Two-Monthly Rituximab Infusions Maintain Target Concentrations: Pharmacokinetic Data of the AGMT-NHL9 Maintenance Study in Patients with Follicular Lymphoma in Complete or Partial Remission.
Authors: Jaeger Ulrich , Krieger Otto , Hopfinger Georg , Skrabs Cathrin , Einberger Christine , Huter Veronika , Hausmaninger Hubert , Drach Johannes , Raderer Markus , Woo Michael , Melzer Helen , Greil Richard , Fridrik Michael A 
Published: April 2020

Maintenance therapy with the monoclonal anti-CD20 antibody Rituximab (R) improves clinical outcome in patients with follicular lymphoma in complete or partial remission (CR, PR) after induction therapy. However, optimal dosing schedule and duration of maintenance therapy are still under investigation. Commonly applied regimen include four doses of 375mg/m2 Rituximab once a week every 6 months, one dose every 3 months, or one dose every 2 months. Maintenance is usually given for 2 years. In addition to clinical trials, pharmacokinetic (PK) studies could help determining optimal dosing of Rituximab. PK values have been obtained during induction therapy in several trials and an association between drug trough levels and clinical effectiveness has been established (25μg/ml in responding patients). However, data on Rituximab PK during maintenance therapy are lacking. The Austrian Cooperative Study Group for Cancer Drug Therapy (AGMT) has conducted a phase II trial in 33 patients with follicular lymphoma in CS III/IV with an induction therapy with 6 cycles of Rituximab (375mg/m2 i.v., day 1), Fludarabine (30mg/m2 p.o., day 2–4)) and Mitoxantron (10mg/m2 i.v., day 1) every 4 weeks (R-FM) (NHL9). Thirty two patients obtaining a CR, CRu or PR received maintenance treatment with Rituximab 375mg/m2 every 2 months for 1 year. Pharmacokinetic data for Rituximab were obtained during induction and maintenance treatment in 16 of these patients. All patients converted from BCL2/IgH PCR positivity to negativity in peripheral blood after R-FM induction. PK serum concentrations during induction corresponded well to known data: A steady increase in pre- and post-dose levels was observed with increasing cycle number. Median, minimum and maximum Rituximab serum concentrations are given in the upper panel of Table 1:

Table 1. Serum concentrations (μg/ml) during R-FM induction and two-monthly maintenance treatment with 375mg/m2 of Rituximab.

R-FM Induction Cycle 1 2 4 6 (Q 4 weeks) min. med. max. min. med. max. min. med. max. min. med. max. Pre-dose N.A. &lt;0.5 N.A. &lt;0.5 16.8 44.8 25.3 56.6 93.2 43.2 66.5 208.3 Post-dose 44.8 161.4 236.7 146.4 204.6 300.5 176.6 218.4 346.2 196.3 249.5 370.2 Interval 2 months R-Maintenance Cycle 1 2 4 6 (Q 2 months) min. med. max. min. med. max. min. med. max. min. med. max. Pre-dose 13.8 41.5 113.7 6.2 31.0 72.8 14.8 35.6 261.2 13.7 26.7 56.0 Post-dose 136.6 237.9 364.6 198.0 235.9 350.7 214.2 235.0 280.9 185.1 249.2 271.1

The median interval between day 1 of the last R-FM induction cycle and the initial dose of R maintenance treatment was 2 months (range 1 – 3). PK values were obtained during maintenance cycles 1, 2, 4, and 6. The median interval from the first Rituximab maintenance infusion to the sixth infusion was 10.4 months (range 9.7 – 10.5). Table 1 (lower panel) shows the median, minimum and maximum drug levels before and after R maintenance infusions. These results indicate that (i) Median Rituximab levels 2 months after the last infusion of induction treatment are still higher than the supposedly active concentration of 25μg/ml; (ii) Rituximab target levels of over 25μg/ml are constantly maintained throughout one year of maintenance. (iii) Rituximab trough levels may still be low in some patients on a two monthly schedule. There was no difference in maintenance trough levels between CR and PR patients. So far, no relapses were observed. We conclude that infusion of Rituximab 375mg/m2 once every two month results in constant active serum levels in patients with follicular lymphoma in complete or partial remission. These data should help designing rational maintenance schedules for future clinical trials.