Supplementary Appendix: Click here to view

Supplementary Appendix: Click here to view. Disclosures and Contributions: Click here PP1 to view. Footnotes Funding: this study was funded by FILO group and F. were also found in another phase II study.4 In pharmacokinetic (PK) studies, patients with CLL exhibited lower RTX exposure PP1 than lymphoma patients.5 The reason of the discrepancy remains unclear but could be related to a larger antigenic burden in patients with CLL. The influence of CD20 burden on RTX PK and response has already been suggested in a syngeneic murine model6 and in patients with diffuse large B-cell lymphoma (DLBCL).7 In CLL, CD20 burden affects RTX PK by increasing the antibody target-mediated elimination,8 but its influence on RTX exposure and outcomes remains to be investigated. We conducted therefore a randomized phase II study evaluating the effectiveness of higher doses of RTX associated with FC (mutational status, FISH analysis (11q deletion or not) and randomly assigned to receive either 6 cycles of FCR (intravenous RTX 375 mg/m2 for the first course, D1 and 500 mg/m2 for the others, oral fludarabine 40 mg/m2/d D2-4, oral cyclophosphamide 250 mg/m2/d D2-4) every 28 days or Dense-FCR with an intensified RTX prephase (500 mg on D0, and 2000 mg on D1, D8 and D15) before the FCR starting at D22. The primary endpoint was the rate of CR with nMRD three months after the end of treatment. MRD was determined by flow cytometry in both peripheral blood (PB) and bone marrow (BM) at M9. nMRD was defined as the detection of less than one CLL cell per 10,000 leukocytes. The CD20 antigen burden was defined as Rabbit polyclonal to PFKFB3 the sum of CD20 antigenic targets estimated on both B-cells in PB (CD20cir) by using CD20-PE QuantiBRITE? reagents and in the lymph nodes (CD20LN) by CT-scan using semi-automated accurate measurement technique.10 RTX exposure was assessed using a semi-mechanistic pharmacokinetic model. One hundred and forty patients were recruited, 69 patients in the FCR arm and 68 patients in the Dense-FCR arm. Both treatment groups were well-balanced with respect to stratification criteria, clinical, biological, and tumor burden parameters (Table 1). Grade 3/4 infusion-related reactions were reported in only two patients in the Dense-FCR arm leading to treatment discontinuation in one patient (status (genotype, which were associated with lower rituximab concentrations in early treatment cycles. Only 32% of the inter-individual variability in the elimination rate was explained by circulating CD20 antigen suggesting that CD20 antigenic mass was not the main factor explaining fast RTX clearance observed in patients with CLL. The reasons of this consumption remain undetermined but could be related to the CD20 internalization observed em in vitro /em .11 This internalization was not observed with type II anti-CD20 PP1 mAbs suggesting a potential advantage obinutuzumab in patients with CLL. Recently, we demonstrated in patients with DLBCL treated with immuno-chemotherapy that tumor burden influenced RTX exposure and patients outcome.7 We then proposed a nomogram providing a rational scheme for increasing the RTX dose in patients according to tumor burden in order to achieve RTX exposures that have a better chance of prolonging the duration of response. CLL and DLBCL seem, therefore, completely different models for RTX PK. In patients with CLL, RTX elimination is fast, not significantly influenced by CD20 antigenic mass and cannot be corrected by higher doses of RTX, while in patients with DLBCL, tumor metabolic volume is the main factor influencing RTX exposure and increasing doses of RTX should increase RTX exposure and improve outcome. Supplementary Material Cartron et al. Supplementary Appendix: Click here to view. Disclosures and Contributions: Click here to view. Footnotes Funding: this study was funded by FILO group and F. Hoffman-La Roche Ltd (Basel, Switzerland). This.