Brief Chemoimmunotherapy Rituximab (R)-FND ± R Maintenance as First Line Treatment in Elderly Patients with Advanced Follicular Lymphoma (FL): Preliminary Analysis of a Prospective Randomized IIL Trial
Authors: Vitolo Umberto , Ladetto Marco , Boccomini Carola , Gamba Enrica , Alvarez Isabel , Baldini Luca , Chiappella Annalisa , Corradini Paolo , De Renzo Amalia , Di Raimondo Francesco , Evangelista Andrea , Gallamini Andrea , Guarini Attilio , Leone Giuseppe , Liberati Anna Marina , Mantoan Barbara , Martelli Maurizio , Orsucci Lorella , Parvis Guido , Petrini Mario , Pinto Antonello , Pogliani Enrico , Pozzi Samantha , Pulsoni Alessandro , Rigacci Luigi , Tarella Corrado , Tucci Alessandra , Zaja Francesco , Gallo Eugenio 
Published: October 2019

Abstract
Introduction: we investigated efficacy and safety of a brief chemo-immunotherapy R-FND with R consolidation followed by randomization between R maintenance or observation in a study specifically devised for elderly.
Material and methods: From January 2004 to December 2007, 235 pts (age 60–75) with untreated advanced stage FL were enrolled into 33 IIL centres and written informed consent was obtained. Treatment plan was: 4 courses of R-FND (375 mg/m2 Rituximab on day 0, 25 mg/m2 fludarabine on dd 1–3, 10 mg/m2 mitoxantrone on day 1, 10 mg dexamethasone on dd 1–3) every 28 days followed by 4 weekly R consolidation; responding pts (CR+CRu+PR) were randomized between R maintenance (375 mg/m2 every 2 months for 4 doses) or observation. Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement was performed on bone marrow (BM) at diagnosis, after R-FND and R consolidation and during maintenance/observation. Preliminary analysis was performed on 158 pts enrolled in the first 3 years of study up to 31, December 2006.
Results: Median age was 65; stage III/IV 19/68%; 57% had BM involvement, 20% B symptoms and 19% LDH >normal; according to FLIPI 11% were at low risk, 32% at intermediate and 57% at high risk. PCR analysis was done in 148 pts at diagnosis: 80 (54%) were Bcl-2 positive. Relevant concomitant illness was observed in 4% of pts, mainly hypertension and chronic pulmonary obstructive disease. Overall response, CR rate and PCR negativity associated with CR after R–FND and R consolidation are shown in the following table. R consolidation converted in CR 28 (45%) of 62 PRs after R-FND.
A high CR rate was achieved also in poor prognosis pts (CR according to FLIPI: Low 63%, Intermediate 75%, High 63%). One hundred and thirty-one pts were randomized between maintenance or observation. Twenty-seven patients were not randomized because of: 12 stable/progressive disease, 9 adverse events, 2 concomitant neoplasia, 2 lost at follow-up, 1 non-compliant and 1 withdrawal of consent not due to toxicity. PCR quantitative analysis is still ongoing; preliminary results in the first 40 pts showed a rapid decrease of Bcl-2 rearrangement below the threshold value in 36 pts after R-FND and in 39 pts after R consolidation. The most frequent CTC grade 3–4 toxicity was neutropenia in 26% of 745 courses, with only 11 serious infections; there was no evidence of cumulative haematological toxicity during treatment. R related reactions were seen in 11% of the courses with R discontinuation in only 2 pts. So far 152 pts are alive, 5 died of lymphoma and 1 of hepatic failure in HBV reactivation.
Conclusions: A brief chemo-immunotherapy R-FND + R consolidation is safe and effective in elderly pts with untreated FL with high CR rate also in high risk pts. Brief chemo-immunotherapy R-FND led to a rapid reduction of Bcl-2 rearrangement in the majority of pts. Correlation between quantitative PCR and clinical response and outcome will be presented. The results of the whole study will provide insights on the role of R maintenance after brief chemo-immunotherapy in such cohort of pts.
N ORR CR Qualitative PCR- associated with CR (66 pts evaluable for clinical and molecular response) Baseline 158 - - - R-FND x 4 158 142 (90%) 80 (51%) 27 (41%) R consolidation 136 131 (83%) 105 (67%) 43 (65%)