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Long-term Efficacy of Rituximab Treatment in Thrombotic Thrombocytopenic Purpura


Table 1: Follow-up of 12 Patients Treated with Rituximab by Authors Case


Age


Number (Years) 1 2 3 4 5 6 7 8 9


10 11 12


57 34 36 46 26 22 45 41 72 51 44 36


Sex Male


Female Female Female Female Male Male


Female Female Female Female Female


Prior TTP episodes


– – – 3 1 1 3 – – – 1 –


PE = plasma exchange; TTP = thrombotic thrombocytopenic purpura.


However, this data was based on a few patients with short follow-up, thus limiting the validity of the estimate. The higher relapse rate of 25% in our cohort is probably due to the longer follow-up period reported in the present study, and possibly reflects the gradual reversal of B-cell depletion and subsequent formation of new antibodies directed against ADAMTS13. Notably, from five patients suffering from partly frequent relapses before initiation of rituximab treatment, three have remained disease-free even after long-term follow-up. Only one patient relapsed after rituximab treatment during the initial TTP episode. All relapsing patients responded to subsequent rituximab therapy. Interestingly, the two patients treated with rituximab during the initial TTP episode, after stopping plasma exchange due to severe allergic reaction, had a sustained response without recurrence of TTP after a follow-up of 36 and 40 months. Both patients had not responded until the end of plasma exchange. Therefore, rituximab as a single agent is able to produce long-term remissions in TTP without continuous plasma exchange. However, the individual contribution of plasma exchange or rituximab to the treatment success remains open to question in the majority of patients. In two patients a maintenance therapy with rituximab was initiated consisting of 375mg/m2 every four weeks. One patient remains disease-free with ongoing maintenance therapy, the other is in sustained complete remission despite the cancellation of maintenance therapy after three months.


about 10%.13,14,26


Treatment of Further Relapse after Rituximab Treatment


and rituximab maintenance may be an option in these patients. However, this has to be weighed against potential long-term side effects, such as progressive multifocal leucoencephalopathy.39


Treatment decision-making in the case of further relapse after rituximab is difficult and not evidence-based. Rituximab has been used as pre-emptive treatment in patients with anti-ADAMTS13 auto- antibodies,38


An


alternative treatment would be a splenectomy, which is supported by data provided by Kappers-Klunne et al.40


Thirty-three patients with TTP


were retrospectively reported who were splectomised due to refractory or relapsing disease. After median follow-up of 109 months the 10-year relapse-free survival was 70%. As these data were generated without rituximab being a treatment alternative, one has to balance the risks of the operation procedure, post-operative complications and infectious complications post-splenectomy against the consequences of long-term B-cell depletion during rituximab maintenance therapy.


EUROPEAN ONCOLOGY & HAEMATOLOGY Safety Considerations


In our patient collective, no treatment-related, especially infectious, complications were reported. In all but two patients, B-cell counts had recovered at the end of follow-up, and one of these two patients is currently treated with rituximab maintenance therapy. This is congruent with previous reports using rituximab in relapsing or refractory TTP. Rituximab is usually well tolerated and acute reactions are usually mild without causing discontinuation of the drug.33 Infusion-related hypersensitivity adverse events including fever and hypotension are in most cases seen during the first infusion and mostly controlled with pre-medication and by slowing or temporary interruption of the infusion. However, rarely, potentially life- threatening complications have been reported. Progressive multifocal leukencephalopathy, a mostly fatal infection caused by the JC virus was described in lymphoma patients pre-treated with rituximab as well as in rare cases of immune-mediated disorders following rituximab treatment.41 cytomegalovirus42


or hepatitis B43 Cardiovascular events, delayed interstitial pneumonitis44


Other viral infections, such as reactivation of are more frequently reported. and renal


toxicity were also described following rituximab treatment. Especially when considering rituximab maintenance in frequently relapsing patients it is necessary to balance the risks and benefits of different treatment options. The risk of long-term B-cell depletion and the associated risk of potential infectious complications need to be weighed against the risks of complications associated with therapeutic plasma exchange including catheter thrombosis, infection of the venous access and transfusion reactions. The Oklahoma Registry group reports a 26% risk per patient for major complications of plasma exchange including a 2.8% fatality rate.45


Conclusion


Currently, data on rituximab treatment in refractory or relapsing TTP are based on case reports or smaller case series. Questions remain, such as timing of initiation of rituximab treatment, duration of treatment and treatment schedule and the schedule of concomitant therapeutic plasma exchange. With these limitations in mind, it appears that rituximab is an effective second-line treatment option for patients with idiopathic TTP, with some patients achieving sustained responses even after long-term follow-up. Prospective multicentre studies are required to determine whether rituximab can be safely used just as salvage therapy or even initially in addition to plasma exchange to decrease the relapse rate after first-line treatment.46,47


n 145 Reason for


Rituximab Initiation Allergy to PE Allergy to PE


Refractory to PE Relapse Relapse Relapse Relapse


Refractory to PE Refractory to PE Refractory to PE Relapse


Refractory to PE


Number of Rituximab Applications 375mg/m2


4 4 4 4 4 4 4 4 7 4 4 2


Follow-up (Months)


36 40 41 52 67 11 46 46 22 67 70 97


Relapse after Rituximab


– – – – 4 1 – – – – – 1


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