Multi-center randomized open label phase II trial on three rituximab dosing schemes in immune thrombocytopenia patients

Abstract

The overall short-term treatment efficacy of rituximab (R) in immune thrombocytopenia (ITP) is reported to be approximately 58%.1,2 With four once-weekly 375 mg/m 2 doses, responses of 31% after two years, 2 and 21% after five years 2 can be expected with a median clinical improvement time of 10.5 1 months, and up to 49 months in other studies. 3 Since lower doses have comparable efficacy, 4 R remains an attractive second-line therapy especially in patients where splenectomy is contraindicated or should be delayed. 1,3,[5][6][7][8] However, there are no known response-modifying factors that can provide an optimal basis for choosing R and its dosing. Moreover, while numbers of ITP patients are limited, knowledge on these issues is mainly derived from (clustered) often small-sized and non-randomized studies. [1][2][3]5,9 Therefore, in order to, firstly, delineate the efficacy and safety of two alternative dosing strategies, and secondly, to study the R-response-modifying factors (RMF), the Dutch Hemato-Oncology Cooperative Group (HOVON) randomized 156 immune thrombocytopenia (ITP) patients between four once-weekly standard 375 mg/m 2 doses (arm A), a 2-weekly 375 mg/m 2 in early responding patients (arm B), and a 2-weekly 750 mg/m 2 regimen (arm C). In more detail, in arm B, when no early (at day 15) response was present or when response was lost within six weeks, another two once-weekly 375 mg/m 2 rituximab infusions were given.Eligible patients needed to be 18 years of age or older and with an ITP relapse or refractoriness (at least 2 platelet counts less than 30x10 9 /L) and at least three weeks after high-dose corticosteroids (≥ 1mg/kg) before start of R (R start); further study details are available in the Online Supplementary Appendix. Complete (CR) good/partial (PR) and moderate (MR) response were defined as platelet counts of 150x10 9 /L or more and 50x10 9 /L or more on 2 consecutive occasions and a platelet count over 30x10 9 /L with at least twice the base-line count, respectively. Retrospectively, responses were also analyzed according to the International Working Group (IWG) ITP trial guidelines. 10 Relapse was defined as a further fall in platelet count to below 30x10 9 /L or below the 2-fold increase of base-line platelet count. Relapse-free survival (RFS), defined as time from response until relapse, emergency treatment, or death, was analyzed using the actuarial Kaplan-Meier method. Patients still alive at the date of last contact were censored. The primary objective of this study was to evaluate the individual treatment arms as sufficiently promising (CR+ PR + MR > 50%) strategies 11 but not to compare the results between the treatment arms. All analyses were performed according to the intention-to-treat principle, irrespective of patients' compliance. Ineligible patients were excluded from all analyses. With 15 patients considered ineligible, and 3 patients who did not start with their assigned R treatment, 138 patients were evaluated for response as primary end point (Table 1).Twelve patients (...

Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta‐analysis

“…Rituximab treatments were generally administered by intravenous injection at 375 mg/m 2 weekly for 4 weeks. The dose was different (100 mg/m 2 ) in two studies (Provan et al , ; Li et al , ), consisted of dose escalation (from 35 to 375 mg/m 2 ) in one study (Saleh et al , ) and the schedule was different in three studies (1–4 cycles) (Peñalver et al , ; Audia et al , ; Zwaginga et al , ).…”

“…Overall study quality was largely reduced to only four randomized trials (Hasan et al , ; Zaja et al , ; Zwaginga et al , ; Li et al , ). Among the non‐randomized studies, 13 were prospective with four Phase I/II trials (Saleh et al , ; Stasi et al , ; Cines & Blanchette, ; Zaja et al , , ; Cooper et al , ; Garcia‐Chavez et al , ; Godeau et al , ; Medeot et al , ; Alasfoor et al , ; Hasan et al , ; Zwaginga et al , ; Li et al , ). Other studies were retrospective (six articles and one abstract presented at anASH meeting) (Narat et al , ; Peñalver et al , ; Provan et al , ; Schweizer et al , ; Audia et al , ; Badar et al , ).…”

“…Individual data were available in 10 studies (Stasi et al , ; Cines & Blanchette, ; Zaja et al , ; Narat et al , ; Garcia‐Chavez et al , ; Provan et al , ; Schweizer et al , ; Alasfoor et al , ; Hasan et al , ; Badar et al , ). Five studies enrolled only non‐splenectomized patients (Provan et al , ; Godeau et al , ; Badar et al , ; Zaja et al , ; Zwaginga et al , ).…”

“…No randomized study has been designed to compare rituximab to splenectomy in chronic ITP patients. The four RCTs retained in this meta‐analysis compare dexamethasone or other regimen to rituximab + dexamethasone (Hasan et al , ; Zaja et al , ) or different rituximab dosing schemes (Zwaginga et al , ; Li et al , ). Their design was different and it was difficult to compare them.…”

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

“…21 Even with rituximab, years after the drug's initial approval, there is still no clear explanation for why some patients respond and others do not, or why increased doses do not improve response rates. In ITP, 100-mg doses of rituximab may be active, 22 but other low doses have not been evaluated, and while different rituximab dosing regimens have been compared, 23 the 375 or 750 mg/m 2 doses are higher than the 80 -320 mg doses of veltuzumab in this study. Furthermore for rituximab, the consensus of the limited studies in ITP is that the response rate at the lower doses (100 mg x 4) is the same as that at higher doses, but the duration of the responses is not as long, which is quite similar to the veltuzumab data reported here.…”