Anthracycline-Fludarabine Containing Regimens with or without Rituximab in the Treatment of Advanced Follicular Lymphoma Patients

Introduction
Recent  experiences  suggest a stepwise improvement in survival outcomes for patients with follicular lymphoma with the introduction of new treatment options.  Here we report the results of 2 subsequent phase II trials conducted by Gruppo Italiano Studio Linfomi (GISL) utilizing CHOP-like plus fludarabine regimens with or without rituximab. Our results confirm an improvement in CR rate and show better survival with the addition of rituximab.

Materials and Methods
The BACOP/FND study (bleomycin, epidoxorubicin, cyclophosphamide, vincristine, prednisone/  fludarabine, mitoxantrone, dexamethasone), registered 144 patients between 1997 and 2002. After 2 BACOP, patients received  4 cycles of FND. Then, responsive patients were randomized to observation  or to receive alpha-IFN + dexamethasone. The BACOP/FR ( BACOP + fludarabine and rituximab) study registered 94 patients  between 2002 and 2006. After 3 BACOP, patients in PR or in CR BCL2⁺ , received 4  cycles of FR. For both trials, eligible patients had histological documented, previously untreated, advanced follicular lymphoma.
Results
BACOP/FND. Response rates by intent to treat analysis were: ORR  90%, CR 62%. No  differences were observed in FFS and OS between the 2 arms of maintenance. At the time of the last follow up, 35 patients had died, 5 lost at follow up, while 85 patients are still alive, 81 with ongoing response and 4 with progressive disease. After a median follow up of 60 months, FFS and OS were  53% and 77% at 4 years, respectively.
BACOP/FR . Response rates by intent to treat analysis were: ORR  93%, CR 79%. At the time of the last follow up, 3 patients had died, 3 patients were lost at follow up, 60  are still alive with ongoing response and 14 with progressive disease. After a median follow up of 36 months , FFS and OS at 4 years were 56% and 97%, respectively.  
PCR assay for BCL2. Forty two of the 80 patients  were found to be positive for BCL2 in the bone marrow obtained prior to treatment. Of these 42 patients,  25 obtained CR molecularly negative. We observed  an improved FFS rate in patients who became BCL negative after treatment.
Toxicity. The most common toxicities were infections and neutropenia. Overall, the haematological toxicities were transient and reversible.
Comparison between the results of the two trials. We observed a CR rate of 62% and 79% and an OS at 4 years of 77% and 97%, respectively in BACOP/FND versus BACOP/FR, and the differences were statistically significant. Side effects were more frequent in BACOP/FND, however, no significant differences  were observed between the 2 trials.
Discussion
The results obtained with BACOP/FR in comparison with those with BACOP/FND were better in terms of response and overall survival, while overall toxicity did not increase, remaining transient and tolerable. Patients who obtained BCL2 clearance in BACOP/FR showed a better FFS in comparison with patients treated with BACOP/FND.  Further, patients treated with rituximab had a better FFS in comparison with all other patients treated only with chemotherapy. Finally, although conclusion between non randomized groups may depend in differences in observed and unobserved prognostic features, we believe that  statistical analysis of our results, suggest that the addition of rituximab to anthracycline-fludarabine  containing chemotherapy regimen has a favourable effect on prognosis of advanced follicular lymphoma