Previous research suggests that the anti- CD20 monoclonal antibody rituximab , at a dose of 375 mg / m 2 , 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 reduceddosing 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 / m 2 ; 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

— JOHN-PAUL WESTWOOD , MD

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 standardand 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 .

TABLE . Outcome Measures for Rituximab Doses

Time to ADAMTS13 recovery 1 ( range = < 1-5 )

Median overall follow-up 15 ( range = 1-141 )

1 ( range = < 1-5 )

17.5 ( range = 1-141 )

2 ( range = < 1-4 )

25 ( range = 9-43 )

1 ( range = < 1-3 )

10 ( range = 3-20 )

Patients requiring retreatment 38 50 % 12 50 % 14 73.7 % 3 17.6 % 10 62.5 % Retreatment episodes per year 0.25 0.17 0.38 0.20 0.29

* CR was defined as ADAMTS13 recovery into the normal range ( ≥60 %). † PR was defined as ADAMTS13 recovery ranging from ≥30 % to 59 %. ± At least PR was defined as ADAMTS13 recovery ≥30 %. CR = complete response ; PR = partial response

2 ( range = < 1-4 )

21 ( range = 3-112 )

36 ASH Clinical News September 2017