Low-Intensity Fludarabine, Cyclophosphamyde, Rituximab (FCR) as Front-Line Treatment for Follicular Lymphoma. Efficacy and Toxicity Profile of the Oral Versus Intravenous Administration.
Authors: Marin-Niebla Ana , Rios-Herranz Eduardo , de la Cruz Vicente Fáatima , Cerezuela Paula , Falantes Jose Francisco , Martino Mariluz , Espigado Ildefonso , Ispizua Alvaro Urbano 
Published: October 2019

Abstract
Abstract 2690
Poster Board II-666

Background
Despite of all the strategies carried out in the management of Follicular Lymphoma (FL), this disease has remained incurable, and still none of the schedules tested in newly diagnosed patients has yielded a “standard” front-line regimen for FL.
The synergistic association of Fludarabine-Cyclophosphamyde (FC) is known as one of the most active regimens for FL, and the addition of Rituximab (R) has improved the efficacy of FCR combination. However, the associated severe myelosuppression when this regimen is administered at standard doses has clearly limited a more extended use. Therefore, different low-intensity schedules have been tested in order to decrease toxicity.
The availability of oral F has allowed a more adequate outpatient management of FCR regimen, with expected similar efficacy as the standard intravenous administration. Oral FCR would carry a better compliance and quality of life during treatment, and of course lower hospital expenses.

Aims
1) To evaluate efficacy and safety of a lower intensity FCR in first-line for FL. 2) To assess the potential advantages in efficacy and toxicity profile of the oral versus intravenous administration.

Methods
Follicular lymphoma (WHO histological grades 1-2) patients (pts) aged = 18, previously untreated, WHO-PS= 2, = 2-fold renal and hepatic function values were eligible.
Outpatient treatment: Intravenous FC/ FCR (iv): Fludarabine (F) 25 mg/m2/d plus Cyclophosphamyde (C) 250 mg/m2/d (d 1-3), Rituximab (R) 375 mg/m2 (d1) × 4 28-day cycles; Oral FCR (po): F 30 mg/m2/d plus C 175 mg/m2/d (d 1-3), R 375 mg/m2/ (d1) × 4-6 28-day cycles. Stages III-IV and FLIPI= 3 patients at diagnosis achieving CR1 received R maintenance: R 375 mg/m2 q/3 months x 8 doses. Toxicity was recorded at every cycle and thereafter during follow-up, and classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0.

Results
From march 1999 to august 2009, 92 pts were prospectively included: M age: 57 (32–81), M:F 44:48, Stages III-IV: 81 (88%), B-symptoms: 29.3%, FLIPI= 3: 36 (39.1%). BM and PB involvement: 52 (56.5%) and 31 (33.7%) respectively. Bcl-2 rearrangement by PCR and/or FISH: 46 (50%).
Thirty-seven (40.3%) pts received FC or FCR iv; 55 (59.7%) FCR po. M number of cycles: 4 (3-4) FC/FCRiv; 6 (3-6) FCRpo.
Eighty-six pts were evaluable for response: ORR rates FCRiv versus FCRpo: 89.2% vs 100% (p=0.03); CR rate FCRiv versus FCRpo: 54% vs 70.9% (p=0.01).
Regarding grades 3-4 (g3-4) toxicity, neutropenia was the most frequent and limiting AE: 53/86 pts presented neutropenia g3-4: 21 (56.7%) and 32 (65.3%) in FCRiv and FCRpo respectively (p=0.02). However, infection rate was 35.1% in FCRiv and 30% in FCRpo (NSD), with a tendency to a higher severity and even causing 1 death FCRiv (NSD). Grade 3-4 thrombocytopenia occurred in 7 FCRiv and 1 FCRpo pts (p=0.03), with severe hemorrhage in 2 FCRiv pts (1 subaracnoid and 1 intestinal in a patient with colon angiodysplasia), and anemia g3-4 in 5 FCRiv and 1 FCRpo (p=0.02). Liver toxicity occurred only with g1-2, and no renal toxicity at all was observed.
Fifty-three pts received R-Maintenance: FCRiv: 25/37 (67.5%), FCRpo: 28/49 (57.1%). Withdrawal of R-maintenance occurred in 21 pts (12 FCRiv; 9 FCRpo) due to neutropenia and mild but recurring infections in 18 (85.7%) and in 3 pts due to progression.
Four pts relapsed with a M TTP: 13 m (9–48); and 3 pts died (1 infection, 2 progression).
Transformation to aggressive NHL occurred in 2 pts, and 1 patient was diagnosed with AML/MDS 4 years after ASCT.
With a MFU: 25.7 m (0.3–119.4), overall survival (OS) was 95.4% (IC 95% = 9.3–100%), mean OS= 114.6 m (IC95% 109.3–119.9) and event-free survival (EFS) -considering progression, relapse or death- was 85.3% (IC95% 73.7–96.8%), mean EFS= 106.2 m (IC95% 96.6–115.8 m. No significant differences were found between oral and iv FCR.

Conclusions
1) Low-dose FCR is a potent first-line and safe regimen for FL (including pts> 60 yo), with very high ORR and CR rates. Oral low-dose FCR shows better results (ORR and CR) than FCRiv in our series.
2) Although neutropenia remains the major concern with this regimen, oral FCR is associated to a lower incidence of mild and severe infections.
Oral low-dose FCR appears as an effective outpatient treatment for untreated FL, with manageable toxicity.

Disclosures:
No relevant conflicts of interest to declare.