Safety and Tolerability of the Combination of Interleukin-2 (rIL-2) and Rituximab in Patients with Refractory/Relapsed Follicular Non Hodgkin Lymphoma. Preliminary Data from the Pearl Study.

Abstract

Background: Rituximab (R) is a chimeric IgG1 mAb antibody directed against the CD20 antigen, expressed on greater than 90% of all B-cell lymphomas. Despite the encouraging results, responses to R monotherapy are usually partial and of limited duration. Therefore, new strategies to increase the clinical effectiveness of R are being explored. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of Rituximab's activity. Studies (Dunne et al. J Immunol 2001; 167:3129–3138) have provided evidence that rIL-2 can augment ADCC and thereby enhance the efficacy of antitumor antibodies such as R.Methods: A multicenter Phase II trial was conducted to evaluate the efficacy of rIL-2+R compared to R alone. Subjects were R naïve with follicular lymphoma who were relapsed or unresponsive to previous chemotherapy. Subjects were randomized 1:1 to either IV R (375 mg/m2) monotherapy (n=29) once weekly (weeks 1–4) or the same dose and schedule of R in combination with SC rIL-2 (n=27) three times weekly at 14 MIU (weeks 2–5) followed by 10 MIU (weeks 6–9). The primary and secondary objectives were to compare overall response rate (ORR) and time to progression (TTP) for subjects receiving rIL-2+R with those receiving R monotherapy. A further objective was to evaluate the safety of an 8-week SC administration of rIL-2 with 4 week IV administration of R. From October 2004 until May 2005, 69 participating centres enrolled 56 patients.Results: Twenty-seven subjects in the combination arm received a mean cumulative dosage of 82.8 MIU (range: 0–96) of rIL-2. The most common adverse events (AEs) observed in this arm were fever, chills and injection site reactions. Safety was comparable in the combination and monotherapy arms for grade 1 (33 vs. 38%) and grade 3 (11 vs. 13%) AEs. Treatment related grade 2 AEs were more common in the combination arm (44% vs 0%) with most related to skin and subcutaneous tissue reactions. No grade 4 AEs were reported. Five patients were withdrawn from the study, three in the combination arm and two in R alone group for disease progression (2 subjects in the combination arm and 1 in the R monotherapy), adverse event (1 in the combination arm related to a R reaction) and withdrawal of consent (1).Conclusions: This preliminary data confirm that the addition of rIL-2 to R therapy appears to be safe and well tolerated. The majority of the subjects were able to receive the total dose of rIL-2. The observed adverse events were manageable and related to skin reactions and flu-like symptoms, as expected with rIL-2. The main reason for study treatment discontinuation was disease progression. Trial assessment is ongoing.