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Clinical Trial
. 2012 Sep;97(9):1431-8.
doi: 10.3324/haematol.2011.059246. Epub 2012 Apr 17.

Rituximab Serum Concentrations During Immuno-Chemotherapy of Follicular Lymphoma Correlate With Patient Gender, Bone Marrow Infiltration and Clinical Response

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Clinical Trial

Rituximab Serum Concentrations During Immuno-Chemotherapy of Follicular Lymphoma Correlate With Patient Gender, Bone Marrow Infiltration and Clinical Response

Ulrich Jäger et al. Haematologica. .
Free PMC article

Abstract

Background: Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics.

Design and methods: Clinical efficacy of immunochemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients.

Results: Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008).

Conclusions: The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).

Figures

Figure 1.
Figure 1.
Detailed pharmacokinetic profiling during R-FM induction and rituximab maintenance. (A) Area under the curve (AUCtotal) during induction cycles 1 and 6 as well as maintenance cycles 1 and 6 shows high inter-individual variability (n=16). (B) Female patients have higher median AUCtotal throughout the study period (AUCtotal men: 81% of that found in women). (C) Patients without bone marrow (BM) infiltration (BM negative) at diagnosis have higher median AUCtotal (AUCtotal in patients with BM infiltration: 76% of that found in BM negative patients). (D) Correlation between AUCtotal and serum trough levels (Ctrough) obtained before rituximab infusions.
Figure 2.
Figure 2.
Association of rituximab trough levels with gender, quality of remission (complete (CR) vs. partial (PR)), progression-free survival (PFS) and clinical relapse. (A) Median Ctrough in ng/mL are higher (median 29%, range 10–70%) in female patients at almost all time points during induction and maintenance treatment (for details see Table 2). (B) Higher rituximab Ctrough correlate with CR rates at the end of R-FM induction. (C-E) Correlation of Ctrough before induction 4, maintenance 4 and maintenance 6 with PFS. Rituximab cut-off levels are given in ng/m. (F) Median rituximab serum levels in patients with continuous CR or PR (dotted line) or clinical relapse. Clinical relapse (black arrows) is preceded by a significant decline in Ctrough before maintenance 6 (last serum level assessment). Time of relapse is given in months after last Ctrough assessment. Patients per time point: continuous remission 7–10, relapse 3–6. The presumptive active serum level of rituximab (25,000 ng/mL) is shown by an interrupted line.

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