Can Reduced-Dose Rituximab Effectively Prevent TTP Recurrence?

Previous research suggests that the anti-CD20 monoclonal antibody rituximab, at a dose of 375 mg/m2, can prevent relapse in patients with thrombotic thrombocytopenic purpura (TTP) and restore patients’ ADAMTS13 levels. Whether that represents the optimal dosing regimen has not been established.

In a multicenter, retrospective cohort study of prophylactic rituximab in patients with TTP, John-Paul Westwood, MD, from the Department of Haematology at the University College London Hospitals in the United Kingdom, and co-authors assessed whether reduced dosing of rituximab could minimize the toxicities associated with repeated exposure to high doses (including infusion-related reactions [IRRs], hepatitis B reactivation, and the development of hypogammaglobulinemia) while maintaining the efficacy of standard dosing.

According to their findings, which were published in Blood Advances, there were no significant differences in ADAMTS13 recovery or TTP relapse between standard- and reduced-dosing groups. However, patients who received reduced rituximab dosing were more likely to require retreatment. “There is no indication that needing more frequent retreatment is necessarily associated with worse outcomes,” the authors wrote, “although receiving rituximab more frequently is likely to be associated with patients being exposed to potential adverse events (AEs),” the authors noted.

The study included 45 patients (median age = 43.5 years; range = 18-78 years) with TTP who received rituximab at six TTP specialty centers in the United Kingdom between 2005 and 2016. Patients were in remission at the time of enrollment and had experienced at least one previous acute TTP episode.

During the study period, patients had a total of 76 TTP episodes. Sixteen episodes were treated with rituximab at doses ranging from 100 to 1,000 mg administered one to five times, and the remaining 60 episodes were treated with rituximab (once-weekly for 4 weeks) at the following schedules:

  • standard dose (375 mg/m2; n=24 episodes)
  • reduced dose (200 mg; n=19 episodes)
  • intermediate dose (500 mg fixed dose; n=17 episodes)

The median ADAMTS13 level at the time of rituximab therapy for all episodes was 5 percent (range = <5-17%).

ADAMTS13 levels returned to the normal range (≥60%) in 60 episodes (78.9%) after a median of one month (range = <1-5 months) following the first rituximab infusion. (See TABLE for a detailed description of responses with each dose level.)

In addition, almost all patients (92.1%) had at least a 30 percent increase in ADAMTS13 (range = 30-118%). Three patients had no ADAMTS13 activity, and one patient was lost to follow-up.

Three relapses occurred (incidence = 3.9%) over a median follow-up of 15 months (range = 1-141 months) at nine, 10, and 32 months after reduced-dose rituximab.

Half of the TTP episodes (n=38) required additional prophylactic rituximab at a median of 17.5 months (range = 9-112 months) after the initial rituximab dose.

The investigators reported that there was no significant difference in the proportion of patients requiring retreatment between the standard- and reduced-dose cohorts (50% vs. 73.7% [n=12/24 vs. n=14/19]; p=0.13). “However, calculation of incidence rate of retreatment revealed that patients with reduced dose have a retreatment rate more than double that of the standard-dose patients (0.38 vs. 0.17 retreatment episodes per year, respectively; p value not provided),” they wrote.

Only three patients (17.6%) in the intermediate-dose group required retreatment, but because follow-up was considerably shorter for that group than for the standard- and reduced-dose cohorts, it was difficult to compare retreatment incidences across groups.

The median treatment-free survival did not differ significantly between the standard- and reduced-dose groups (29 months vs. 25 months; p=0.25), though the incidence of retreatment episodes per year appeared to be higher in the standard-dose group (0.17 vs. 0.38; p=0.039).

No patients reported hepatitis B reactivation.

Given the low retreatment incidence in the intermediate-dose group, the authors concluded that the rituximab 500 mg fixed dose “may provide a compromise in elective rituximab dosing: less therapy but attainment of a more prolonged remission between treatments.”

The authors noted the difficulties of drawing conclusions about the heterogeneous group of 16 patients who received variable doses of rituximab, and said that the study was limited by its retrospective design, variable lengths of follow-up, and small patient numbers.

The authors report funding from Ablynx NV, Novartis, and Pfizer.


Reference

Westwood JP, Thomas M, Alwan F, et al. Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens. Blood Adv. 2017;11:1159-66.

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