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Thrombotic Thrombocytopenic Purpura

multimers as well as auto-antibodies to ADAMTS13 and replacing the vWF-cleaving protease activity.26,27

Therapeutic plasma exchange is

the only therapy for TTP with proven efficacy in prospective randomised clinical trials. The Canadian Apheresis Study Group compared plasma infusion (30ml/kg initially, then 15ml/kg daily) with plasma exchange (1.5 plasma volume/day for ten days, then one plasma volume/day) and demonstrated increased survival in the plasma exchange arm (78 versus 63%).25 similar results.28

Other studies reported

As a result of this therapeutic intervention the overall survival could be improved from 10% to more than 80%.29,30


In case of plasma-refractory TTP, which is defined as persistent thrombocytopenia or lactate dehydrogenase elevation after a total of seven daily plasma exchange procedures, current guidelines advise to intensify plasma exchange and to add corticosteroids.27

up to one-third of patients relapse after successful treatment of an acute episode, and especially patients who present initially with severe ADAMTS13 deficiency have a significantly increased risk of relapsing TTP.26,31

The advice of additional corticosteroids is mainly based on clinical experience and case series, but has not yet been proved in controlled clinical trials. Other additional therapy with immunosuppressive drugs such as azathioprine, cyclophosphamide or cyclosporine has not been proved to be beneficial.32

Rituximab as Second-line Treatment No specific standard treatment schedule exists for second-line treatment of refractory or relapsing TTP. If rituximab was used as a treatment option in this situation, it was mainly administered at doses of 375mg/m2 weekly for an average of four doses, in the same manner as the treatment schedule in non-Hodgkin’s lymphoma. In most cases rituximab was administered in parallel to continued therapeutic plasma exchange. Using this regimen, the majority of patients with refractory or relapsing TTP achieved complete remission with complete clinical and laboratory responses including normal ADAMTS13 level and disappearance of anti-ADAMTS13 antibodies.26,33 number of patients have been reported worldwide.

However, only a small

The largest case series describing 25 patients with acute refractory and relapsing TTP treated with rituximab was published by Scully et al.14

longer follow-up periods are required to assess the exact benefit of this therapy and also to take into account late relapses.

Long-term Follow-up After Rituximab Treatment To address these concerns in our patient cohort, we re-evaluated all patients with non-familial idiopathic TTP refractory to plasma exchange or with recurrent disease treated with rituximab between 2000 and 2008 at the University Hospital of Cologne with a median follow-up of almost 50 months, reflecting the longest follow-up period after rituximab treatment reported to date.37

Diagnosis of TTP was based on clinical and laboratory findings – including consumptive thrombocytopenia, haemolytic anaemia and elevated schistocytes in the peripheral blood smear – irrespective of ADAMTS13 activity. All patients were initially treated with standard treatment including daily plasma exchange with fresh frozen plasma (1.5 times plasma volume) and corticosteroids. The decision to initiate rituximab treatment was made in the case of non-response to daily plasma exchange, severe allergic reactions to plasma exchange leading to treatment discontinuation or relapse after initial successful therapy. In the period 2000 to 2008, 30 patients with an acute episode of non-familial idiopathic TTP were treated at the University Hospital of Cologne. Twelve patients receiving treatment with rituximab were identified and re-examined. Due to different pathophysiology, patients with TTP secondary to bone marrow transplantation, rheumatological diseases or active cancer were excluded.

In most cases, the treatment schedule consisted of rituximab at a dose of 375mg/m2 per week for four consecutive weeks administered in parallel to daily plasma exchange, except for two patients with intolerance to plasma exchange after a total of 22 and 10 exchange procedures respectively, leading to plasma exchange therapy disruption. After application of rituximab, plasma exchange was interrupted for 24 hours. In general, plasma exchange was continued until clinical remission and platelet count above 150 x 109/l for longer than 48 hours.

All patients initially achieved clinical remission; however, median follow-up was only 10 months (one to 33 months). Ling et al. reported 13 patients with refractory or relapsing TTP, of which 12 patients achieved complete response after rituximab treatment during median follow-up of 24 months.34

Longer follow-up is reported by Jasti et al.,35

describing 12 patients with TTP. Of the 11 patients with refractory TTP treated with rituximab during the acute episode, two patients died and nine were in ongoing complete remission after follow-up between one and 79 months. One patient with relapsed TTP was in remission for two years, and the subsequent relapse was again successfully treated with rituximab. Altogether, more than 100 patients have been reported to have received second-line treatment with rituximab, two-thirds because of refractory disease to standard treatment and one-third because of recurrent disease. More than 90% of patients achieved complete remission after rituximab. In the reported cases, only 10–13% of patients relapsed after rituximab treatment after a median follow-up of 11 months.13,14

Further research should focus on

long-term follow-up, especially when considering that B-cell recovery typically occurs nine to 12 months after rituximab application. Longer follow-up is required to address the possible long-term side effects of rituximab and the overall safety of this treatment.36

Moreover, despite the initial high response rates after rituximab treatment, 144

At the time of initial TTP diagnosis, the median age of the 12 patients was 42.5 years, and 75% of patients were female. At presentation, the mean platelet count was decreased to 19.8 x 109/l and mean lactate dehydrogenase (LDH) was elevated to 1018U/l (reference <250U/l). All patients had plasma exchange with fresh frozen plasma and steroid treatment prior to rituximab, and four patients had been additionally treated with vincristine (2mg intravenous). Seven patients were treated during the first episode of acute TTP, among whom five received rituximab because of an insufficient response to standard therapy with plasma exchange: two patients suffered from severe allergic reaction leading to disruption of plasma exchange after 22 and 10 exchange procedures, respectively. Five patients received rituximab because of relapse after at least one prior episode of acute TTP initially successfully treated with standard therapy. Baseline characteristics of all patients are shown in Table 1. Due to assay availability, unfortunately only in a minority of patients, ADAMTS13 activity was analysed before initiation of rituximab therapy. After application of rituximab, no severe acute side effects were noted and all patients responded with complete remission. This is in line with previous data reporting acute response rates of >90%.26,34

After nearly 50 months follow-up, three of 12 patients had relapsed. Previous reports have estimated the relapse rate after rituximab at


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