Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by widespread platelet thrombi in the microvasculture. A decrease in von Willebrand factor-cleaving protease activity (VWF-CPA) has been demonstrated in the majority of patients with TTP [1,2]. The absence of VWF-CPA due to deficiency or inhibitory antibodies lead to the appearance of unusually large von Willbrand factor multimers in the circulation of patients with TTP [1,2]. These multimers are normally degraded by the protease and have high affinity for platelets.

Rituximab is a chimeric monoclonal antibody against the CD20 antigen expressed on the surface of B lymphocytes. In addition to the role of rituximab in the treatment of lymphomas, the drug has been used successfully in autoimmune disorders [3,4]. In the current report, we present our experience in the treatment of refractory or chronic relapsing TTP using rituximab.

The diagnosis of TTP was based on the presence of thrombocytopenia (platelets <150 000 µL−1), anemia (hemoglobin <10 g dL−1), elevated lactate dehydrogenase (LDH >420 U L−1) and the presence of at least 10 fragmented red blood cells per high power field. Although haptoglobin, indirect billirubin and VWF-CPA and the presence of inhibitory antibodies against VWF-CPA were assessed prior to therapy, this data was not required for confirmation of TTP.

Treatment consisted of rituximab 375 mg m−2 intravenously administered weekly for a total of four doses. The drug was administered 3–4 h following plasma exchange (PLEX). Treatment with PLEX 40–60 mL kg−1 day−1 was continued concomitantly with rituximab until platelet recovery. Measurements of VWF-CPA and antibodies to VWF-CPA were performed within a week of normalization of LDH and platelet count and repeated at 1 and 3 months, thereafter. No corticosteroids or other immunosuppressive therapy was used concomitantly with rituximab. Response to treatment was defined as increase in platelet count >150 000 µL−1 and decrease in LDH <420 U L−1.

Table 1 shows the characteristics and results of treatment of the five patients treated with rituximab. At the time of treatment with rituximab, the median hemoglobin was 9.2 g dL−1, median platelet count 14 200 µL−1, and median LDH was 3460 U L−1. All patients had decreased haptoglobin and elevated indirect bilirubin. The mean duration of TTP prior to rituximab infusion was 9.5 months (range 3.5–23 months). The median days of PLEX before the administration of rituximab was 71 days, while a median of 14 days of PLEX (range, 12–18 days) was used concomitant with rituximab.

Table 1.  Characteristics of five patients with refractory TTP treated with rituximab
PatientAge (years)Duration of TTP (months)Underlying conditionVWF-CPA %Inhibitor to VWF-CPAPrior therapyTime to normal LDH (days) Time to normal platelets (days)Time to normal PCA (days)Duration of response (months)
  1. VWF-CPA, von Willebrand factor-cleaving protease activity; PLEX, plasma exchange; FFP, fresh frozen plasma.

132None<1+Prednisone, PLEX, vincristine, splenectomy29242913
23723None<1+Prednisone, PLEX, vincristine, cyclophosphamide, splenectomy3531429
3257None<1+PLEX, prednisone, vincristine, cyclo- phosphamide, splenectomy32262910
43119Familial<1PLEX, FFP infusion, prednisone, vincristine, cyclorporine4639NA12
5525Lung cancer4PLEX, prednisone, immunoadsorption, vincristine

Of the five patients, four achieved complete and sustained remission after the administration of rituximab. The median time to achieving normal platelets and normal LDH was 31 and 35 days, respectively. A total of four patients had normal VWF-CPA within a median of 35.5 days following rituximab infusion. The median duration of response was 11 months. None of the responders experienced a relapse during the follow-up period. Toxicity was mainly infusion-related and included fever, chills, headache, nausea and hypotension. The vast majority of these adverse events occurred during the first infusion and did not warrant the discontinuation of rituximab in any patient.

Decrease in plasma VWF-CPA caused by inhibitory antibodies has been demonstrated in patients with the non-familial or classic form of TTP [1,2]. Constitutional deficiency of the protease, however, appears to be the underlying mechanism for the familial form of the disease. This strongly suggests the presence of autoimmune dysfunction in the majority of patients with TTP. Rituximab has been used with some success in patients with autoimmune hematologic disorders [3,4]. The administration of rituximab causes depletion of B cells expressing the surface antigen CD20. The mechanism of cell killing is thought to be secondary to antibody-dependent cellular toxicity and complement activation. Suppression of autoreactive B cells may explain the sustained response attained when using rituximab in the treatment of lymphomas and autoimmune disorders [3,4].

In this report, four of five patients achieved durable remission confirming the successful outcome using rituximab in refractory TTP recently reported by other investigators [5–7]. The dose and frequency of administration of rituximab in the current series is based on the experience in the treatment of non-Hodgkin's lymphoma. The time to recovery of platelet counts in our patients is consistent with the results observed in patients with idiopathic thrombocytopenic purpura [4]. All patients in that study received rituximab in a dose and frequency similar to the current series.

Because of the limited available experience in the treatment of TTP with rituximab, it is difficult to make direct comparison with the results obtained from other investigators [5–7]. For example, one patient with chronic relapsing TTP achieved a rather short remission with two doses and a sustained remission after four infusions of rituximab [6]. In another case, full recovery of platelet count and durable remission was achieved after only two doses of rituximab [5]. Therefore, the number of doses of rituximab required to achieve response in patients with refractory TTP is worth addressing in future trials. It is also important to emphasize that PLEX was used on a daily basis in our patients until platelet recovery. Unfortunately, no information is currently available on whether rituximab is removable by PLEX. As plasma levels of rituximab were not measured in this group of patients, it is difficult to assess the impact of PLEX on the efficacy of rituximab. As would be expected intuitively, durable remission correlated well with recovery of VWF-CPA and resolution of the inhibitor. The duration and type of treatment previously administered did not influence the response to rituximab in this study. However, it is important to note that the non-responder in our series had an underlying condition (malignancy) that typically does not respond well to PLEX and other therapeutic strategies.

In summary, rituximab is potentially an effective and well tolerated agent in patients with refractory TTP. The frequency of infusion and sequence of administration, i.e. immediately after failure of PLEX or following splenectomy should be further investigated.


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  2. References
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