Results of a Phase II Randomizing Intensified Rituximab Pre-Phase Followed By Standard FCR Vs Standard FCR in Previously Untreated Patients with Active B-Chronic Lymphocytic Leukemia (B-CLL). CLL2010FMP (for fit medically patients): A Study of the french Cooperative Group on CLL and WM (FCGCLL/MW) and the “Groupe Ouest-Est d’Etudes Des Leucémies Aigües Et Autres Maladies Du sang” (GOELAMS)

Introduction: Rituximab dosing regimen is largely empirical in CLL patients and phase I study has suggested a dose response relationship in previously treated CLL patients. Pharmacokinetics data from REACH study, randomising FCR and FC for relapsed/refractory CLL, showed a correlation between rituximab exposure evaluated by AUC and C_through and clinical response. Pharmacokinetics analyses showed a faster clearance (CL2) of rituximab in CLL patients compared to non-Hodgkin’s lymphoma patients. We purposed to intensify rituximab regimen before the first course of FCR in order to improve rituximab exposure and increase response rate in untreated, medically fit CLL patients.

Patients and Methods: Medically fit patients (cumulative illness rating scale (CIRS) score of up to 6), less than 65 years old, without 17p deletion, were enrolled between july 2012 and october 2013. Patients were stratified according to IGHV mutational status and 11q deletion. They were randomly assigned to receive either intensified pre-phase of rituximab: 500 mg total dose at day (D)0 (250 mg D-1, 250 mg D0 if leucocyte > 25 G/L), 2000 mg total dose at D1,D8 and D15 followed by 6 cycles of FCR (F 40mg/m² PO D1-3 and C 250 mg/m² PO D1–3; R: 500 mg/m² D1 q 28 days: R-dense arm) or 6 cycles of FCR without prephase (F 40mg/m² PO D1-3 and C 250 mg/m² PO D1–3; R: 375 mg/m² D1 cycle 1 and 500 mg/m² D1 cycle 2-6 q 28 days, standard arm). Adverse events (AEs) were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). The primary endpoint was the complete response (CR+CRi) rate according to iwCLL 2008 criteria associated with undetectable minimal residual disease (uMRD; < 10^-4 by 8 colors FC assay) in peripheral blood and bone marrow 3 months after the last cycle.

Results: 140 patients were included in this randomized phase II trial. Three patients were excluded of the analyse because of consent withdrawal: (n=1); haemolytic anemia (n=1) or detectable AgHbS (n=1). A total of 137 patients were analysed for response (ITT), 68 patients in R-dense arm, 69 in standard arm. Patients’ characteristics were well balanced between the two arms. The toxicity of rituximab intensified pre-phase was low with only one patient experiencing a grade ≥ 3 infusion related reaction, six and 12 patients experiencing neutropenia grade ≥ 3 at D8 and D15, respectively. Lymphocyte counts decreased rapidely and was lower than 5.0 G/L in 31%, 51% and 65% of patients at D8, D15 and D22. Six of 55 patients evaluable for MRD after rituximab-intensified pre-phase had less than 1% of clonal circulating cells. Toxicity of FCR was not statistically different between the two arms with 31% and 26.5% of neutropenia grade ≥ 3 for R-dense arm and standard arm, respectively. ORR were 96% (CR+CRi: 56%, PR+PRn: 40%) and 93% (CR+CRi: 55%, PR+PRn: 38%) in R-dense arm and standard-arm, respectively. The rate of CR+CRi with uMRD in marrow and peripheral blood was 26.5% and 24.6% for R-dense arm and standard arm, respectively.

Conclusion: Intensified rituximab pre-phase is safe in untreated medically fit CLL patients and most of patients reached normal lymphocyte count at the end of this pre-phase. However, intensified rituximab pre-phase followed by FCR did not allow to significantly increase CR+CRi with uMRD rate compared to standard FCR. Longer follow-up of these patients is warranted.