Factors Prognostic for Response and Event Free Survival and Treatment Related Toxicity in 306 Patients with Follicular or Mantle Cell Lymphoma Randomized to Single Agent Rituximab Given at the Standard or at a Prolonged Schedule.

We analyzed the clinical and biological prognostic factors for efficacy and described the toxicity of treatment by study arm for 306 patients participating in two identical and parallel trials, one in follicular (FL) and one in mantle cell lymphoma (MCL). Chemotherapy naïve or pre-treated patients were treated with 4 weekly doses of rituximab (induction). Those responding or with stable disease were randomized to either no further treatment (arm A) or 4 more doses of rituximab given at 2-month intervals (arm B). Characteristics of the patients (4 variables), previous treatment (6 variables), disease (9 variables), histology (26 variables), blood cell counts (6 variables), lymphocytes subsets (5 variables), blood chemistry values (8 variables) and Fc receptor phenotype (3 variables) were collected at trial entry and during follow-up.We constructed multivariate models to identify prognostic factors for response and for event-free survival (EFS). In 273 eligible and evaluable cases the response rate was 44%. In these patients, the favorable prognostic factors for response were a disease diameter < 5 cm (odds ratio =2.5, p=0.0006), a follicular histology (OR=2.4, p=0.0029), a normal hemoglobin (OR= 2.4, p=0.0033) and a low blood lymphocyte count (OR=2.0, p=0.02), all determined at treatment start. At a median follow up of 54 months, the EFS for all 212 randomized cases was 9.1 months in arm A and 15.4 months in arm B (p=0.005). Factors prognostic for EFS in a multivariate model based on 162 patients were: having responded to rituximab induction (hazard ratio=0.44, p<0.0001), Ann Arbor stage < IV (HR=0.48, p<0.0001), an Fc receptor with the VV phenotype at position 152 (HR=0.55, p=0.02) and a high blood lymphocyte count at randomization (HR=0.67, p=0.04). During treatment, B-cells were suppressed as expected (i.e. up to week 8) to a median level of 21 % compared to the value at treatment start (p<0.0001). After one year, patients in arm A tended to recover better (median level 81%, 22 patients) than patients in arm B (median level 50%, 35 patients). Accordingly, after 1 year the median IgM level decreased to 73% of baseline in arm B (50 patients) whereas in arm A the median level recovered to 100% (30 patients). Serious adverse events possibly or probably related to treatment were 13 infections, 6 cardiac events and 5 intestinal complications, resulting in 7 deaths. Further 11 serious events were all non fatal and of various nature (infusion reaction, cytopenias, renal, neurologic, metabolic). The incidence of these reactions was similar in arms A and B. There were 16 cases of second tumor: 10 in patients receiving induction only, 6 in patients receiving prolonged treatment. At 4.5 years median follow-up, we confirm that single agent rituximab is a valid treatment, particularly for patients with follicular histology, low tumor load and normal hemoglobin. A prolonged schedule improves EFS in responding patients without causing additional toxicity, despite of a prolonged inhibition of the cellular and humoral immunity. The phenotype of the Fc receptor is confirmed to be a prognostic factor for EFS, but its determination is presently not routinely feasible.