Sequential Brief Chemo-Immunotherapy FND + Rituximab in Elderly Patients with Advanced Stage Follicular Lymphoma (FL): High Clinical and Molecular Remission Rate Associated with a Prolonged Failure-Free Survival.
Authors: Vitolo Umberto , Boccomini Carola , Ladetto Marco , Pogliani Enrico , Scalabrini Delia Rota , Tarella Corrado , Castellino Claudia , Aglietta Massimo , Astolfi Monica , Carpaneto Andrea , Corradini Paolo , Darbesio Antonella , De Crescenzo Alberto , Levis Alessandro , Liberati Anna Marina , Morandi Sergio , Orsucci Lorella , Pregno Patrizia , Rigacci Luigi , Rossini Fausto , Tonso Anna , Gallo Eugenio 
Published: October 2019

Abstract
Introduction: Elderly patients (pts) with FL do worse than younger ones and the aim of the treatment is usually palliation rather than cure. In order to outline a treatment plan specifically devised for elderly pts with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy FND plus Rituximab.
Patients and methods: from March 1999 to March 2003, 80 elderly pts (age >60) with advanced stage FL at diagnosis were enrolled. Treatment plan was: 4 courses of FND (Fludarabine 25 mg/m2 days 1–3, Mitoxantrone 10 mg/m2 day 1 and Dexamethasone 20 mg days 1–3) followed by 4 Rituximab infusions at 375 mg/m2/week; pts in partial remission received 2 further FND and 2 Rituximab infusions. PCR molecular monitoring for the presence of IgH/Bcl2 and/or Ig heavy chain gene rearrangement was performed at the beginning of the treatment, after FND, after Rituximab and during follow-up time on bone marrow (BM) samples.
Results: median age was 66 (range 60–78); 42 males and 38 females; 16% had stage II, 12% stage III and 72% stage IV disease; 61% had BM involvement; 41% had bulky disease and 24% were at high risk according to IPI score. PCR molecular analysis was performed in 46 pts at diagnosis: 63% were Bcl2 rearranged and 37% were not; IgH rearrangement was detected in 24% of Bcl2 negative pts. Up to date, 70 pts are evaluable. Overall response at the end of treatment was achieved in 63 pts (90%) with 58 pts (83%) in complete remission (CR) and 5 pts (7%) in partial remission (PR). Six pts (9%) did not respond and one patient (1%) died of neutropenic sepsis during a FND course. The addition of Rituximab allowed to increase CR rate from 44% (31 pts) after FND to 83% (58 pts); 73% of responding pts did so with a brief treatment program (4 FND + 4 Rituximab). Patients with adverse prognostic features at diagnosis responded as well as those with more favorable ones with no significant differences in CR rates: BM+ 89%, BM- 79%; low IPI 83%, high IPI 82%; Bulky+ 85%, Bulky- 79%; stage II 90%, III 87%, IV 84%. A thorough molecular analysis is ongoing; to date a molecular marker was detectable in 26 pts. After FND 9/26 pts (35%) did not show anymore BM molecular disease, while PCR negativity was achieved in 23/26 pts (88%) after Rituximab treatment. With a median follow-up of 30 months, 3-yr failure free survival was 50% for the whole series of pts. Failures were observed more frequently in PCR+ pts: all 3 PCR+ pts failed compared to only 7/23 PCR- pts (p=.01). The toxicity was mild with grade 3–4 neutropenia reported in 22% of FND courses, but only 3 pts developed grade 3–4 infections. The whole program was performed in an outpatient setting. Rituximab toxicity was as expected.
Conclusions: a brief course of chemo-immunotherapy is able to achieve high clinical and molecular response rates in elderly pts with low toxicity. The sequential use of FND and Rituximab induces a CR rate >80% also in unfavorable subsets of pts. The achievement of PCR negative status correlates with a lower risk of failure.