiving high-dose therapy and autograft.35 A recent surveillance study by the Spanish Lymphoma Group (GELTAMO) group has further stressed the risk of secondary MDS/AL in FL patients undergoing autograft.36 Moreover, both the GITIL and GELTAMO studies indicated a trend for increased risk for secondary solid tumors when autograft is delivered along with rituximab.35,36 Thus, the risk for late occurrence of secondary malignancy is a main issue in the long-term management of FL patients. This concern must be kept in mind in the long-term assessment of the efficacy
of novel drugs and drug combinations.33,34,37-39
The present study allows identification of the factors
favoring the long-term survival of high-risk FL patients treated with rituximab-containing chemotherapy. Somewhat unexpectedly, CR achievement proved to be the strongest prerequisite for long-term survival. Several recent observations indicate that response to initial treatment along with the achievement of a strong and durable response may favorably affect long-term outcome.31,40-44 The present update clearly demonstrates in a prospective study that CR achievement shows the strongest association with prolonged survival. The importance of the response depth for long-term survival is confirmed by our molecular moni- toring of measurable residual disease (MRD) performed in a subset of patients. Most studies have shown a remarkable prognostic value of MRD assessment in terms of PFS and response duration.9,17,20,45,46 Nevertheless, the impact on OS could not be fully addressed in most studies, usually because of inadequate follow up.47,48 Here, it was possible to demonstrate for the first time that MRD assessment is pre- dictive for both PFS and OS, and that MR was associated with a prolonged survival.
The association of response depth with long-term sur- vival in our FL series is further substantiated by the obser- vation that a good proportion of patients (approx. 37% of the whole series) could survive in their first CR at long term. The DFS curves were definitely promising, with a 13-year estimate as high as 65% in R-HDS-treated patients. Moreover, most patients achieving MR following induction treatment maintained their MR during long-term molecular monitoring. Taken together, these results indicate that an extensive disease response in FL may translate into both prolonged survival and in the long-term persistence of CR; a state that has been described as functional cure in other clinical settings. This in turn raises the issue of the curability of FL, at least in patients with a high-risk clinical presenta- tion such as those selected in the present study.
Funding
This work was supported in part by the Ministero Italiano Università e Ricerca (MIUR), Rome, Italy (grant PRIN 2010- 2011, pr. N.: 2010B5B2NL), and by Banca del Piemonte (Torino, Italy). 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 pro- vided free rituximab for all patients. We are indebted to GITMO (Gruppo Italiano Trapianto Midollo Osseo) and to IIL, now merged into FIL (Fondazione Italiana Linfomi) for their fundamen- tal participation in the development and completion of the study.
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