The Effect of Plasma Exchange on Rituximab Levels and Response to Rituximab in Patients with Acute Idiopathic Thrombotic Thrombocytopenic Pupura (TTP).

Most cases of acute idiopathic TTP have ADAMTS13 activity <5% and detectable anti-ADAMTS13 IgG. Rituximab, a monoclonal anti-CD20 antibody, is known to be an effective adjunct to eradicate the antibody. The initial doses of Rituximab are often given in the period that the patient is receiving plasma exchange (PEX). In order to ascertain whether Rituximab is removed by PEX and whether this affects response to treatment, we serially measured ADAMTS13 activity, anti-ADAMTS13 IgG level and serum Rituximab concentrations in patients who were treated with Rituximab within 3 days of admission for acute idiopathic TTP. Rituximab levels were measured before and after PEX, after each dose and then in remission. In addition we measured the above parameters in two patients who received Rituximab electively (not concurrently with plasma exchange). The ADAMTS13 activity (normal value >66%) was measured using a collagen binding assay while the anti-ADAMTS13 IgG (normal range <4%) and Rituximab levels (lower limit of detection 10mcg/ml) were measured using ELISA techniques. 16 patients (11 female, 5 male; median age 39y (range 13y – 75y)) with acute idiopathic TTP were treated with Rituximab. All patients had PEX from admission to remission, received Rituximab 375mg/m2 once weekly for 4 weeks and pulsed methylprednisolone 1g daily for three days. At presentation, all patients had ADAMTS13 activity <5% and anti-ADAMTS13 IgG (median 39.5%; range 12–85%). The median follow up was 6 months (m) (range 1–12 m). 14 patients received 4 doses of Rituximab, 2 received 6 doses. One patient died of TTP related complications before the third dose. The median number of PEX after the first dose of Rituximab was 15 (range 5–21). The median serum Rituximab concentration following each dose was: 1st dose 154 mcg/ml (range 108–467mcg/ml); 2nd dose 175 mcg/ml (range 116–436mcg/ml); 3rd dose 187.5 mcg/ml (157–301mcg/ml); 4th dose 216 mcg/ml (155–243mcg/ml); 5th 155 mcg/ml; 6th 211 mcg/ml. All PEX patients had Rituximab levels <10 mcg/ml immediately prior to the 2nd dose. Of those still being exchanged, 5/7 had levels <10 mcg/ml prior to 3rd dose and 5/6 patients had levels <10mcg/ml prior to the 4th dose. In contrast all the patients who had finished PEX had detectable Rituximab prior to their next dose. The median reduction in Rituximab per PEX expressed as a percentage of the pre-PEX level was 65 % (range 45–72%). The reduction was similar for 1.0 volume (65%) and 1.5 volume exchanges (70%). Rituximab was detected in the PEX fluid. Following completion of Rituximab therapy, the median concentration was 32mcg/ml (range 11–55mcg/ml) at 1m, 20 mcg/ml (range <10 – 42mcg/ml) at 2m and 16 mcg/ml (range <10– 20mcg/ml) at 3m. Seven patients reached 4 month follow up and had levels <10mcg/ml. Patients who had fewer than 10 PEX had higher median Rituximab levels (20mcg/ml) at 3m than those who had more than 10 PEX (Rituximab <10mcg/ml). There was no significant difference in ADAMTS13 activity or anti-ADAMTS IgG levels between these groups at 3m (patients receiving <10 PEX: mean activity 38% and IgG 6%; Patients receiving >10 PEX: mean activity 36% and IgG 15%). In 2 patients receiving elective Rituximab, the median concentrations before and after each dose were: 235mcg/ml after the 1st dose, 95mcg/ml before and 233mcg/ml after 2nd dose, 119mcg/ml before and 289mcg/ml after the 3rd dose, 167mcg/ml before and 373mcg/ml after 4th dose. Follow up is too short to correlate levels and ADAMTS13 activity/anti-ADAMTS13 IgG levels. There have been no relapses in any of the patients. In conclusion, Rituximab is removed by plasma exchange. The peak doses achieved are higher in those not receiving concurrent PEX. Higher Rituximab levels are associated with fewer PEX. Rituximab was still detectable at a low level in a third of patients 3 months after treatment but not at 4 months. Measurement of Rituximab levels will help to modify Rituximab doses and modification of the dosing schedule using higher initial doses or more frequent dosing may achieve higher levels earlier in treatment and a shorter time to remission. Longer term follow will also help to determine whether the peak Rituximab concentration achieved correlates with duration of remission.