Front-Line Chemo-Immunotherapy Rituximab-FC + Rituximab Maintenance in Patients with Untreated Advanced Stage Non Follicular Lymphoma (INFL): Update of a Prospective Study of the Intergruppo Italiano Linfomi and Roche (ML18324).

Fludarabine in combination with cyclophosphamide (FC) plus rituximab (R) is an effective treatment for newly diagnosed as well as relapsed low-grade non-Hodgin's lymphoma (NHL). The role of maintenance treatment with R has been demonstrated in relapsed/resistant follicular NHL improving overall and progression-free survival. We investigated efficacy and safety of the chemo-immunotherapy FCR followed by rituximab maintenance treatment in patients with advanced untreated indolent B-cell non follicular lymphomas (INFL).

from July 2005 to May 2007, 47 pts whit untreated advanced stage INFL (23 lymphocytic, 20 limphoplasmacytic and 4 nodal marginal zone NHL) were enrolled by 10 IIL centres, in an open label, single arm, multicenter phase II study. Treatment plan was: 6 courses of FC (Fludarabine, 25 mg/m² i.v. plus Cyclophosphamide, 250 mg/m², days 2–4) every 28 days plus 8 doses of R (375 mg/m² , day 1 every FC cycle and day 14 of cycles 4 and 5) followed by R maintenance (375 mg/m² every two months for 4 doses). Prophylactic antibiotic treatment with cotrimoxazole (two tablets three times a week) and antifungal profilaxis with itraconazole was planned from the beginning of chemotherapy to three months later or until normalization of CD4 count. The primary endpoint of this study is the percentage of failure free patients after two years from the treatment start.

all the patients were evaluable for safety analysis and 46/47 pts were evaluable in terms of intention to treat analysis. Median age was 59 years (31–68) and M/F ratio was 28/18; stages II/III/IV were 2/2/44; B symptoms and splenomegaly were observed in 11 and 14 pts respectively; FLIPI scores were: 0–1 in 16 pts (34.8%), score 2 in 19 pts (41.3%) and score ≥ 3 in 11 pts (23.9%). Forty-one patients (87.2%) completed the planned therapeutic program; the remaining 6 patients stopped the treatment for SAE (4 pts) or for other reasons (2 pts) after 9 courses (1 pt), 8 (1 pt), 6 (2 pts), 3 (1 pt) and 1 (1 pt). Overall response at the end of treatment was 80.4% with 60.9% CR and 19.5% PR. One patient relapsed during maintenance phase. All the patients are still alive.

A total of 279 courses of FC were given to 47 patients. All the patients presented at least one toxic/adverse events (AE); 11 pts developed 12 serious AEs, but only 6 were related to therapy. Seventeen pts had to interrupt (4 pts), delay or reduce therapy. Three hundred twenty related AEs were registered: grade 1–2: 228 events; grade 3–4: 92 events. Among these last the most frequent was neutropenia: 30 pts presented 83 episodes whose grade 3–4 related to the therapy were 58. During maintenance phase, 4 episodes of neutropenia occurred (2 of grade 3–4). Sixteen pts presented 31 infective episodes; the most frequent were: 5 Herpes zoster infections, 5 pneumonia (1 mycotic) and 4 urinary tract infections.

in a series of INFL at diagnosis, FCR regimen is effective with a very high CR rate. The toxicity was acceptable and the schedule can be considered safe although the frequence of neutropenia and infective events require a close surveillance. The next year of follow-up will allow us to establish the failure free survival after two years from the treatment start.

Vitolo:Roche: Lecture fees. Morra:Roche: Lecture fees.