Front-Line Brief Chemo-Immunotherapy Rituximab (R)-FND + Rituximab Consolidation ± Rituximab Maintenance in Elderly Patients with Untreated Advanced Stage Follicular Lymphoma (FL): First Interim Analysis of a Prospective Randomized Study (ML17638)
Authors: Vitolo Umberto , Ladetto Marco , Gamba Enrica , Baldini Luca , Ceccarelli Manuela , Chiappella Annalisa , De Renzo Amalia , Di Raimondo Francesco , Gallamini Andrea , Guarini Attilio , Mantoan Barbara , Martelli Maurizio , Alvarez Isabel , Orsucci Lorella , Parvis Guido , Petrini Mario , Pinto Antonello , Pogliani Enrico Maria , Pozzi Samantha , Pulsoni Alessandro , Rigacci Luigi , Tucci Alessandra , Zaja Francesco , Gallo Eugenio 
Published: October 2019

Abstract
Introduction: FL is common in elderly and the aim of treatment is usually palliation. With the aim to plan a treatment devised for elderly patients (pts) with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy R-FND + R consolidation followed by randomization between R maintenance or observation.
Patients and methods: From January 2004 to July 2007, 206 elderly pts (age 60–75) with advanced stage FL at diagnosis were enrolled into 33 IIL centres. An interim analysis was planned to evaluate safety and response of chemo-immunotherapy before randomization, after the first 80 randomized pts (January 2004 to December 2005). This analysis included 95 pts recruited within this time frame. Treatment plan was: 4 courses of R-FND (R 375 mg/m2 d0, Fludarabine 25 mg/m2 dd1-3, Mitoxantrone 10 mg/m2 d1, Dexamethasone 10 mg dd1-3) followed by consolidation with 4 weekly R infusions; responding pts (CR+CRu+PR) were randomized between R maintenance (375 mg/m2 every 2 months for 4 doses) or observation. PCR molecular monitoring for IgH/Bcl-2 gene rearrangement was performed on bone marrow (BM) samples at diagnosis, after R-FND, after R consolidation and during maintenance/observation time.
Results: Median age was 65 years (range 60–75); 39 males; advanced stage II 14%, stage III 16% and stage IV 70%; 63% had BM involvement and 20% B symptoms. According to FLIPI pts were: 8% score 1, 32% score 2 and 60% score ≥ 3. PCR analysis was carried out in 79 pts at diagnosis: 58% were Bcl-2 positive and 42% were not. Eighty pts were randomized between maintenance or observation; 15 pts were not due to: progressive disease 6, stable disease 2, adverse events 3, concomitant neoplasia 1, withdrawal of consent 1, lost 2. Overall response after R-FND + R was achieved in 80 pts (84%) with 68 (71%) complete remissions (CR+CRu) and 12 (13%) partial remissions (PR). Thirty-seven pts were in PR or SD after 4 R-FND, 20 of them (54%) converted to CR following further R consolidation. Of the 46 pts Bcl-2 rearranged at diagnosis, PCR negativity was achieved in 36 (78%) after R-FND + R consolidation. A total of 457 courses of R-FND and R were given to 95 pts. The most frequent severe toxicity (CTC grade 3–4) was neutropenia reported in 25% of the courses. Nevertheless only 6 serious infections were recorded. Pulmonary and cardiac toxicities were < 1%. Rituximab infusion related reactions (any grade) were seen in 9% of the courses and required R discontinuation in only 2 pts. So far 92 pts are alive and 3 have died of lymphoma.
Conclusions: A brief course of chemo-immunotherapy R-FND + R consolidation is safe and effective with a high CR rate and PCR negativity in elderly pts with untreated FL with advanced stage and high FLIPI score. Future analysis of the entire study will give further information on the role of R maintenance after R-chemotherapy in such cohort of patients.