Rituximab in the treatment of TTP

Abstract

Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening disorder, for which mortality remains relatively unchanged since the introduction of plasma therapy. Improved understanding of the pathophysiology has identified that the majority of cases result from antibodies directed against ADAMTS 13, which is required to cleave von Willebrand Factor. The use of monoclonal anti-CD 20 therapy removes IgG antibodies, resulting in increased ADAMTS 13 activity, improved time to remission and prevention of recurrent relapses. While further follow-up is required, the side effect profile of anti-CD 20 therapy appears improved compared to conventional immunosuppressive treatments. The use of ADAMTS 13 activity for monitoring can identify patients at risk of a TTP relapse and pre emptive therapy with an anti-CD 20 can be considered.

Keywords:

• TTP
• Anti-ADAMTS 13 igG
• Rituximab

Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening illness that can affect any age, but typically affects women in their 3rd and 4th decade. Over the last decade there has been a significant increase in the understanding of the pathophysiology and treatment of this disorder. It remains a medical emergency, requiring prompt diagnosis and treatment.

In the late 1990s, a deficiency in an enzyme required to cleave von Willebrand Factor and antibodies to this enzyme was identified. Subsequently it was identified as a protease, specifically, ADAMTS 13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13). Deficiency (<5–10%) of ADAMTS 13, during an acute TTP episode, in the majority of cases, is associated with antibodies, primarily IgG, to ADAMTS 13. TTP is therefore, in most cases, an idiopathic, autoimmune disorder.1

The mainstay of treatment, on diagnosis of TTP when a patient presents with thrombocytopenia and microangiopathic haemolytic anaemia, is plasma exchange (PEX). The only randomized trial undertaken in TTP, published in 1991, confirmed the superiority of PEX compared to plasma infusion, associated with reduced mortality.2 Anecdotally, steroids are used acutely, in conjunction to PEX, even before a clear understanding of the disease pathogenesis was understood. In patients with refractory or relapsing disease, further immunosuppressive or immunomodulatory therapies have been used. However, they have been subject to case reports or small series and their benefit not confirmed.

Rituximab is a chimeric mouse-human monoclonal antibody against CD 20. CD20 is a transmembrane protein found exclusively on B lymphocytes, specifically on preB and mature lymphocytes. CD 20 is not shed from B cells and does not internalize on antibody binding. Once bound to CD 20, Rituximab affects cell death by a number of mechanisms, including antibody dependent cell mediated cytotoxicity, Complement dependent cytotoxicity and apoptosis. Apart from the rapid reduction in pathogenic antibody production, via its effects on B lymphocytes, there also appears to be modulation of the T-cell function, including CD4+ T lymphocytes and regulatory T cells. Initially developed in non Hodgkin’s lymphoma, Rituximab subsequently received a license in Rheumatoid arthritis. However, it has been used in a number of other antibody mediated diseases, including TTP.

There were a number of cases and small series in the literature, proceeding two larger publications. In the first, six patients were included during an acute refractory TTP episode and five patients with severe relapsing TTP and persistent anti-ADAMTS13 antibodies were prophylactically treated during remission.3 Treatment with Rituximab led to clinical remission in all cases of acute refractory TTP. In all patients, anti-ADAMTS13 antibodies disappeared, and a significant (18–75%) plasma ADAMTS13 activity was detected following treatment. From the UK cohort, 25 patients with refractory or relapsing TTP cases were included. Once again, the utility of ADAMTS 13 assays for activity and IgG antibody demonstrated the effect of therapy and maintenance of remission while ADAMTS 13 activity was in the normal range. Remission was attained within 11 days of initiating Rituximab.4 In both series, complete remission was achieved in all patients. More recently, 22 patients with relapsing or refractory TTP received four infusions of Rituximab over 15 days. In the Rituximab-treated patients, the time to complete remission was significantly shortened, with only a small reduction in plasma volume required to achieve a durable remission. However, by day 35, all Rituximab treated cases had achieved a durable remission, compared to only 78% of historical controls. Rituximab treated patients had a quicker recovery of ADAMTS 13 activity and reduced one-year relapse rates.5

In other autoimmune diseases, monitoring of the effect of anti-CD20 therapy is undertaken by CD19 levels. However, in TTP, CD 19 levels, which typically return to normal within 6–12 months after therapy, are not associated with relapse. Furthermore, the availability of ADAMTS 13 monitoring in remission can be used as a biomarker for elective therapy, which has been used by a number of groups. Rituximab is given in clinical remission, when ADAMTS 13 activity falls e.g. to <5–10%, to successfully prevent further acute presentation. There are a number of cases in the literature, where elective Rituximab is given to prevent relapse.6 Overall, results demonstrated that Rituximab can be used as a pre-emptive therapy and re-treatment with Rituximab should be considered.

As a follow-up to the beneficial effect in refractory/relapsing disease, Rituximab was given during acute TTP presentation, in 40 patients, within 3 days of admission, (in conjunction with standard therapy, typically plasma exchange±steroids). This was a safety and efficacy trial, for which matched historic controls were used for comparison. More than a third of all the trial patients were admitted to the intensive care unit, of which 15% of the total group required intubation and ventilation. Before the second Rituximab infusion (between day 8–11 of admission) more than 60% had a platelet count >50×10⁹/l and 38% of cases had normal platelet counts (>150×10⁹/l). Other important, although not unexpected information included, the significant need for more PEX to remission in the non-Caucasian group. Data from other autoimmune diseases have suggested more resistant disease, requiring more therapy. Excluding the patients admitted to ICU, the total inpatient stay was reduced by 7 days, compared to historical controls. This effect was most evident in Caucasian patients. Acute TTP relapse was also significantly reduced in the patients receiving Rituximab (10% trial patients at a median of 27 months compared to 57% of historical controls, at a median of 18 months).7

There are other groups of TTP patients to consider who have received Rituximab as part of their treatment. Adolescents appear a unique category. The patients are more likely to be female and presentation at a median of 13 years may suggest a hormonal association. They required more PEX to remission and were less likely to achieve normal ADAMTS 13 activity despite treatment including Rituximab.8

Data currently focuse on the use of Rituximab in idiopathic TTP, for which there is no obvious precipitant and IgG antibodies to ADAMTS 13 can be detected. About 15% of all TTP presentations have an underlying precipitant. HIV-TTP, with improvements in assay techniques, have identified a low (<5%) ADAMTS 13 activity at presentation. While the majority of cases achieve complete remission with highly active anti-retroviral therapy, and hence a reduction in viral load, in conjunction with PEX, Rituximab has been successfully used in approximately 10% of cases who fail to achieve complete remission.9 Pregnancy is another well documented association with acute TTP. Pregnancy associated TTP may be either late onset congenital or acquired, antibody mediated. Rituximab may be used acutely, especially in the post-partum period, or electively to ensure a full term normal delivery in patients who fail to achieve a normal ADAMTS 13 activity with persistent antibody, despite clinical remission in the non-pregnant state.

The Rituximab regime most frequently used is the standard lymphoma protocol doses of 375 mg/m² weekly for 4 weeks. However, data suggest removal of Rituximab with PEX, based on peak and trough levels.10 The median fall in Rituximab pre PEX was 65% and the median time to undetectable Rituximab in patients who were plasma exchanged (compared to those who received elective Rituximab and therefore no PEX) was 5 months, ranging from 0 to 12 months. B-cell return, as measured by CD 20 levels was 7 months (3–24). Indeed, more frequent therapy every 3–4 days has been studied, based on PEX clearance, and has been used day 0, +3, +7 and day 14.5

An ongoing suggestion is to use low dose Rituximab, e.g. 100 mg, as this has been shown to be of benefit in other autoimmune diseases such as immune thrombocytopenia. However, the concern in TTP is using lower doses of Rituximab may not lead to sufficient tissue B-cell depletion to reduce antibody production and give a sustained remission. Lower Rituximab levels in follow-up lead to earlier B-cell reconstitution, and potentially higher anti-ADAMTS13 antibody levels. There may be an advantage in elective use, but in acute disease the current recommendation is 375 mg/m². Further clinical trials in the most appropriate timing and dosage are needed.

Safety remains a further concern with Rituximab, especially if repeat courses are used. The acute symptoms can be reduced by giving the first dose slowly, especially if associated cardiac disease and raised Troponin T levels; infusions over 12 hours appear safe. Anaphylaxis is a theoretical risk. Acute (with respiratory infiltrates) and delayed (with arthralgia) serum sickness has been documented. Resolution has been achieved with a short course of steroids and does not appear to preclude further use of Rituximab in the future. All patients should have their hepatitis B status recorded before starting Rituximab and lamivudine given if previous/active hepatitis B infection is noted. Neutropenia can be seen, but to date, has been identified in routine blood tests, has not been associated with sepsis and appears self-resolving. Infections and hypogammaglobulinaemia were a particular concern, but clinically have not been an issue in TTP. Progressive multifocal leukencephalopathy has been identified in patients with systemic lupus erythematosis who have received Rituximab. However, there is a similar incidence in patients who have not received Rituximab. While the risk is small in TTP, as there is usually associated T-cell immunosuppressive therapy, patients need to be informed.

In conclusion, monoclonal antibody therapy directed at B lymphocytes, reducing the polyclonal response directed at the protease ADAMTS 13, has improved time to remission and relapse rates in acute TTP. Use in the elective setting has helped prevent further episodes, which are still associated with a mortality of 20%. Further improvements in therapies are needed, with an improved understanding of the optimal dose and timing of infusion. Central to the understanding and monitoring of the effects of Rituximab or any future therapies are sensitive reproducible assays for ADAMTS 13.