Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response.

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).

• Authors: Ulrich Jäger, Michael Fridrik, Markus Zeitlinger, Daniel Heintel, Georg Hopfinger, Sonja Burgstaller, Christine Mannhalter, Wilhelm Oberaigner, Edit Porpaczy, Cathrin Skrabs, Christine Einberger, Johannes Drach, Markus Raderer, Alexander Gaiger, Monique Putman, Richard Greil, Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) Investigators
• Journal: Haematologica (Haematologica) Vol. 97 Issue 9 Pg. 1431-8 (Sep 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22511498 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• Rituximab
• Mitoxantrone
• Vidarabine
• fludarabine

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Murine-Derived (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (blood, pharmacokinetics, therapeutic use)
• Bone Marrow (drug effects, immunology, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Follow-Up Studies
• Humans
• Lymphoma, Follicular (drug therapy, immunology, mortality)
• Male
• Middle Aged
• Mitoxantrone (administration & dosage)
• Neoplasm Recurrence, Local (drug therapy, immunology, mortality)
• Pilot Projects
• Prognosis
• Prospective Studies
• Remission Induction
• Rituximab
• Sex Factors
• Survival Rate
• Tissue Distribution
• Vidarabine (administration & dosage, analogs & derivatives)