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We previously demonstrated that children with mature B-NHL with advanced disease, CNS positive and/or Burkitt leukemia (B-ALL), have an 80% 5 yr EFS with FAB multiagent chemotherapy, however, an attempt to reduce cytotoxic chemotherapy (dose and duration) led to an inferior EFS (Cairo et al, Blood, 2007). The FAB group C therapy backbone is associated with substantial acute toxicity with > 50% incidence of grade III/IV mucositis and infection during both induction cycles and a 5% incidence of toxic deaths during therapy. (Cairo et al, Blood, 2007). Furthermore, pts are at high risk of tumor lysis (TLS) (16%) and renal failure (10%) during initiation of low dose cytoxan/Oncovin/prednisone (COP) reduction therapy and allopurinol prophylaxis (Cairo et al, Blood, 2007). 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 (Pfreundsch?h et al, Lancet Oncology, 2006 and Coiffier et al, NEJM, 2002, respectively). Furthermore, rasburicase is more effective than allopurinol in rapidly reducing hyperuricemia in children and adolescents at high risk of TLS. (Goldman/Cairo et al, Blood, 2001). We therefore hypothesized that the addition of rituximab (anti-CD20 antibody) to the FAB group C chemotherapy induction and consolidation backbone and the addition of rasburicase to reduction therapy in children and adolescents with newly diagnosed high-risk mature B-NHL would be safe and well tolerated. We now report the preliminary results of 42 eligible pts with group C (25% blasts in BM and/or CNS+) enrolled on COG ANHL01P1 through January 2009. Therapy consisted of FAB Group C1 therapy (adria 1 hr infusion) as we have previously described (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 day 0 in COPADM2 and day 0 in CYVE 1 + 2 (4 doses, subpilot) and day -2 and day 0 in COPADM 1 + 2 and day 0 in CYVE 1 + 2 (six doses, pilot), respectively. Toxicity was measured according to the NCI CTCAE 3.0. LTLS and CTLS were defined as per Cairo/Bishop classification (Cairo et al, BJH, 2004). Median age 9.5 yrs, M/F 4/1, Burkitt 82%, CNS+ 34%, Uric acid ' 8 mg/dl 45%, LDH 2 time upper institutional limits 86%. The addition of rituximab was safe and well tolerated with 237 infusions and only one reported grade III allergic reaction directly related to rituximab. Two toxic deaths (pulmonary aspergillosis unrelated to study drugs and grade V typhlitis during the second induction cycle) occurred among the first 25 group C patients and the study was temporally closed to accrual in October 2006. No further toxic deaths have been reported among an additional 17 eligible patients enrolled since August 2008. The incidence of grade III/IV mucositis during COPADM 1 + 2 was 30% and 23% (Adria 1 hr), respectively, compared to 68% and 52% in FABLMB96 (Adria 6 hr). Similarly, the incidence of grade III/IV neutropenia/infection during the same two courses was 62% and 51%, respectively, compared to 80% and 76% in FABLMB 96. With non-alkaline hydration and rasburicase, 94% pts had an improved estimated glomerular filtration rate (GFR) at day 7 of reduction. The initial mean GFR ? SD vs. end of COP were 108 ? 42 and 173 ? 64 ml/min/1.73m2, respectively (p < 0.05). In pts without TLS at presentation, 19% and 0% developed laboratory TLS and clinical TLS after rasburicase. There were no toxicities definitely or probably related to rasburicase therapy. Among the 42 eligible patients, one patient failed to obtain a CR and progressed on therapy. In summary, the addition of rasburicase to FAB COP reduction is well tolerated and demonstrates excellent control of tumor lysis and prevention of renal failure. Finally, the addition of Rituximab to FAB COPADM 1 + 2 and CYVE 1+2 is well tolerated and does not increase the rate of mucositis and infection during induction. Based on these results, a future randomized international study is being planned to determine if the addition of rituximab to the FAB chemotherapy backbone in children with advanced stage (BM?CNS) mature B-NHL will significantly increase EFS/OS.
