Safety, Efficacy and Rituximab Levels Following Chemoimmunotherapy (Rituximab + FAB Chemotherapy) in Children and Adolescents with Mature B-Cell Non-Hodgkin Lymphoma (B-NHL): A Children’s Oncology Group Report

We previously demonstrated that children with mature B-NHL with local, intermediate and advanced disease have a 99%, 92%, and 80% 5 yr EFS, respectively, with FAB multiagent chemotherapy (Gerrard/Cairo/Patte et al, Br J Haem, 2008, Patte/Gerrard/Cairo et al, Blood, 2007, and Cairo/Gerrard/Patte et al, Blood, 2007). Despite these outstanding clinical results, the incidence of grade III/IV mucositis and infection ranges from 40–70% resulting in prolonged hospitalization and increased costs. Furthermore, subsets of pts have a poorer prognosis; poor COP response, PBML, combined BM/CNS, high tumor burden by LDH 2 upper limits, and/or complex cytogenetics. We previously demonstrated CD20, the receptor to the chimeric antibody rituximab, is expressed in over 98% of all children with mature B-NHL (Perkins/Cairo et al, Clin Adv Hem, 2003). In adults (30–60 yrs) and elderly adults (□ 60 yrs) with DLBCL, the addition of rituximab to CHOP or CHOP like chemotherapy has significantly increased the EFS and OS (Pfreundschüh et al, Lancet Oncology, 2006 and Coiffier et al, NEJM, 2002, respectively). We therefore hypothesized that the addition of rituximab (anti-CD20 antibody) to the FAB chemotherapy backbone in children and adolescents with newly diagnosed intermediate risk (restricted to Stage III/IV) mature B-NHL would be safe and well tolerated and result in 90% 3 yr EFS. We now report the results of 48 pts with stage III/IV (<25% blasts in BM and no CNS) enrolled on COG ANHL01P1. Therapy consisted of FAB Group B4 therapy (adria 1 hr infusion) as we have previously described (Patte/Cairo et al, Blood, 2007) with the addition of rasburicase (0.2 mg/kg/dose), generously supplied by Sanofi-Aventis, during the COP reduction and rituximab 375 mg/m²/dose, generously supplied by Genentech, day -2 and ay 0 in COPADM2 and day 0 in CYM 1 + 2 (4 doses, subpilot) and day -2 and day 0 in COPADM 1 + 2 and day 0 in CYM 1 + 2 (six doses, pilot), respectively. Rituximab levels were measured at baseline, 30–60 minutes after Day -2 and Day 0 in COPADM 1 (pilot) + 2 (subpilot) and 1, 3, and 6 months after the last dose of rituximab and measured by ELISA with a purified polyclonal goat anti-rituximab antibody as the capture reagent and goat antibody to mouse IgG-conjugated to horseradish peroxidase as the detection reagent (detection limit of 0.5 mcg/mL). Toxicity was measured according to the NCI CTCAE 3.0 and EFS and OS were calculated by the KM method. Median age 11 (1–23 yrs), M/F (4:1), Burkitt (59%), DLBCL (24%), PMBL (5%), 11% NOS. LDH 2 time upper institutional limits (45%). The addition of rituximab was safe and well tolerated with 274 infusions and there were no SAEs probably or definitely attributed to rituximab. The incidence of grade III/IV mucositis during COPADM 1 + 2 was 14 and 11%, respectively, compared to 43 and 31% in FABLMB96. Similarly, the incidence of grade III/IV neutropenia/infection during the same two courses was 47% and 29%, respectively, compared to grade IV infection, 49 and 25% in FABLMB 96. The incidence of TLS was only 2.5% during COP-rasburicase reduction. Probability of 1 yr EFS and OS was 96% (95% CI: 88–100%) and 100%, respectively compared to 86% EFS for Stage III/IV intermediate risk pts in FABLMB 96 study. The peak rituximab level 30–60 minutes after the first infusion on day -2, day 0 in COPADM 1 + 2 was 220.4±10.5, 307.7±377.6, 267.3±66.0, and 402.1±38.6 mcg/mL, respectively. The trough levels prior to the second rituximab dose in COPADM 1 + 2 was 128.9±16.9 and 208.5±15.3 mcg/mL, respectively. The levels 1, 3 and 6 months post the last dose of rituximab was 75.0±14.7, 13.0±3.3 and 1.1±0.15 mcg/mL, respectively. There was no significant difference in rituximab levels in BL vs. other mature B-NHL and age < 8 vs 8 yrs. In summary, the addition of rasburicase to FAB COP reduction and rituximab to FAB COPADM 1 + 2 and CYM 1+2 is well tolerated. Rituximab levels are comparable to levels in adults, and in the serum up to 3 months past the last dose. The addition of rituximab to FAB therapy is associated with a superior EFS and OS as compared to similar historical groups of patients and histology treated with FAB chemotherapy alone. Future randomized studies will be required to determine if the addition of rituximab to the FAB chemotherapy backbone in children with intermediate and advanced mature B-NHL will significantly increase EFS/OS and/or facilitate the reduction of intensity of cytotoxic chemotherapy without a diminution in long-term EFS.