Potentially Cured Follicular Lymphoma (PC-FL). an Analysis of 56 Cases with Prognostic Factors Evaluation
Authors: Ferrari Samantha , Tucci Alessandra , Valimberti Gloria , Anastasia Antonella , Bottelli Chiara , Petullà Marta , Motta Marina , Passi Angela , Rossi Giuseppe 
Published: October 2019

Abstract
Introduction: Advanced stage follicular lymphoma (FL) is generally considered incurable. Although multiple remissions after treatment are possible, relapse is considered the rule, and the time to progression tends to become shorter after each relapse (Johnson, JCO 1995). Over the last decades, after the introduction of monoclonal anti-CD20 antibodies and of better treatment programs, the prognosis of FL has markedly improved from a median OS of 7 years to a 10-year OS rate >80%. Moreover, clinical observations of patients (pts) experiencing very long progression-free periods despite more than one previous treatment failure, have become not rare, suggesting that some pts could achieve operational FL cure. To assess the frequency of those prolonged long-term remissions and search for potential predictive factors, we have retrospectively analyzed the consecutive series of pts with FL seen at our institution.
Methods: FL pts, aged >18 years, in maintained remission for more than 5 years after at least two lines of treatment were selected as "potentially cured" FL (PC-FL) and analyzed in detail. Their main characteristics at diagnosis and at last relapse, the different lines of treatment received and the time intervals (time to next treatment: TTNT) between them, were recorded and compared with those of FL pts seen in the same period (control group). Treatment strategies used were grouped and defined as follows: radiotherapy or surgery, for stage I-II (local), anthracycline and/or alkylating agents regimens (Alk/Ant), purine analogues regimens (Pur), monoclonal antibodies/radioimmunoconjugates as single agent (MoAb), autologous transplantation (ASCT).
Results and discussion: Among 385 consecutive FL pts seen from January 1987 to December 2011, 56 (14,5%) met criteria for PC-FL. Their clinicopathological features at diagnosis, compared to controls, are shown in Table I. There were no significant differences except for a younger age (51 vs 58 years, p<0.00016) and for a lower frequency of grade 3a histology (p=0.04) in PC-FL pts. First line treatment used did also not differ (p=0.29). Among PC-FL pts, 33 received two, 16 received 3 and 7 more than 3 treatment lines. The median duration of last complete remission was 118+ months, whereas the median duration of the remission preceding the last treatment had been 24 months; disease duration from diagnosis to the last relapse preceding long term remission had been 50,5 months. The last treatments received before long-term remission were variable including local in 10 (18%), Alk/Ant in 5 (9%), Pur in 11 (19%), MoAb in 10 (18%) and ASCT in 20 (36%). Pts characteristics at last relapse and remission duration were similar among different treatment subgroups, except that more pts in localized stage received local treatments. Comparing clinicopathological characteristics of PC-FL pts at diagnosis and at last relapse there were no differences except for FLIPI score, which was significantly lower at relapse (low FLIPI 34% at diagnosis, 68% at relapse, p=0.002). First-line and last treatments were similar except that more pts underwent ASCT as last treatment, as expected since frontline ASCT is not recommended. In 10 pts TTNT after first-line was longer than 5 years and 7 of them are still in prolonged remission (median 11+ years) after second-line treatment, representing a particularly favorable subgroup. In 26 (46%) of PC-FL pts TTNT was shorter than 24 months after first line therapy. Among 14 of them who received R-chemo at diagnosis (POD24, Casulo, JCO 2015), 8 (57%) obtained long remission after ASCT, given in second line in six. Conversely, ASCT was used in only 1 of 12 pts not receiving Rituximab at diagnosis.
Conclusions: Approximately 15% of FL pts could currently achieve a very prolonged remission of about 10 years, even after multiple relapses. Its duration was 5x that of the last treatment line and more than twice that of active lymphoma, strongly suggesting the possibility of having achieved lymphoma cure. Younger age and grade 1-2 FL histology at diagnosis, and FLIPI low risk at relapse favored the achievement of PC-FL status. No specific treatment was associated with PC-FL and even an early relapse after first line treatment did not preclude to reach PC-FL, although early ASCT may be more effective for POD24 patients. Whether the achievement of PC-FL status may be related to biological factors will be interesting to be investigated in the next future.

Disclosures
Rossi: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria.